National Cancer Institute
Post Date: Aug 24, 2017
Expert-reviewed information summary about the genetics of breast and gynecologic cancers, including information about specific genes and family cancer syndromes. The summary also contains information about interventions that may influence the risk of developing breast and gynecologic cancers in individuals who may be genetically susceptible to these diseases. Psychosocial issues associated with genetic testing are also discussed.
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of breast and gynecologic cancers. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Genetics of Breast & Gynecologic Cancers
Genetics of Breast and Gynecologic Cancers
This executive summary reviews the topics covered in this PDQ summary on the genetics of breast and gynecologic cancers, with hyperlinks to detailed sections below that describe the evidence on each topic.
- Inheritance and Risk
Factors suggestive of a genetic contribution to both breast cancer and gynecologic cancer include 1) an increased incidence of these cancers among individuals with a family history of these cancers; 2) multiple family members affected with these and other cancers; and 3) a pattern of cancers compatible with autosomal dominant inheritance. Both males and females can inherit and transmit an autosomal dominant cancer predisposition gene.
Additional factors coupled with family history—such as reproductive history, oral contraceptive and hormone replacement use, radiation exposure early in life, alcohol consumption, and physical activity—can influence an individual’s risk of developing cancer.
Risk assessment models have been developed to clarify an individual's 1) lifetime risk of developing breast and/or gynecologic cancer; 2) likelihood of having a pathogenic variant in BRCA1 or BRCA2; and 3) likelihood of having a pathogenic variant in one of the mismatch repair genes associated with Lynch syndrome.
- Associated Genes and Syndromes
Breast and ovarian cancer are present in several autosomal dominant cancer syndromes, although they are most strongly associated with highly penetrant germline pathogenic variants in and . Other genes, such as , (associated with Li-Fraumeni syndrome), (associated with Cowden syndrome), (associated with diffuse gastric and lobular breast cancer syndrome), and (associated with Peutz-Jeghers syndrome), confer a risk to either or both of these cancers with relatively high penetrance.
Inherited endometrial cancer is most commonly associated with Lynch syndrome, a condition caused by inherited pathogenic variants in the highly penetrant mismatch repair genes , , , , and . Colorectal cancer (and, to a lesser extent, ovarian cancer and stomach cancer) is also associated with Lynch syndrome.
Additional genes, such as , , , and , are associated with breast and/or gynecologic cancers with moderate penetrance. Genome-wide searches are showing promise in identifying common, low-penetrance susceptibility alleles for many complex diseases, including breast and gynecologic cancers, but the clinical utility of these findings remains uncertain.
- Clinical Management
Breast cancer screening strategies, including breast magnetic resonance imaging and mammography, are commonly performed in carriers of pathogenic variants and in individuals at increased risk of breast cancer. Initiation of screening is generally recommended at earlier ages and at more frequent intervals in individuals with an increased risk due to genetics and family history than in the general population. There is evidence to demonstrate that these strategies have utility in early detection of cancer. In contrast, there is currently no evidence to demonstrate that gynecologic cancer screening using cancer antigen 125 testing and transvaginal ultrasound leads to early detection of cancer.
Risk-reducing surgeries, including risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), have been shown to significantly reduce the risk of developing breast and/or ovarian cancer and improve overall survival in carriers of and pathogenic variants. Chemoprevention strategies, including the use of tamoxifen and oral contraceptives, have also been examined in this population. Tamoxifen use has been shown to reduce the risk of contralateral breast cancer among carriers of and pathogenic variants after treatment for breast cancer, but there are limited data in the primary cancer prevention setting to suggest that it reduces the risk of breast cancer among healthy female carriers of pathogenic variants. The use of oral contraceptives has been associated with a protective effect on the risk of developing ovarian cancer, including in carriers of and pathogenic variants, with no association of increased risk of breast cancer when using formulations developed after 1975.
- Psychosocial and Behavioral Issues
Psychosocial factors influence decisions about genetic testing for inherited cancer risk and risk-management strategies. Uptake of genetic testing varies widely across studies. Psychological factors that have been associated with testing uptake include cancer-specific distress and perceived risk of developing breast or ovarian cancer. Studies have shown low levels of distress after genetic testing for both carriers and noncarriers, particularly in the longer term. Uptake of RRM and RRSO also varies across studies, and may be influenced by factors such as cancer history, age, family history, recommendations of the health care provider, and pretreatment genetic education and counseling. Patients' communication with their family members about an inherited risk of breast and gynecologic cancer is complex; gender, age, and the degree of relatedness are some elements that affect disclosure of this information. Research is ongoing to better understand and address psychosocial and behavioral issues in high-risk families.
Among women in the United States, breast cancer is the most commonly diagnosed cancer after nonmelanoma skin cancer, and it is the second leading cause of cancer deaths after lung cancer. In 2017, an estimated 255,180 new cases of breast cancer (including 2,470 cases in men) will be diagnosed, and 41,070 deaths (including 460 deaths in men) will occur. The incidence of breast cancer, particularly for estrogen receptor (ER)–positive cancers occurring after age 50 years, is declining and has declined at a faster rate since 2003; this may be temporally related to a decrease in hormone replacement therapy (HRT) after early reports from the Women’s Health Initiative (WHI). An estimated 22,440 new cases of ovarian cancer are expected in the United States in 2017, with an estimated 14,080 deaths. Ovarian cancer is the fifth most deadly cancer in women. An estimated 61,380 new cases of endometrial cancer are expected in the United States in 2017, with an estimated 10,920 deaths. (Refer to the PDQ summaries on Breast Cancer Treatment; Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment; and Endometrial Cancer Treatment for more information about breast, ovarian, and endometrial cancer rates, diagnosis, and management.)
A possible genetic contribution to both breast and ovarian cancer risk is indicated by the increased incidence of these cancers among women with a family history (refer to the Risk Factors for Breast Cancer, Risk Factors for Ovarian Cancer, and Risk Factors for Endometrial Cancer sections below for more information), and by the observation of some families in which multiple family members are affected with breast and/or ovarian cancer, in a pattern compatible with an inheritance of autosomal dominant cancer susceptibility. Formal studies of families (linkage analysis) have subsequently proven the existence of autosomal dominant predispositions to breast and ovarian cancer and have led to the identification of several highly penetrant genes as the cause of inherited cancer risk in many families. (Refer to the PDQ summary Cancer Genetics Overview for more information about linkage analysis.) Pathogenic variants in these genes are rare in the general population and are estimated to account for no more than 5% to 10% of breast and ovarian cancer cases overall. It is likely that other genetic factors contribute to the etiology of some of these cancers.
Risk Factors for Breast Cancer
Refer to the PDQ summary on Breast Cancer Prevention for information about risk factors for breast cancer in the general population.
The cumulative risk of breast cancer increases with age, with most breast cancers occurring after age 50 years. Breast cancer (and ovarian cancer, to a lesser degree) tends to occur at an earlier age in women with a genetic susceptibility than it does in women with sporadic cases.
Family history including inherited cancer genes
In cross-sectional studies of adult populations, 5% to 10% of women have a mother or sister with breast cancer, and about twice as many have either a first-degree relative (FDR) or a second-degree relative with breast cancer. The risk conferred by a family history of breast cancer has been assessed in case-control and cohort studies, using volunteer and population-based samples, with generally consistent results. In a pooled analysis of 38 studies, the relative risk (RR) of breast cancer conferred by an FDR with breast cancer was 2.1 (95% confidence interval [CI], 2.0–2.2). Risk increases with the number of affected relatives, age at diagnosis, the occurrence of bilateral or multiple ipsilateral breast cancers in a family member, and the number of affected male relatives. A large population-based study from the Swedish Family Cancer Database confirmed the finding of a significantly increased risk of breast cancer in women who had a mother or a sister with breast cancer. The hazard ratio (HR) for women with a single breast cancer in the family was 1.8 (95% CI, 1.8–1.9) and was 2.7 (95% CI, 2.6–2.9) for women with a family history of multiple breast cancers. For women who had multiple breast cancers in the family, with one occurring before age 40 years, the HR was 3.8 (95% CI, 3.1–4.8). However, the study also found a significant increase in breast cancer risk if the relative was aged 60 years or older, suggesting that breast cancer at any age in the family carries some increase in risk.
One of the largest studies of twins ever conducted, with 80,309 monozygotic twins and 123,382 dizygotic twins, reported a heritability estimate for breast cancer of 31% (95% CI, 11%–51%). If a monozygotic twin had breast cancer, her twin sister had a 28.1% probability of developing breast cancer (95% CI, 23.9%–32.8%), and if a dizygotic twin had breast cancer, her twin sister had a 19.9% probability of developing breast cancer (95% CI, 17%–23.2%). These estimates suggest a 10% higher risk of breast cancer for monozygotic twins than for dizygotic twins. However, a high rate of discordance even between monozygotic twins suggests that environmental factors also have a role in modifying breast cancer risk.
(Refer to the Penetrance of BRCA pathogenic variants section of this summary for a discussion of familial risk in women from families with pathogenic variants who themselves test negative for the family pathogenic variant.)
In general, breast cancer risk increases with early menarche and late menopause and is reduced by early first full-term pregnancy. There may be an increased risk of breast cancer in carriers of and pathogenic variants with pregnancy at a younger age (before age 30 years), with a more significant effect seen for carriers of pathogenic variants. Likewise, breastfeeding can reduce breast cancer risk in carriers of (but not ) pathogenic variants. Regarding the effect of pregnancy on breast cancer outcomes, neither diagnosis of breast cancer during pregnancy nor pregnancy after breast cancer seems to be associated with adverse survival outcomes in women who carry a or pathogenic variant. Parity appears to be protective for carriers of and pathogenic variants, with an additional protective effect for live birth before age 40 years.
Reproductive history can also affect the risk of ovarian cancer and endometrial cancer. (Refer to the Reproductive History sections in the Risk Factors for Ovarian Cancer and Risk Factors for Endometrial Cancer sections of this summary for more information.)
Oral contraceptives (OCs) may produce a slight increase in breast cancer risk among long-term users, but this appears to be a short-term effect. In a meta-analysis of data from 54 studies, the risk of breast cancer associated with OC use did not vary in relationship to a family history of breast cancer.
OCs are sometimes recommended for ovarian cancer prevention in carriers of and pathogenic variants. (Refer to the Oral Contraceptives section in the Risk Factors for Ovarian Cancer section of this summary for more information.) Although the data are not entirely consistent, a meta-analysis concluded that there was no significant increased risk of breast cancer with OC use in carriers of pathogenic variants. However, use of OCs formulated before 1975 was associated with an increased risk of breast cancer (summary relative risk [SRR], 1.47; 95% CI, 1.06–2.04). (Refer to the Reproductive factors section in the Clinical Management of Carriers of BRCA Pathogenic Variants section of this summary for more information.)
Hormone replacement therapy
Data exist from both observational and randomized clinical trials regarding the association between postmenopausal HRT and breast cancer. A meta-analysis of data from 51 observational studies indicated a RR of breast cancer of 1.35 (95% CI, 1.21–1.49) for women who had used HRT for 5 or more years after menopause. The (NCT00000611), a randomized controlled trial of about 160,000 postmenopausal women, investigated the risks and benefits of HRT. The estrogen-plus-progestin arm of the study, in which more than 16,000 women were randomly assigned to receive combined HRT or placebo, was halted early because health risks exceeded benefits. Adverse outcomes prompting closure included significant increase in both total (245 vs. 185 cases) and invasive (199 vs. 150 cases) breast cancers (RR, 1.24; 95% CI, 1.02–1.5, < . 001) and increased risks of coronary heart disease, stroke, and pulmonary embolism. Similar findings were seen in the estrogen-progestin arm of the prospective observational Million Women’s Study in the United Kingdom. The risk of breast cancer was not elevated, however, in women randomly assigned to estrogen-only versus placebo in the WHI study (RR, 0.77; 95% CI, 0.59–1.01). Eligibility for the estrogen-only arm of this study required hysterectomy, and 40% of these patients also had undergone oophorectomy, which potentially could have impacted breast cancer risk.
The association between HRT and breast cancer risk among women with a family history of breast cancer has not been consistent; some studies suggest risk is particularly elevated among women with a family history, while others have not found evidence for an interaction between these factors. The increased risk of breast cancer associated with HRT use in the large meta-analysis did not differ significantly between subjects with and without a family history. The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for pathogenic variants. Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk. The effect of HRT on breast cancer risk among carriers of or pathogenic variants has been studied in the context of bilateral risk-reducing oophorectomy, in which short-term replacement does not appear to reduce the protective effect of oophorectomy on breast cancer risk. (Refer to the Hormone replacement therapy in carriers of BRCA1/BRCA2 pathogenic variants section of this summary for more information.)
Hormone use can also affect the risk of developing endometrial cancer. (Refer to the Hormones section in the Risk Factors for Endometrial Cancer section of this summary for more information.)
Observations in survivors of the atomic bombings of Hiroshima and Nagasaki and in women who have received therapeutic radiation treatments to the chest and upper body document increased breast cancer risk as a result of radiation exposure. The significance of this risk factor in women with a genetic susceptibility to breast cancer is unclear.
Preliminary data suggest that increased sensitivity to radiation could be a cause of cancer susceptibility in carriers of or pathogenic variants, and in association with germline and variants.
The possibility that genetic susceptibility to breast cancer occurs via a mechanism of radiation sensitivity raises questions about radiation exposure. It is possible that diagnostic radiation exposure, including mammography, poses more risk in genetically susceptible women than in women of average risk. Therapeutic radiation could also pose a carcinogenic risk. A cohort study of carriers of and pathogenic variants treated with breast-conserving therapy, however, showed no evidence of increased radiation sensitivity or sequelae in the breast, lung, or bone marrow of carriers. This finding was confirmed in a retrospective cohort study of 691 patients with -associated breast cancer who were followed up for a median of 8.6 years. No association between receiving adjuvant radiation therapy and increased risk of contralateral breast cancer was observed in the entire cohort, including the subset of patients younger than 40 years at primary breast cancer diagnosis. Conversely, radiation sensitivity could make tumors in women with genetic susceptibility to breast cancer more responsive to radiation treatment. Studies examining the impact of radiation exposure, including, but not limited to, mammography, in carriers of and pathogenic variants have had conflicting results. A large European study showed a dose-response relationship of increased risk with total radiation exposure, but this was primarily driven by nonmammographic radiation exposure before age 20 years. Subsequently, no significant association was observed between prior mammography exposure and breast cancer risk in a prospective study of 1,844 carriers and 502 carriers without a breast cancer diagnosis at time of study entry; average follow-up time was 5.3 years. (Refer to the Mammography section in the Clinical Management of Carriers of BRCA Pathogenic Variants section of this summary for more information about radiation.)
The risk of breast cancer increases by approximately 10% for each 10 g of daily alcohol intake (approximately one drink or less) in the general population. Prior studies of carriers of pathogenic variants have found no increased risk associated with alcohol consumption.
Physical activity and anthropometry
Weight gain and being overweight are commonly recognized risk factors for breast cancer. In general, overweight women are most commonly observed to be at increased risk of postmenopausal breast cancer and at reduced risk of premenopausal breast cancer. Sedentary lifestyle may also be a risk factor. These factors have not been systematically evaluated in women with a positive family history of breast cancer or in carriers of cancer-predisposing pathogenic variants, but one study suggested a reduced risk of cancer associated with exercise among carriers of and pathogenic variants.
Benign breast disease and mammographic density
Benign breast disease (BBD) is a risk factor for breast cancer, independent of the effects of other major risk factors for breast cancer (age, age at menarche, age at first live birth, and family history of breast cancer). There may also be an association between BBD and family history of breast cancer.
An increased risk of breast cancer has also been demonstrated for women who have increased density of breast tissue as assessed by mammogram, and breast density is likely to have a genetic component in its etiology.
Other risk factors, including those that are only weakly associated with breast cancer and those that have been inconsistently associated with the disease in epidemiologic studies (e.g., cigarette smoking), may be important in women who are in specific genotypically defined subgroups. One study found a reduced risk of breast cancer among carriers of pathogenic variants who smoked, but an expanded follow-up study failed to find an association.
Risk Factors for Ovarian Cancer
Refer to the PDQ summary on Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Prevention for information about risk factors for ovarian cancer in the general population.
Ovarian cancer incidence rises in a linear fashion from age 30 years to age 50 years and continues to increase, though at a slower rate, thereafter. Before age 30 years, the risk of developing epithelial ovarian cancer is remote, even in hereditary cancer families.
Family history including inherited cancer genes
Although reproductive, demographic, and lifestyle factors affect risk of ovarian cancer, the single greatest ovarian cancer risk factor is a family history of the disease. A large meta-analysis of 15 published studies estimated an odds ratio of 3.1 for the risk of ovarian cancer associated with at least one FDR with ovarian cancer.
Nulliparity is consistently associated with an increased risk of ovarian cancer, including among carriers of pathogenic variants, yet a meta-analysis identified a risk reduction only in women with four or more live births. Risk may also be increased among women who have used fertility drugs, especially those who remain nulligravid. Several studies have reported a risk reduction in ovarian cancer after OC use in carriers of pathogenic variants; a risk reduction has also been shown after tubal ligation in carriers, with a statistically significant decreased risk of 22% to 80% after the procedure. Breastfeeding for more than 12 months may also be associated with a reduction in ovarian cancer among carriers of / pathogenic variants. On the other hand, evidence is growing that the use of menopausal HRT is associated with an increased risk of ovarian cancer, particularly in long-time users and users of sequential estrogen-progesterone schedules.
Bilateral tubal ligation and hysterectomy are associated with reduced ovarian cancer risk, including in carriers of pathogenic variants. Ovarian cancer risk is reduced more than 90% in women with documented or pathogenic variants who chose risk-reducing salpingo-oophorectomy (RRSO). In this same population, risk-reducing oophorectomy also resulted in a nearly 50% reduction in the risk of subsequent breast cancer. (Refer to the RRSO section of this summary for more information about these studies.)
Use of OCs for 4 or more years is associated with an approximately 50% reduction in ovarian cancer risk in the general population. A majority of, but not all, studies also support OCs being protective among carriers of pathogenic variants. A meta-analysis of 18 studies including 13,627 carriers of pathogenic variants reported a significantly reduced risk of ovarian cancer (SRR, 0.50; 95% CI, 0.33–0.75) associated with OC use. (Refer to the Oral contraceptives section in the Chemoprevention section of this summary for more information.)
Risk Factors for Endometrial Cancer
Refer to the PDQ summary on Endometrial Cancer Prevention for information about risk factors for endometrial cancer in the general population.
Age is an important risk factor for endometrial cancer. Most women with endometrial cancer are diagnosed after menopause. Only 15% of women are diagnosed with endometrial cancer before age 50 years, and fewer than 5% are diagnosed before age 40 years. Women with Lynch syndrome tend to develop endometrial cancer at an earlier age, with the median age at diagnosis of 48 years.
Family history including inherited cancer genes
Although the hyperestrogenic state is the most common predisposing factor for endometrial cancer, family history also plays a significant role in a woman’s risk for disease. Approximately 3% to 5% of uterine cancer cases are attributable to a hereditary cause, with the main hereditary endometrial cancer syndrome being Lynch syndrome, an autosomal dominant genetic condition with a population prevalence of 1 in 300 to 1 in 1,000 individuals. (Refer to the Lynch Syndrome section in the PDQ summary on Genetics of Colorectal Cancer for more information.)
Non-Lynch syndrome genes may also contribute to endometrial cancer risk. In an unselected endometrial cancer cohort undergoing multigene panel testing, approximately 3% of patients tested positive for a germline pathogenic variant in non-Lynch syndrome genes, including , , , , , , , , , and . Notably, patients with pathogenic variants in non-Lynch syndrome genes were more likely to have serous tumor histology than were patients without pathogenic variants. Furthermore, although the overall risk of endometrial cancer after RRSO was not increased among carriers of pathogenic variants, these patients seemed to have an increased risk of serous and serous-like endometrial cancer.
Reproductive factors such as multiparity, late menarche, and early menopause decrease the risk of endometrial cancer because of the lower cumulative exposure to estrogen and the higher relative exposure to progesterone.
Hormonal factors that increase the risk of type I endometrial cancer are better understood. All endometrial cancers share a predominance of estrogen relative to progesterone. Prolonged exposure to estrogen or unopposed estrogen increases the risk of endometrial cancer. Endogenous exposure to estrogen can result from obesity, polycystic ovary syndrome, and nulliparity, while exogenous estrogen can result from taking unopposed estrogen or tamoxifen. Unopposed estrogen increases the risk of developing endometrial cancer by twofold to twentyfold, proportional to the duration of use. Tamoxifen, a selective estrogen receptor modulator, acts as an estrogen agonist on the endometrium while acting as an estrogen antagonist in breast tissue, and increases the risk of endometrial cancer. In contrast, OCs, the levonorgestrel-releasing intrauterine system, and combination estrogen-progesterone hormone replacement therapy all reduce the risk of endometrial cancer through the antiproliferative effect of progesterone acting on the endometrium.
Autosomal Dominant Inheritance of Breast and Gynecologic Cancer Predisposition
Autosomal dominant inheritance of breast and gynecologic cancers is characterized by transmission of cancer predisposition from generation to generation, through either the mother’s or the father’s side of the family, with the following characteristics:
- Inheritance risk of 50%. When a parent carries an autosomal dominant genetic predisposition, each child has a 50:50 chance of inheriting the predisposition. Although the risk of inheriting the predisposition is 50%, not everyone with the predisposition will develop cancer because of incomplete penetrance and/or gender-restricted or gender-related expression.
- Both males and females can inherit and transmit an autosomal dominant cancer predisposition. A male who inherits a cancer predisposition can still pass the altered gene on to his sons and daughters.
Breast and ovarian cancer are components of several autosomal dominant cancer syndromes. The syndromes most strongly associated with both cancers are the syndromes associated with or pathogenic variants. Breast cancer is also a common feature of Li-Fraumeni syndrome due to pathogenic variants and of Cowden syndrome due to pathogenic variants. Other genetic syndromes that may include breast cancer as an associated feature include heterozygous carriers of the ataxia telangiectasia gene and Peutz-Jeghers syndrome. Ovarian cancer has also been associated with Lynch syndrome, basal cell nevus (Gorlin) syndrome (OMIM), and multiple endocrine neoplasia type 1 (OMIM). Lynch syndrome is mainly associated with colorectal cancer and endometrial cancer, although several studies have demonstrated that patients with Lynch syndrome are also at risk of developing transitional cell carcinoma of the ureters and renal pelvis; cancers of the stomach, small intestine, liver and biliary tract, brain, breast, prostate, and adrenal cortex; and sebaceous skin tumors (Muir-Torre syndrome).
Germline pathogenic variants in the genes responsible for these autosomal dominant cancer syndromes produce different clinical phenotypes of characteristic malignancies and, in some instances, associated nonmalignant abnormalities.
The family characteristics that suggest hereditary cancer predisposition include the following:
- Multiple cancers within a family.
- Cancers typically occur at an earlier age than in sporadic cases (defined as cases not associated with genetic risk).
- Two or more primary cancers in a single individual. These could be multiple primary cancers of the same type (e.g., bilateral breast cancer) or primary cancer of different types (e.g., breast cancer and ovarian cancer in the same individual or endometrial and colon cancer in the same individual).
- Cases of male breast cancer. The inheritance risk for autosomal dominant genetic conditions is 50% for both males and females, but the differing penetrance of the genes may result in some unaffected individuals in the family.
Figure 1 and Figure 2 depict some of the classic inheritance features of a and pathogenic variant, respectively. Figure 3 depicts a classic family with Lynch syndrome. (Refer to the Standard Pedigree Nomenclature figure in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for definitions of the standard symbols used in these pedigrees.)
Figure 1. BRCA1 pedigree. This pedigree shows some of the classic features of a family with a BRCA1 pathogenic variant across three generations, including affected family members with breast cancer or ovarian cancer and a young age at onset. BRCA1 families may exhibit some or all of these features. As an autosomal dominant syndrome, a BRCA1 pathogenic variant can be transmitted through maternal or paternal lineages, as depicted in the figure.
Figure 2. BRCA2 pedigree. This pedigree shows some of the classic features of a family with a BRCA2 pathogenic variant across three generations, including affected family members with breast (including male breast cancer), ovarian, pancreatic, or prostate cancers and a relatively young age at onset. BRCA2 families may exhibit some or all of these features. As an autosomal dominant syndrome, a BRCA2 pathogenic variant can be transmitted through maternal or paternal lineages, as depicted in the figure.
Figure 3. Lynch syndrome pedigree. This pedigree shows some of the classic features of a family with Lynch syndrome, including affected family members with colon cancer or endometrial cancer and a younger age at onset in some individuals. Lynch syndrome families may exhibit some or all of these features. Lynch syndrome families may also include individuals with other gastrointestinal, gynecologic, and genitourinary cancers, or other extracolonic cancers. As an autosomal dominant syndrome, Lynch syndrome can be transmitted through maternal or paternal lineages, as depicted in the figure.
There are no pathognomonic features distinguishing breast and ovarian cancers occurring in carriers of or pathogenic variants from those occurring in noncarriers. Breast cancers occurring in carriers of pathogenic variants are more likely to be ER-negative, progesterone receptor–negative, HER2/neu receptor–negative (i.e., triple-negative breast cancers), and have a basal phenotype. -associated ovarian cancers are more likely to be high-grade and of serous histopathology. (Refer to the Pathology of breast cancer and Pathology of ovarian cancer sections of this summary for more information.)
Some pathologic features distinguish carriers of Lynch syndrome–associated pathogenic variants from noncarriers. The hallmark feature of endometrial cancers occurring in Lynch syndrome is mismatch repair (MMR) defects, including the presence of microsatellite instability (MSI), and the absence of specific MMR proteins. In addition to these molecular changes, there are also histologic changes including tumor-infiltrating lymphocytes, peritumoral lymphocytes, undifferentiated tumor histology, lower uterine segment origin, and synchronous tumors.
Considerations in Risk Assessment and in Identifying a Family History of Breast and Ovarian Cancer Risk
The accuracy and completeness of family histories must be taken into account when they are used to assess risk. A reported family history may be erroneous, or a person may be unaware of relatives affected with cancer. In addition, small family sizes and premature deaths may limit the information obtained from a family history. Breast or ovarian cancer on the paternal side of the family usually involves more distant relatives than does breast or ovarian cancer on the maternal side, so information may be more difficult to obtain. When self-reported information is compared with independently verified cases, the sensitivity of a history of breast cancer is relatively high, at 83% to 97%, but lower for ovarian cancer, at 60%. Additional limitations of relying on family histories include adoption; families with a small number of women; limited access to family history information; and incidental removal of the uterus, ovaries, and/or fallopian tubes for noncancer indications. Family histories will evolve, therefore it is important to update family histories from both parents over time. (Refer to the Accuracy of the family history section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)
Models for Prediction of Breast and Gynecologic Cancer Risk
Models to predict an individual’s lifetime risk of developing breast and/or gynecologic cancer are available. In addition, models exist to predict an individual’s likelihood of having a pathogenic variant in , , or one of the MMR genes associated with Lynch syndrome. (Refer to the Models for prediction of the likelihood of a BRCA1 or BRCA2 pathogenic variant section of this summary for more information about some of these models.) Not all models can be appropriately applied to all patients. Each model is appropriate only when the patient’s characteristics and family history are similar to those of the study population on which the model was based. Different models may provide widely varying risk estimates for the same clinical scenario, and the validation of these estimates has not been performed for many models.
Breast cancer risk assessment models
In general, breast cancer risk assessment models are designed for two types of populations: 1) women without a pathogenic variant or strong family history of breast or ovarian cancer; and 2) women at higher risk because of a personal or family history of breast cancer or ovarian cancer. Models designed for women of the first type (e.g., the Gail model, which is the basis for the Breast Cancer Risk Assessment Tool [BCRAT]) , and the Colditz and Rosner model ) require only limited information about family history (e.g., number of FDRs with breast cancer). Models designed for women at higher risk require more detailed information about personal and family cancer history of breast and ovarian cancers, including ages at onset of cancer and/or carrier status of specific breast cancer-susceptibility alleles. The genetic factors used by the latter models differ, with some assuming one risk locus (e.g., the Claus model ), others assuming two loci (e.g., the International Breast Cancer Intervention Study [IBIS] model and the BRCAPRO model ), and still others assuming an additional polygenic component in addition to multiple loci (e.g., the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm [BOADICEA] model ). The models also differ in whether they include information about nongenetic risk factors. Three models (Gail/BCRAT, Pfeiffer, and IBIS) include nongenetic risk factors but differ in the risk factors they include (e.g., the Pfeiffer model includes alcohol consumption, whereas the Gail/BCRAT does not). These models have limited ability to discriminate between individuals who are affected and those who are unaffected with cancer; a model with high discrimination would be close to 1, and a model with little discrimination would be close to 0.5; the discrimination of the models currently ranges between 0.56 and 0.63). The existing models generally are more accurate in prospective studies that have assessed how well they predict future cancers.
In the United States, BRCAPRO, the Claus model, and the Gail/BCRAT are widely used in clinical counseling. Risk estimates derived from the models differ for an individual patient. Several other models that include more detailed family history information are also in use and are discussed below.
Additional considerations for clinical use of breast cancer risk assessment models
The Gail model is the basis for the BCRAT, a computer program available from the National Cancer Institute (NCI) by calling the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). This version of the Gail model estimates only the risk of invasive breast cancer. The Gail/BCRAT model has been found to be reasonably accurate at predicting breast cancer risk in large groups of white women who undergo annual screening mammography; however, reliability varies depending on the cohort studied. Risk can be overestimated in the following populations:
- Women who do not adhere to screening recommendations.
- Women in the highest-risk strata.
The Gail/BCRAT model is valid for women aged 35 years and older. The model was primarily developed for white women. Extensions of the Gail model for African American women have been subsequently developed to calibrate risk estimates using data from more than 1,600 African American women with invasive breast cancer and more than 1,600 controls. Additionally, extensions of the Gail model have incorporated high-risk single nucleotide polymorphisms and pathogenic variants; however, no software exists to calculate risk in these extended models. Other risk assessment models incorporating breast density have been developed but are not ready for clinical use.
Generally, the Gail/BCRAT model should not be the sole model used for families with one or more of the following characteristics:
- Multiple affected individuals with breast cancer or ovarian cancer (especially when one or more breast cancers are diagnosed before age 50 years).
- A woman with both breast and ovarian cancer.
- Ashkenazi Jewish ancestry with at least one case of breast or ovarian cancer (as these families are more likely to have a hereditary cancer susceptibility syndrome).
Commonly used models that incorporate family history include the IBIS, BOADICEA, and BRCAPRO models. The IBIS/Tyrer-Cuzick model incorporates both genetic and nongenetic factors. A three-generation pedigree is used to estimate the likelihood that an individual carries either a pathogenic variant or a hypothetical low-penetrance gene. In addition, the model incorporates personal risk factors such as parity, body mass index (BMI); height; and age at menarche, first live birth, menopause, and HRT use. Both genetic and nongenetic factors are combined to develop a risk estimate. The BOADICEA model examines family history to estimate breast cancer risk and also incorporates both and non- genetic risk factors. The most important difference between BOADICEA and the other models using information on is that BOADICEA assumes an additional polygenic component in addition to multiple loci, which is more in line with what is known about the underlying genetics of breast cancer. The BOADICEA model has also been expanded to include additional pathogenic variants, including , , and . However, the discrimination and calibration for these models differ significantly when compared in independent samples; the IBIS and BOADICEA models are more comparable when estimating risk over a shorter fixed time horizon (e.g., 10 years), than when estimating remaining lifetime risk. As all risk assessment models for cancers are typically validated over a shorter time horizon (e.g., 5 or 10 years), fixed time horizon estimates rather than remaining lifetime risk may be more accurate and useful measures to convey in a clinical setting.
In addition, readily available models that provide information about an individual woman’s risk in relation to the population-level risk depending on her risk factors may be useful in a clinical setting (e.g., Your Disease Risk). Although this tool was developed using information about average-risk women and does not calculate absolute risk estimates, it still may be useful when counseling women about prevention. Risk assessment models are being developed and validated in large cohorts to integrate genetic and nongenetic data, breast density, and other biomarkers.
Ovarian cancer risk assessment models
Two risk prediction models have been developed for ovarian cancer. The Rosner model included age at menopause, age at menarche, oral contraception use, and tubal ligation; the concordance statistic was 0.60 (0.57–0.62). The Pfeiffer model included oral contraceptive use, menopausal hormone therapy use, and family history of breast cancer or ovarian cancer, with a similar discriminatory power of 0.59 (0.56–0.62). Although both models were well calibrated, their modest discriminatory power limited their screening potential.
Endometrial cancer risk assessment models
The Pfeiffer model has been used to predict endometrial cancer risk in the general population. For endometrial cancer, the relative risk model included BMI, menopausal hormone therapy use, menopausal status, age at menopause, smoking status, and OC use. The discriminatory power of the model was 0.68 (0.66–0.70); it overestimated observed endometrial cancers in most subgroups but underestimated disease in women with the highest BMI category, in premenopausal women, and in women taking menopausal hormone therapy for 10 years or more.
In contrast, MMRpredict, PREMM(1,2,6), and MMRpro are three quantitative predictive models used to identify individuals who may potentially have Lynch syndrome. MMRpredict incorporates only colorectal cancer patients but does include MSI and immunohistochemistry (IHC) tumor testing results. PREMM(1,2,6) accounts for other Lynch syndrome–associated tumors but does not include tumor testing results. MMRpro incorporates tumor testing and germline testing results, but is more time intensive because it includes affected and unaffected individuals in the risk-quantification process. All three predictive models are comparable to the traditional Amsterdam and Bethesda criteria in identifying individuals with colorectal cancer who carry MMR gene pathogenic variants. However, because these models were developed and validated in colorectal cancer patients, the discriminative abilities of these models to identify Lynch syndrome are lower among individuals with endometrial cancer than among those with colon cancer. In fact, the sensitivity and specificity of MSI and IHC in identifying carriers of pathogenic variants are considerably higher than the prediction models and support the use of molecular tumor testing to screen for Lynch syndrome in women with endometrial cancer.
Table 1 summarizes salient aspects of breast and gynecologic cancer risk assessment models that are commonly used in the clinical setting. These models differ by the extent of family history included, whether nongenetic risk factors are included, and whether carrier status and polygenic risk are included (inputs to the models). The models also differ in the type of risk estimates that are generated (outputs of the models). These factors may be relevant in choosing the model that best applies to a particular individual.
Penetrance of Inherited Susceptibility to Hereditary Breast and/or Gynecologic Cancers
The proportion of individuals carrying a pathogenic variant who will manifest a certain disease is referred to as penetrance. In general, common genetic variants that are associated with cancer susceptibility have a lower penetrance than rare genetic variants. This is depicted in Figure 4. For adult-onset diseases, penetrance is usually described by the individual carrier's age, sex, and organ site. For example, the penetrance for breast cancer in female carriers of pathogenic variants is often quoted by age 50 years and by age 70 years. Of the numerous methods for estimating penetrance, none are without potential biases, and determining an individual carrier's risk of cancer involves some level of imprecision.
Figure 4. Genetic architecture of cancer risk. This graph depicts the general finding of a low relative risk associated with common, low-penetrance genetic variants, such as single-nucleotide polymorphisms identified in genome-wide association studies, and a higher relative risk associated with rare, high-penetrance genetic variants, such as pathogenic variants in the BRCA1/BRCA2 genes associated with hereditary breast and ovarian cancer and the mismatch repair genes associated with Lynch syndrome.
Throughout this summary, we discuss studies that report on relative and absolute risks. These are two important but different concepts. Relative risk (RR) refers to an estimate of risk relative to another group (e.g., risk of an outcome like breast cancer for women who are exposed to a risk factor RELATIVE to the risk of breast cancer for women who are unexposed to the same risk factor). RR measures that are greater than 1 mean that the risk for those captured in the numerator (i.e., the exposed) is higher than the risk for those captured in the denominator (i.e., the unexposed). RR measures that are less than 1 mean that the risk for those captured in the numerator (i.e., the exposed) is lower than the risk for those captured in the denominator (i.e., the unexposed). Measures with similar relative interpretations include the odds ratio (OR), hazard ratio, and risk ratio.
Absolute risk measures take into account the number of people who have a particular outcome, the number of people in a population who could have the outcome, and person-time (the period of time during which an individual was at risk of having the outcome), and reflect the absolute burden of an outcome in a population. Absolute measures include risks and rates and can be expressed over a specific time frame (e.g., 1 year, 5 years) or overall lifetime. Cumulative risk is a measure of risk that occurs over a defined time period. For example, overall lifetime risk is a type of cumulative risk that is usually calculated on the basis of a given life expectancy (e.g., 80 or 90 years). Cumulative risk can also be presented over other time frames (e.g., up to age 50 years).
Large relative risk measures do not mean that there will be large effects in the actual number of individuals at a population level because the disease outcome may be quite rare. For example, the relative risk for smoking is much higher for lung cancer than for heart disease, but the absolute difference between smokers and nonsmokers is greater for heart disease, the more-common outcome, than for lung cancer, the more-rare outcome.
Therefore, in evaluating the effect of exposures and biological markers on disease prevention across the continuum, it is important to recognize the differences between relative and absolute effects in weighing the overall impact of a given risk factor. For example, the magnitude is in the range of 30% (e.g., ORs or RRs of 1.3) for many breast cancer risk factors, which means that women with a risk factor (e.g., alcohol consumption, late age at first birth, oral contraceptive use, postmenopausal body size) have a 30% relative increase in breast cancer in comparison with what they would have if they did not have that risk factor. But the absolute increase in risk is based on the underlying absolute risk of disease. Figure 5 and Table 2 show the impact of a relative risk factor in the range of 1.3 on absolute risk. (Refer to the Standard Pedigree Nomenclature figure in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for definitions of the standard symbols used in these pedigrees.) As shown, women with a family history of breast cancer have a much higher benefit from risk factor reduction on an absolute scale.
Figure 5. These five pedigrees depict probands with varying degrees of family history. Table 2 accompanies this figure.
With the increasing use of multigene panel tests (see below), a framework for cancer risk management among individuals with pathogenic variants detected in novel genes has been described that incorporates data on age-specific, lifetime, and absolute cancer risks. The framework suggests initiating screening in these individuals at the age when their 5-year cancer risk approaches that at which screening is routinely initiated for women in the general population (approximately 1% for breast cancer in the United States). As a result, the age at which to begin screening will vary depending on the gene.
Multigene (Panel) Testing
Since the availability of next-generation sequencing and the Supreme Court of the United States ruling that human genes cannot be patented, several clinical laboratories now offer genetic testing through multigene panels at a cost comparable to single-gene testing. Even testing for and is a limited panel test of two genes. Approximately 25% of all ovarian/fallopian tube/peritoneal cancers are due to a heritable genetic condition. Of these, about one-quarter (6% of all ovarian/fallopian tube/peritoneal cancers) are caused by genes other than and , including many genes associated with the Fanconi anemia pathway or otherwise involved with homologous recombination. In a population of ovarian cancer patients who test negative for and pathogenic variants, multigene panel testing can reveal actionable pathogenic variants. In an unselected population of breast cancer patients, the prevalence of and pathogenic variants was 6.1%, while the prevalence of pathogenic variants in other breast/ovarian cancer–predisposing genes was 4.6%. In an unselected population of endometrial cancer patients, the prevalence of Lynch syndrome pathogenic variants (, , , , and ) was 5.8%; the prevalence of pathogenic variants in other actionable genes was 3.4%. A caveat is the possible finding of a variant of uncertain significance, for which the clinical significance remains unknown. Many centers now offer a multigene panel test instead of just and testing if there is a concerning family history of syndromes other than hereditary breast and ovarian cancer, or more importantly, to gain as much genetic information as possible with one test, particularly if there may be insurance limitations.
(Refer to the Multigene [panel] testing section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information about multigene testing, including genetic education and counseling considerations and research examining the use of multigene testing.)
High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes
BRCA1 and BRCA2
Epidemiologic studies have clearly established the role of family history as an important risk factor for both breast and ovarian cancers. After gender and age, a positive family history is the strongest known predictive risk factor for breast cancer. However, it has long been recognized that in some families, there is hereditary breast cancer, which is characterized by an early age of onset, bilaterality, and the presence of breast cancer in multiple generations in an apparent autosomal dominant pattern of transmission (through either the maternal or the paternal lineage), sometimes including tumors of other organs, particularly the ovary and prostate gland. It is now known that some of these “cancer families” can be explained by specific pathogenic variants in single cancer susceptibility genes. The isolation of several of these genes, which when altered are associated with a significantly increased risk of breast/ovarian cancer, makes it possible to identify individuals at risk. Although such cancer susceptibility genes are very important, highly penetrant germline pathogenic variants are estimated to account for only 5% to 10% of breast cancers overall.
A 1988 study reported the first quantitative evidence that breast cancer segregated as an autosomal dominant trait in some families. The search for genes associated with hereditary susceptibility to breast cancer has been facilitated by studies of large kindreds with multiple affected individuals and has led to the identification of several susceptibility genes, including , , , , and . Other genes, such as the mismatch repair genes , , , and , have been associated with an increased risk of ovarian cancer, but have not been consistently associated with breast cancer.
In 1990, a susceptibility gene for breast cancer was mapped by genetic linkage to the long arm of chromosome 17, in the interval 17q12-21. The linkage between breast cancer and genetic markers on chromosome 17q was soon confirmed by others, and evidence for the coincident transmission of both breast and ovarian cancer susceptibility in linked families was observed. The gene (OMIM) was subsequently identified by positional cloning methods and has been found to contain 24 exons that encode a protein of 1,863 amino acids. Germline pathogenic variants in are associated with early-onset breast cancer, ovarian cancer, and fallopian tube cancer. (Refer to the Penetrance of BRCA pathogenic variants section of this summary for more information.) Male breast cancer, pancreatic cancer, testicular cancer, and early-onset prostate cancer may also be associated with pathogenic variants in ; however, male breast cancer, pancreatic cancer, and prostate cancer are more strongly associated with pathogenic variants in .
A second breast cancer susceptibility gene, , was localized to the long arm of chromosome 13 through linkage studies of 15 families with multiple cases of breast cancer that were not linked to . Pathogenic variants in (OMIM) are associated with multiple cases of breast cancer in families, and are also associated with male breast cancer, ovarian cancer, prostate cancer, melanoma, and pancreatic cancer. (Refer to the Penetrance of BRCA pathogenic variants section of this summary for more information.) is a large gene with 27 exons that encode a protein of 3,418 amino acids. While not homologous genes, both and have an unusually large exon 11 and translational start sites in exon 2. Like , appears to behave like a tumor suppressor gene. In tumors associated with both and pathogenic variants, there is often loss of the wild-type allele.
Pathogenic variants in and appear to be responsible for disease in 45% of families with multiple cases of breast cancer only and in up to 90% of families with both breast and ovarian cancer.
BRCA1 and BRCA2 function
Most and pathogenic variants are predicted to produce a truncated protein product, and thus loss of protein function, although some missense pathogenic variants cause loss of function without truncation. Because inherited breast/ovarian cancer is an autosomal dominant condition, persons with a or pathogenic variant on one copy of chromosome 17 or 13 also carry a normal allele on the other paired chromosome. In most breast and ovarian cancers that have been studied from carriers of pathogenic variants, deletion of the normal allele results in loss of all function, leading to the classification of and as tumor suppressor genes. In addition to, and as part of, their roles as tumor suppressor genes, and are involved in myriad functions within cells, including homologous DNA repair, genomic stability, transcriptional regulation, protein ubiquitination, chromatin remodeling, and cell cycle control.
Pathogenic variants in BRCA1 and BRCA2
Nearly 2,000 distinct variants and sequence variations in and have already been described. Approximately 1 in 400 to 800 individuals in the general population may carry a germline pathogenic variant in or . The variants that have been associated with increased risk of cancer result in missing or nonfunctional proteins, supporting the hypothesis that and are tumor suppressor genes. While a small number of these pathogenic variants have been found repeatedly in unrelated families, most have not been reported in more than a few families.
Variant-screening methods vary in their sensitivity. Methods widely used in research laboratories, such as single-stranded conformational polymorphism analysis and conformation-sensitive gel electrophoresis, miss nearly a third of the variants that are detected by DNA sequencing. In addition, large genomic alterations such as translocations, inversions, or large deletions or insertions are missed by most of the techniques, including direct DNA sequencing, but testing for these is commercially available. Such rearrangements are believed to be responsible for 12% to 18% of inactivating variants but are less frequently seen in and in individuals of Ashkenazi Jewish (AJ) descent. Furthermore, studies have suggested that these rearrangements may be more frequently seen in Hispanic and Caribbean populations.
Variants of uncertain significance
Germline pathogenic variants in the genes are associated with an approximately 60% lifetime risk of breast cancer and a 15% to 40% lifetime risk of ovarian cancer. There are no definitive functional tests for or ; therefore, the classification of nucleotide changes to predict their functional impact as deleterious or benign relies on imperfect data. The majority of accepted pathogenic variants result in protein truncation and/or loss of important functional domains. However, 10% to 15% of all individuals undergoing genetic testing with full sequencing of and will not have a clearly pathogenic variant detected but will have a variant of uncertain (or unknown) significance (VUS). VUS may cause substantial challenges in counseling, particularly in terms of cancer risk estimates and risk management. Clinical management of such patients needs to be highly individualized and must take into consideration factors such as the patient’s personal and family cancer history, in addition to sources of information to help characterize the VUS as benign or deleterious. Thus an improved classification and reporting system may be of clinical utility.
A comprehensive analysis of 7,461 consecutive full gene sequence analyses performed by Myriad Genetic Laboratories, Inc., described the frequency of VUS over a 3-year period. Among subjects who had no clearly pathogenic variant, 13% had VUS defined as “missense mutations and mutations that occur in analyzed intronic regions whose clinical significance has not yet been determined, chain-terminating mutations that truncate BRCA1 and BRCA2 distal to amino acid positions 1853 and 3308, respectively, and mutations that eliminate the normal stop codons for these proteins.” The classification of a sequence variant as a VUS is a moving target. An additional 6.8% of subjects with no clear pathogenic variants had sequence alterations that were once considered VUS but were reclassified as a polymorphism, or occasionally as a pathogenic variant.
The frequency of VUS varies by ethnicity within the U.S. population. African Americans appear to have the highest rate of VUS. In a 2009 study of data from Myriad, 16.5% of individuals of African ancestry had VUS, the highest rate among all ethnicities. The frequency of VUS in Asian, Middle Eastern, and Hispanic populations clusters between 10% and 14%, although these numbers are based on limited sample sizes. Over time, the rate of changes classified as VUS has decreased in all ethnicities, largely the result of improved variant classification algorithms. VUS continue to be reclassified as additional information is curated and interpreted. Such information may impact the continuing care of affected individuals.
A number of methods for discriminating deleterious from neutral VUS exist and others are in development including integrated methods (see below). Interpretation of VUS is greatly aided by efforts to track VUS in the family to determine if there is cosegregation of the VUS with the cancer in the family. In general, a VUS observed in individuals who also have a pathogenic variant, especially when the same VUS has been identified in conjunction with different pathogenic variants, is less likely to be in itself deleterious, although there are rare exceptions. As an adjunct to the clinical information, models to interpret VUS have been developed, based on sequence conservation, biochemical properties of amino acid changes, incorporation of information on pathologic characteristics of - and -related tumors (e.g., -related breast cancers are usually estrogen receptor [ER]–negative), and functional studies to measure the influence of specific sequence variations on the activity of BRCA1 or BRCA2 proteins. When attempting to interpret a VUS, all available information should be examined.
Population estimates of the likelihood of having a BRCA1 or BRCA2 pathogenic variant
Statistics regarding the percentage of individuals found to be carriers of pathogenic variants among samples of women and men with a variety of personal cancer histories regardless of family history are provided below. These data can help determine who might best benefit from a referral for cancer genetic counseling and consideration of genetic testing but cannot replace a personalized risk assessment, which might indicate a higher or lower pathogenic variant likelihood based on additional personal and family history characteristics.
In some cases, the same pathogenic variant has been found in multiple apparently unrelated families. This observation is consistent with a founder effect, wherein a pathogenic variant identified in a contemporary population can be traced to a small group of founders isolated by geographic, cultural, or other factors. Most notably, two specific pathogenic variants (185delAG and 5382insC) and a pathogenic variant (6174delT) have been reported to be common in AJs. However, other founder pathogenic variants have been identified in African Americans and Hispanics. The presence of these founder pathogenic variants has practical implications for genetic testing. Many laboratories offer directed testing specifically for ethnic-specific alleles. This greatly simplifies the technical aspects of the test but is not without limitations. Although a prior study estimated that up to 15% of and pathogenic variants that occur among Ashkenazim are nonfounder pathogenic variants, a later study of AJ individuals who had comprehensive testing as their initial test or who had reflex testing ordered only if testing for the three common AJ founder pathogenic variants was negative suggests that the true incidence of nonfounder pathogenic variants is closer to 7%.
Among the general population, the likelihood of having any variant is as follows:
- General population (excluding Ashkenazim): about 1 in 400 (~0.25%).
- Women with breast cancer (any age): 1 in 50 (2%).
- Women with breast cancer (younger than 40 years): 1 in 10 (10%).
- Men with breast cancer (any age): 1 in 20 (5%).
- Women with ovarian cancer (any age): 1 in 8 to 1 in 10 (10%–15%).
Among AJ individuals, the likelihood of having any variant is as follows:
- General AJ population: 1 in 40 (2.5%).
- Women with breast cancer (any age): 1 in 10 (10%).
- Women with breast cancer (younger than 40 years): 1 in 3 (30%–35%).
- Men with breast cancer (any age): 1 in 5 (19%).
- Women with ovarian cancer or primary peritoneal cancer (all ages): 1 in 3 (36%–41%).
Two large U.S. population-based studies of breast cancer patients younger than 65 years examined the prevalence of and pathogenic variants in various ethnic groups. The prevalence of pathogenic variants in breast cancer patients by ethnic group was 3.5% in Hispanics, 1.3% to 1.4% in African Americans, 0.5% in Asian Americans, 2.2% to 2.9% in non-AJ whites, and 8.3% to 10.2% in AJ individuals. The prevalence of pathogenic variants by ethnic group was 2.6% in African Americans and 2.1% in whites.
A study of Hispanic patients with a personal or family history of breast cancer and/or ovarian cancer, who were enrolled through multiple clinics in the southwestern United States, examined the prevalence of and pathogenic variants. pathogenic variants were identified in 189 of 746 patients (25%) (124 , 65 ); 21 of the 189 (11%) pathogenic variants identified were large rearrangements, of which 13 (62%) were the exon 9–12 deletion. An unselected cohort of 810 women of Mexican ancestry with breast cancer were tested; 4.3% had a pathogenic variant. Eight of the 35 pathogenic variants identified also were the exon 9–12 deletion. In another population-based cohort of 492 Hispanic women with breast cancer, the exon 9–12 deletion was found in three patients, suggesting that this variant may be a Mexican founder pathogenic variant and may represent 10% to 12% of all pathogenic variants in similar clinic- and population-based cohorts in the United States. Within the clinic-based cohort, there were nine recurrent pathogenic variants, which accounted for 53% of all variants observed in this cohort, suggesting the existence of additional founder pathogenic variants in this population.
A retrospective review of 29 AJ patients with primary fallopian tube tumors identified germline pathogenic variants in 17%. Another study of 108 women with fallopian tube cancer identified pathogenic variants in 55.6% of the Jewish women and 26.4% of non-Jewish women (30.6% overall). Estimates of the frequency of fallopian tube cancer in carriers of pathogenic variants are limited by the lack of precision in the assignment of site of origin for high-grade, metastatic, serous carcinomas at initial presentation.
Population screening has identified carriers in a number of AJ populations who would not have met criteria for family-based testing. This could potentially expand the number of individuals who could benefit from preventive strategies. Because the detection rate is highly dependent on the prevalence of pathogenic variants in a population, it is not clear how applicable this approach would be for other populations, including other founder pathogenic variant populations. Another unanswered question is whether adequate genetic counseling can be provided for whole populations.
Clinical criteria and models for prediction of the likelihood of a BRCA1 or BRCA2 pathogenic variant
Several studies have assessed the frequency of or pathogenic variants in women with breast or ovarian cancer. Personal characteristics associated with an increased likelihood of a and/or pathogenic variant include the following:
- Breast cancer diagnosed at an early age. (Some studies use age 40 years as a cutoff, while others use age 50 years.)
- Ovarian cancer.
- Bilateral breast cancer.
- A history of both breast and ovarian cancer.
- Breast cancer diagnosed in a male at any age.
- Triple-negative breast cancer diagnosed in women younger than 60 years.
- AJ background.
Family history characteristics associated with an increased likelihood of carrying a and/or pathogenic variant include the following:
- Multiple cases of breast cancer.
- Both breast and ovarian cancer.
- One or more breast cancers in male family members.
- AJ background.
Clinical criteria and practice guidelines for identifying individuals who may have a BRCA1 or BRCA2 pathogenic variant
Several professional organizations and expert panels, including the American Society of Clinical Oncology, the National Comprehensive Cancer Network (NCCN), the American Society of Human Genetics, the American College of Medical Genetics and Genomics, the National Society of Genetic Counselors, the U.S. Preventive Services Task Force, and the Society of Gynecologic Oncologists, have developed clinical criteria and practice guidelines that can be helpful to health care providers in identifying individuals who may have a or pathogenic variant.
Models for prediction of the likelihood of a BRCA1 or BRCA2 pathogenic variant
Many models have been developed to predict the probability of identifying germline pathogenic variants in individuals or families. These models include those using logistic regression, genetic models using Bayesian analysis (BRCAPRO and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm [BOADICEA]), and empiric observations, including the Myriad prevalence tables.
In addition to BOADICEA, BRCAPRO is commonly used for genetic counseling in the clinical setting. BRCAPRO and BOADICEA predict the probability of being a carrier and produce estimates of breast cancer risk (see Table 3). The discrimination and accuracy (factors used to evaluate the performance of prediction models) of these models are much higher for these models' ability to report on carrier status than for their ability to predict fixed or remaining lifetime risk.
BOADICEA is a polygenetic model that uses complex segregation analysis to examine both breast cancer risk and the probability of having a or pathogenic variant. Even among experienced providers, the use of prediction models has been shown to increase the power to discriminate which patients are most likely to be carriers of pathogenic variants. Most models do not include other cancers seen in the and spectrum, such as pancreatic cancer and prostate cancer. Interventions that decrease the likelihood that an individual will develop cancer (such as oophorectomy and mastectomy) may influence the ability to predict and pathogenic variant status. One study has shown that the prediction models for genetic risk are sensitive to the amount of family history data available and do not perform as well with limited family information. BOADICEA is being expanded to incorporate additional risk variants (genome-wide association study [GWAS] single nucleotide polymorphisms [SNPs]) to better predict pathogenic variant status and to improve the accuracy of breast cancer and ovarian cancer risk estimates.
The performance of the models can vary in specific ethnic groups. The BRCAPRO model appeared to best fit a series of French Canadian families. There have been variable results in the performance of the BRCAPRO model among Hispanics, and both the BRCAPRO model and Myriad tables underestimated the proportion of carriers of pathogenic variants in an Asian American population. BOADICEA was developed and validated in British women. Thus, the major models used for both overall risk (Table 1) and genetic risk (Table 3) have not been developed or validated in large populations of racially and ethnically diverse women. Of the commonly used clinical models for assessing genetic risk, only the Tyrer-Cuzick model contains nongenetic risk factors.
The power of several of the models has been compared in different studies. Four breast cancer genetic-risk models, BOADICEA, BRCAPRO, IBIS, and eCLAUS, were evaluated for their diagnostic accuracy in predicting pathogenic variants in a cohort of 7,352 German families. The family member with the highest likelihood of carrying a pathogenic variant from each family was screened for pathogenic variants. Carrier probabilities from each model were calculated and compared with the actual variants detected. BRCAPRO and BOADICEA had significantly higher diagnostic accuracy than IBIS or eCLAUS. Accuracy for the BOADICEA model was further improved when statuses of the tumor markers ER, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu) were included in the model. The inclusion of these biomarkers has been shown to improve the performance of BRCAPRO.
Genetic testing for and pathogenic variants has been available to the public since 1996. As more individuals have undergone testing, risk assessment models have improved. This, in turn, gives providers better data to estimate an individual patient’s risk of carrying a pathogenic variant, but risk assessment continues to be an art. There are factors that might limit the ability to provide an accurate risk assessment (i.e., small family size, paucity of women, or ethnicity) including the specific circumstances of the individual patient (such as history of disease or risk-reducing surgeries).
Penetrance of BRCA pathogenic variants
The proportion of individuals carrying a pathogenic variant who will manifest the disease is referred to as penetrance. (Refer to the Penetrance of Inherited Susceptibility to Hereditary Breast and/or Gynecologic Cancers section of this summary for more information.)
Numerous studies have estimated breast and ovarian cancer penetrance in carriers of and pathogenic variants. Risk of both breast and ovarian cancer is consistently estimated to be higher in carriers of pathogenic variants than in carriers of pathogenic variants. Results from two large meta-analyses are shown in Table 4. One study analyzed pooled pedigree data from 22 studies involving 289 and 221 pathogenic variant–positive individuals. Index cases from these studies had female breast cancer, male breast cancer, or ovarian cancer but were unselected for family history. A subsequent study combined penetrance estimates from the previous study and nine others that included an additional 734 and 400 pathogenic variant–positive families. The estimated cumulative risks of breast cancer by age 70 years in these two meta-analyses were 55% to 65% for carriers of pathogenic variants and 45% to 47% for carriers of pathogenic variants. Ovarian cancer risks were 39% for carriers of pathogenic variants and 11% to 17% for carriers of pathogenic variants.
While the cumulative risks of developing cancer by age 70 years are higher for carriers of pathogenic variants than for pathogenic variants, the relative risks (RRs) of breast cancer decline more with age in carriers of pathogenic variants. Studies of penetrance for carriers of specific individual variants are not usually large enough to provide stable estimates, but numerous studies of the Ashkenazi founder pathogenic variants have been conducted. One group of researchers analyzed the subset of families with one of the Ashkenazi founder pathogenic variants from their larger meta-analyses and found that the estimated penetrance for the individual pathogenic variants was very similar to the corresponding estimates among all carriers. A later study of 4,649 women with pathogenic variants reported significantly lower RRs of breast cancer in those with the 6174delT variant than in those with other variants (hazard ratio [HR], 0.35; confidence interval [CI], 0.18–0.69).
One study provided prospective 10-year risks of developing cancer among asymptomatic carriers at various ages. Nonetheless, making precise penetrance estimates in an individual carrier is difficult. The lifetime risks of ovarian cancer are 5.2% in carriers of pathogenic variants, 5.8% in carriers of pathogenic variants, and 12% in carriers of pathogenic variants. Risk-reducing salpingo-oophorectomy (RRSO) may be considered for these patients upon completion of childbearing.
Data from the Consortium of Investigators of Modifiers of (CIMBA), comprising 19,581 carriers of pathogenic variants and 11,900 carriers of pathogenic variants, were analyzed to estimate HRs for breast cancer and ovarian cancer by pathogenic variant type, function, and nucleotide position. Breast cancer cluster regions and ovarian cancer cluster regions were found in both genes. Risks for incidence of breast cancer and ovarian cancer and age at diagnosis differed by variant class. Further evaluation of these findings is needed before they can be translated into clinical practice.
Several studies have suggested that pathogenic variants may be associated with genetic anticipation. One study evaluated 176 families with or pathogenic variants and at least two consecutive generations of the same cancer. The probands’ generations were diagnosed with breast cancer an estimated 6.8 years earlier than the parents’ generations and 9.8 years earlier than the grandparents' generations. Similarly, another study showed a difference in age at breast cancer diagnosis between 80 mother-and-daughter paired pathogenic variant carriers but only if the mother was diagnosed with breast cancer after age 50 years. Another cohort study of 106 paired women from two consecutive generations with a known pathogenic variant in the family estimated a 6- to 8-year earlier age at onset in subsequent generations.
RRSO and/or use of oral contraceptives have been shown to alter risk. (Refer to the RRSO section and the Oral contraceptives section of this summary for more information.) Other potentially modifiable reproductive and hormonal factors can also affect risk. Genetic modifiers of penetrance of breast cancer and ovarian cancer are increasingly under study but are not clinically useful at this time. (Refer to the Modifiers of risk in carriers of BRCA1 and BRCA2 pathogenic variants section for more information.) While the average breast cancer and ovarian cancer penetrances may not be as high as initially estimated, they are substantial, both in relative and absolute terms, particularly in women born after 1940. A higher risk before age 50 years has been consistently seen in more recent birth cohorts, and additional studies will be required to further characterize potential modifying factors to arrive at more precise individual risk projections. Precise penetrance estimates for less common cancers, such as pancreatic cancer, are lacking.
Contralateral breast cancer (CBC) in carriers of BRCA pathogenic variants
The increased risk of CBC among carriers of and pathogenic variants has been confirmed in several large studies, with fairly consistent results, as summarized in Table 5.
Published results include a large study by the German Consortium for Hereditary Breast and Ovarian Cancer, which estimated the risk of CBC in members of families with known and pathogenic variants. At 25 years after the first breast cancer, the risk of CBC was close to 50% in both and families. The risk was also inversely correlated with age in this study, with the highest risks seen in women whose first breast cancer was before age 40 years.
Subsequently, results from the Women's Environmental Cancer and Radiation Epidemiology (WECARE) study, a large, population-based, nested case-control study of CBC, reported a 10-year risk of CBC of 15.9% among carriers of pathogenic variants and a risk of 4.9% among noncarriers. Risks were also inversely related to age at first diagnosis in this study and were 1.8-fold higher in those with a first-degree relative (FDR) with breast cancer.
A larger study of members of families in the Netherlands reported similar 10-year risks of CBC for women from and families (34.2% and 29.2%, respectively).
A comparison of 655 women with pathogenic variants undergoing either breast-conserving therapy or mastectomy noted that both treatment groups experienced high rates of CBC, exceeding 50% by 20 years of follow-up. Rates were significantly higher among women with pathogenic variants than in women with pathogenic variants, and among women whose first breast cancer occurred at or before age 35 years.
In a study of 810 women with stage I or stage II breast cancer who had a or pathogenic variant identified in the family, 149 (18.4%) developed CBC; the 15-year actuarial risk was 36.1% among carriers of pathogenic variants and 28.5% among carriers of pathogenic variants. Risks were higher among women diagnosed before age 50 years than among women diagnosed at age 50 years or older (37.6% vs. 16.8%; = .003). Furthermore, the risk of CBC varied by family history among women whose initial breast cancer was diagnosed before age 50 years. For these women, the CBC risk among those with 0, 1, or 2 or more FDRs with breast cancer diagnosed before age 50 years was 33.4%, 39.1%, and 49.7%, respectively.
The risk of CBC after a first breast cancer in and carriers has been examined in both retrospective and prospective observational epidemiological studies. A systematic review and quantitative meta-analysis of these epidemiologic studies (18 retrospective and 2 prospective cohort studies) reported 5-year cumulative risks of CBC of 15% (95% CI, 9.50%–20%) in carriers and 9% (95% CI, 5%–14%) in carriers. When the prospective studies were analyzed separately, the 5-year cumulative risk increased to 23.4% (95% CI, 9.1%–39.5%) in carriers and to 17.5% (95% CI, 9.1%–39.5%) in carriers. The discrepancies in the reported frequencies may be inherent due to the potential for biases introduced in retrospective series.
Similarly, in a Dutch cohort of 6,294 patients (including 200 carriers and 71 carriers) with invasive breast cancer diagnosed before age 50 years, and a median follow-up of 12.5 years, the 10-year risks of CBC were 21.1% (95% CI, 15.4–27.4) for carriers, 10.8% (95% CI, 4.7–19.6) for carriers, and 5.1% (95% CI, 4.5–5.7) for noncarriers. Age at first breast cancer diagnosis was predictive of the 10-year cumulative risk of CBC among carriers only. Specifically, the CBC risk among carriers diagnosed before age 41 years was 23.9% (, 25.5%; , 17.2%); in contrast, CBC among those diagnosed between 41 and 49 years was 12.6% (, 15.6%; , 7.2%).
Thus, in summary, despite differences in study design, study sites, and sample sizes, the data on CBC among women with pathogenic variants show several consistent findings:
- The risk at all time points studied is significantly higher than that among sporadic controls.
- The risk continues to rise with time since first breast cancer, and reaches 20% to 30% at 10 years of follow-up, and 40% to 50% at 20 years in most studies.
- Some, but not all, studies show an excess of CBC among carriers compared with carriers.
- The risk of CBC is greatest among women whose first breast cancer occurs at a young age, and thus is inversely associated with age.
Refer to the Risk-reducing mastectomy section of this summary for information about the use of risk-reducing surgery in carriers of pathogenic variants. Refer to the Chemoprevention section of this summary for information about the use of tamoxifen as a risk-reduction strategy for CBC in carriers of pathogenic variants.
Breast cancer as a second malignancy in carriers of BRCA pathogenic variants
Two genetic registry–based studies have recently explored the risk of primary breast cancer after -related ovarian cancer. In one study, 164 carriers with primary epithelial ovarian, fallopian tube or primary peritoneal cancer were followed for subsequent events. The risk of metachronous breast cancer at 5 years after a diagnosis of ovarian cancer was lower than previously reported for unaffected carriers. In this series, overall survival was dominated by ovarian cancer-related deaths. A similar study compared the risk of primary breast cancer in -related ovarian cancer patients and unaffected carriers. The 2-year, 5-year, and 10-year risks of primary breast cancer were all statistically significantly lower in patients with ovarian cancer. The risk of CBC among women with a unilateral breast cancer before their ovarian cancer diagnosis was also lower than in women without ovarian cancer, although the difference did not reach statistical significance. These studies suggest that treatment for ovarian cancer, namely oophorectomy and platinum-based chemotherapy, may confer protection against subsequent breast cancer. In a single-institution cohort study of 364 patients with epithelial ovarian cancer who underwent pathogenic variant testing, 135 (37.1%) were found to carry a germline or pathogenic variant. Of the 135 carriers, 12 (8.9%) developed breast cancer. All breast cancers were stage 0 to stage II and diagnosed as follows: mammogram (7), palpable mass (3), and incidental finding during risk-reducing mastectomy (2). At median follow-up of 6.3 years, of the 12 patients with breast cancer after ovarian cancer, three died of recurrent ovarian cancer and one died of metastatic breast cancer. The majority of these cancers were detected with mammogram or clinical exam, suggesting additional breast surveillance with other modalities or risk-reducing surgery may be of questionable value.
Cancers other than female breast/ovarian
Female breast and ovarian cancers are clearly the dominant cancers associated with and . pathogenic variants also confer an increased risk of fallopian tube and primary peritoneal carcinomas. One large study from a familial registry of carriers of pathogenic variants has found a 120-fold RR of fallopian tube cancer among carriers of pathogenic variants compared with the general population. The risk of primary peritoneal cancer among carriers of pathogenic variants with intact ovaries is increased but remains poorly quantified, despite a residual risk of 3% to 4% in the 20 years after RRSO. (Refer to the RRSO section in the Ovarian cancer section of this summary for more information.)
Pancreatic, male breast, and prostate cancers have also been consistently associated with pathogenic variants, particularly with . Other cancers have been associated in some studies. The strength of the association of these cancers with pathogenic variants has been more difficult to estimate because of the lower numbers of these cancers observed in carriers of pathogenic variants.
Men with pathogenic variants, and to a lesser extent pathogenic variants, are at increased risk of breast cancer with lifetime risks estimated at 5% to 10% and 1% to 2%, respectively. Men carrying pathogenic variants, and to a lesser extent pathogenic variants, have an approximately threefold to sevenfold increased risk of prostate cancer. -associated prostate cancer also appears to be more aggressive. (Refer to the section in the PDQ summary on Genetics of Prostate Cancer for more information.)
Studies of familial pancreatic cancer (FPC) and unselected series of pancreatic cancer have also supported an association with , and to a lesser extent, . Overall, it appears that between 3% to 15% of families with FPC may have germline pathogenic variants, with risks increasing with more affected relatives. Similarly, studies of unselected pancreatic cancers have reported pathogenic variant frequencies between 3% to 7%, with these numbers approaching 10% in those of AJ descent. The lifetime risk of pancreatic cancer in carriers is estimated to be 3% to 5%, compared with an estimated lifetime risk of 0.5% by age 70 years in the general population. A large, single-institution study of more than 1,000 carriers of pathogenic variants found a 21-fold increased risk of pancreatic cancer among carriers and a 4.7-fold increased risk among carriers of pathogenic variants, compared with incidence in the general population. Other cancers associated with pathogenic variants in some, but not all, studies include melanoma, biliary cancers, and head and neck cancers, but these risks appear modest (<5% lifetime risk) and are less well studied.
The first Breast Cancer Linkage Consortium study investigating cancer risks reported an excess of colorectal cancer in carriers (RR, 4.1; 95% CI, 2.4–7.2). This finding was supported by some, but not all, family-based studies. However, unselected series of colorectal cancer that have been exclusively performed in the AJ population have not shown elevated rates of or pathogenic variants. Taken together, the data suggest little, if any, increased risk of colorectal cancer, and possibly only in specific population groups. Therefore, at this time, carriers of pathogenic variants should adhere to population-screening recommendations for colorectal cancer.
No increased prevalence of hereditary pathogenic variants was found among 200 Jewish women with endometrial carcinoma or 56 unselected women with uterine papillary serous carcinoma. (Refer to the Risk-reducing salpingo-oophorectomy section in the Ovarian cancer section of this summary for more information.)
Cancer risk in individuals who test negative for a known familial BRCA1/BRCA2 pathogenic variant ("true negative")
There is conflicting evidence as to the residual familial risk among women who test negative for the pathogenic variant segregating in the family. An initial study based on prospective evaluation of 353 women who tested negative for the pathogenic variant segregating in the family found that five incident breast cancers occurred during more than 6,000 person-years of observation, for a lifetime risk of 6.8%, a rate similar to the general population. A report that the risk may be as high as fivefold in women who tested negative for the or pathogenic variant in the family was followed by numerous letters to the editor suggesting that ascertainment biases account for much of this observed excess risk. Four additional analyses have suggested an approximate 1.5-fold to 2-fold excess risk. In one study, two cases of ovarian cancer were reported. Several studies have involved retrospective analyses; all studies have been based on small observed numbers of cases and have been of uncertain statistical and clinical significance.
Results from numerous other prospective studies have found no increased risk. A study of 375 women who tested negative for a known familial pathogenic variant in or reported two invasive breast cancers, two breast cancers, and no ovarian cancers diagnosed, with a mean follow-up of 4.9 years. Four invasive breast cancers were expected, whereas two were observed. Another study of similar size but longer follow-up (395 women and 7,008 person-years of follow-up) also found no statistically significant overall increase in breast cancer risk among variant-negative women (observed/expected [O/E], 0.82; 95% CI, 0.39–1.51), although women who had at least one FDR with breast cancer had a nonsignificant increased risk (O/E, 1.33; 95% CI, 0.41–2.91). A study of 160 and 132 pathogenic variant–positive families from the Breast Cancer Family Registry found no evidence for increased risk among noncarriers in these families. In a large study of 722 variant-negative women from Australia in whom six invasive breast cancers were observed after a median follow-up of 6.3 years, the standardized incidence ratio (SIR) was not significantly elevated (SIR, 1.14; 95% CI, 0.51–2.53). Based on available data, it appears that women testing negative for known familial pathogenic variants can adhere to general population screening guidelines unless they have sufficient additional risk factors, such as a personal history of atypical hyperplasia of the breast or family history of breast cancer in relatives who do not carry the familial pathogenic variant.
Breast and ovarian cancer risk in breast cancer families without detectable BRCA1/BRCA2 pathogenic variants ("indeterminate")
The majority of families with site-specific breast cancer test negative for and have no features consistent with Cowden syndrome or Li-Fraumeni syndrome. Five studies using population-based and clinic-based approaches have demonstrated no increased risk of ovarian cancer in such families. Although ovarian cancer risk was not increased, breast cancer risk remained elevated.
Modifiers of risk in carriers of BRCA1 and BRCA2 pathogenic variants
Pathogenic variants in and confer high risks of breast and ovarian cancers. The risks, however, are not equal in all pathogenic variant carriers and have been found to vary by several factors, including type of cancer, age at onset, and variant position. This observed variation in penetrance has led to the hypothesis that other genetic and/or environmental factors modify cancer risk in carriers of pathogenic variants. There is a growing body of literature identifying genetic and nongenetic factors that contribute to the observed variation in rates of cancers seen in families with pathogenic variants.
Genetic modifiers of breast and ovarian cancer risk
The largest studies investigating genetic modifiers of breast and ovarian cancer risk to date have come from CIMBA, a large international effort with genotypic and phenotypic data on more than 15,000 and 10,000 carriers. Using candidate gene analysis and GWAS, CIMBA has identified several loci associated both with increased and decreased risk of breast cancer and ovarian cancer. Some of the SNPs are related to subtypes of breast cancer, such as hormone-receptor and HER2/neu status. The risks conferred are all modest but if operating in a multiplicative fashion could significantly impact risk of cancer in carriers of pathogenic variants. Currently, these SNPs are not being tested for or used in clinical decision making.
Some genotype-phenotype correlations have been identified in both and pathogenic variant families. None of the studies have had sufficient numbers of pathogenic variant–positive individuals to make definitive conclusions, and the findings are probably not sufficiently established to use in individual risk assessment and management. In 25 families with pathogenic variants, an ovarian cancer cluster region was identified in exon 11 bordered by nucleotides 3,035 and 6,629. A study of 164 families with pathogenic variants collected by the Breast Cancer Linkage Consortium confirmed the initial finding. Pathogenic variants within the ovarian cancer cluster region were associated with an increased risk of ovarian cancer and a decreased risk of breast cancer in comparison with families with variants on either side of this region. In addition, a study of 356 families with protein-truncating pathogenic variants collected by the Breast Cancer Linkage Consortium reported breast cancer risk to be lower with variants in the central region (nucleotides 2,401–4,190) compared with surrounding regions. Ovarian cancer risk was significantly reduced with variants 3’ to nucleotide 4,191. These observations have generally been confirmed in subsequent studies. Studies in Ashkenazim, in whom substantial numbers of families with the same pathogenic variant can be studied, have also found higher rates of ovarian cancer in carriers of the :185delAG variant, in the 5' end of , compared with carriers of the :5382insC variant in the 3' end of the gene. The risk of breast cancer, particularly bilateral breast cancer, and the occurrence of both breast and ovarian cancer in the same individual, however, appear to be higher in carriers of the :5382insC pathogenic variant compared with carriers of :185delAG and :6174delT variants. Ovarian cancer risk is considerably higher in carriers of pathogenic variants, and it is uncommon before age 45 years in carriers of the :6174delT pathogenic variant.
In an Australian study of 122 families with a pathogenic variant in , large genomic rearrangement variants were associated with higher-risk features in breast and ovarian cancers, including younger age at breast cancer diagnosis and higher incidence of bilateral breast cancer.
Pathology of breast cancer
Several studies evaluating pathologic patterns seen in -associated breast cancers have suggested an association with adverse pathologic and biologic features. These findings include higher than expected frequencies of medullary histology, high histologic grade, areas of necrosis, trabecular growth pattern, aneuploidy, high S-phase fraction, high mitotic index, and frequent variants. In a large international series of 3,797 carriers of pathogenic variants, the median age at breast cancer diagnosis was 40 years. Of breast tumors arising in carriers, 78% were ER-negative; 79% were PR-negative; 90% were HER2-negative; and 69% were triple-negative. These findings were consistent with multiple smaller series. In addition, the proportion of ER-negative tumors significantly decreased as the age at breast cancer diagnosis increased.
There is considerable, but not complete, overlap between the triple-negative and basal-like subtype cancers, both of which are common in -associated breast cancer, particularly in women diagnosed before age 50 years. A small proportion of -related breast cancers are ER-positive, which are associated with later age of onset. These ER-positive cancers have clinical behavior features that are "intermediate" between ER-negative cancers and ER-positive sporadic breast cancers, raising the possibility that there may be a unique mechanism by which they develop.
The prevalence of germline pathogenic variants in women with triple-negative breast cancer is significant, both in women undergoing clinical genetic testing (and thus selected in large part for family history) and in unselected triple-negative patients, with pathogenic variants reported in 9% to 35%. Notably, studies have demonstrated a high rate of pathogenic variants in unselected women with triple-negative breast cancer, particularly in those diagnosed before age 50 years. A large report of 1,824 patients with triple-negative breast cancer unselected for family history, recruited through 12 studies, identified 14.6% with a pathogenic variant in an inherited cancer susceptibility gene. pathogenic variants accounted for the largest proportion (8.5%), followed by (2.7%); (1.2%); and , , and (0.3%–0.5% for each gene). In this study, those with pathogenic variants in or other inherited cancer genes were diagnosed at an earlier age and had higher grade tumors than those without pathogenic variants. Specifically, among carriers of pathogenic variants, the average age at diagnosis was 44 years, and 94% had high-grade tumors. One study examined 308 individuals with triple-negative breast cancer; pathogenic variants were present in 45. Pathogenic variants were seen both in women unselected for family history (11 of 58; 19%) and in those with family history (26 of 111; 23%). A meta-analysis based on 2,533 patients from 12 studies was conducted to assess the risk of a pathogenic variant in high-risk women with triple-negative breast cancer. Results indicated that the RR of a pathogenic variant among women with versus without triple-negative breast cancer is 5.65 (95% CI, 4.15–7.69), and approximately two in nine women with triple-negative disease harbor a pathogenic variant. Interestingly, a study of 77 unselected patients with triple-negative breast cancer in which 15 (19.5%) had a germline or somatic pathogenic variant demonstrated a lower risk of relapse in those with pathogenic variant–associated triple-negative breast cancer than in those with non--associated triple-negative breast cancer; this study was limited by its size. A second study examining clinical outcomes in -associated versus non--associated triple-negative breast cancer showed no difference, although there was a trend toward more brain metastases in those with -associated breast cancer. In both of these studies, all but one carrier of pathogenic variants received chemotherapy.
It has been hypothesized that many tumors are derived from the basal epithelial layer of cells of the normal mammary gland, which account for 3% to 15% of unselected invasive ductal cancers. If the basal epithelial cells of the breast represent the breast stem cells, the regulatory role suggested for wild-type may partly explain the aggressive phenotype of -associated breast cancer when function is damaged. Further studies are needed to fully appreciate the significance of this subtype of breast cancer within the hereditary syndromes.
The most accurate method for identifying basal-like breast cancers is through gene expression studies, which have been used to classify breast cancers into biologically and clinically meaningful groups. This technology has also been shown to correctly differentiate - and -associated tumors from sporadic tumors in a high proportion of cases. Notably, among a set of breast tumors studied by gene expression array to determine molecular phenotype, all tumors with alterations fell within the basal tumor subtype; however, this technology is not in routine use due to its high cost. Instead, immunohistochemical markers of basal epithelium have been proposed to identify basal-like breast cancers, which are typically negative for ER, PR, and HER2, and stain positive for cytokeratin 5/6, or epidermal growth factor receptor. Based on these methods to measure protein expression, a number of studies have shown that the majority of -associated breast cancers are positive for basal epithelial markers.
There is growing evidence that preinvasive lesions are a component of the phenotype. The Breast Cancer Linkage Consortium initially reported a relative lack of an component in associated breast cancers, also seen in two subsequent studies of carriers. However, in a study of 369 ductal carcinoma (DCIS) cases, and pathogenic variants were detected in 0.8% and 2.4%, respectively, which is only slightly lower than previously reported prevalence in studies of invasive breast cancer patients. A retrospective study of breast cancer cases in a high-risk clinic found similar rates of preinvasive lesions, particularly DCIS, among 73 -associated breast cancers and 146 pathogenic variant–negative cases. A study of AJ women, stratified by whether they were referred to a high-risk clinic or were unselected, showed similar prevalence of DCIS and invasive breast cancers in referred patients compared with one-third lower DCIS cases among unselected subjects. Similarly, data about the prevalence of hyperplastic lesions have been inconsistent, with reports of increased and decreased prevalence. Similar to invasive breast cancer, DCIS diagnosed at an early age and/or with a family history of breast and/or ovarian cancer is more likely to be associated with a pathogenic variant.
Overall evidence suggests DCIS is part of the spectrum, particularly ; however, the prevalence of pathogenic variants in DCIS patients, unselected for family history, is less than 5%.
The phenotype for -related tumors appears to be more heterogeneous and is less well-characterized than that of , although they are generally positive for ER and PR. A large international series of 2,392 carriers of pathogenic variants found that only 23% of tumors arising in carriers of pathogenic variants were ER-negative; 36% were PR-negative; 87% were HER2-negative; and 16% were triple-negative. A large report of 1,824 patients with triple-negative breast cancer unselected for family history, recruited through 12 studies, identified 2.7% with a pathogenic variant. (Refer to the BRCA1 pathology section of this summary for more information about this study.) A report from Iceland found less tubule formation, more nuclear pleomorphism, and higher mitotic rates in -related tumors than in sporadic controls; however, a single founder pathogenic variant (999del5) accounts for nearly all hereditary breast cancer in this population, thus limiting the generalizability of this observation. A large case series from North America and Europe described a greater proportion of -associated tumors with continuous pushing margins (a histopathologic description of a pattern of invasion), fewer tubules and lower mitotic counts. Other reports suggest that -related tumors include an excess of lobular and tubulolobular histology. In summary, histologic characteristics associated with pathogenic variants have been inconsistent.
Role of BRCA1 and BRCA2 in sporadic breast cancer
Given that germline pathogenic variants in or lead to a very high probability of developing breast cancer, it was a natural assumption that these genes would also be involved in the development of the more common nonhereditary forms of the disease. Although somatic pathogenic variants in and are not common in sporadic breast cancer tumors, there is increasing evidence that hypermethylation of the gene promoter (BRCA1) and loss of heterozygosity (LOH) (BRCA2) are frequent events. In fact, many breast cancers have low levels of the mRNA, which may result from hypermethylation of the gene promoter. Approximately 10% to 15% of sporadic breast cancers appear to have promoter hypermethylation, and even more have downregulation of BRCA1 by other mechanisms. Basal-type breast cancers (ER negative, PR negative, HER2 negative, and cytokeratin 5/6 positive) more commonly have BRCA1 dysregulation than other tumor types. -related tumor characteristics have also been associated with constitutional methylation of the promoter. In a study of 255 breast cancers diagnosed before age 40 years in women without germline pathogenic variants, methylation of in peripheral blood was observed in 31% of women whose tumors had multiple -associated pathological characteristics (e.g., high mitotic index and growth pattern including multinucleated cells) compared with less than 4% methylation in controls. (Refer to the BRCA1 pathology section for more information.) Although hypermethylation has not been reported for pathogenic variants, the locus on chromosome 13q is the target of frequent LOH in breast cancer. Targeted therapies are being developed for tumors with loss of BRCA1 or BRCA2 protein expression.
Pathology of ovarian cancer
Ovarian cancers in women with and pathogenic variants are more likely to be high-grade serous adenocarcinomas and are less likely to be mucinous or borderline tumors. Fallopian tube cancer and peritoneal carcinomas are also part of the -associated disease spectrum.
Histopathologic examinations of fallopian tubes removed from women with a hereditary predisposition to ovarian cancer show dysplastic and hyperplastic lesions that suggest a premalignant phenotype. Occult carcinomas have been reported in 2% to 11% of adnexa removed from carriers of pathogenic variants at the time of risk-reducing surgery. Most of these occult lesions are seen in the fallopian tubes, which has led to the hypothesis that many -associated ovarian cancers may actually have originated in the fallopian tubes. Specifically, the distal segment of the fallopian tubes (containing the fimbriae) has been implicated as a common origin of the high-grade serous cancers seen in pathogenic variant carriers, based on the close proximity of the fimbriae to the ovarian surface, exposure of the fimbriae to the peritoneal cavity, and the broad surface area in the fimbriae. Because of the multicentric origin of high-grade serous carcinomas from Müllerian-derived tissue, staging of ovarian, tubal, and peritoneal carcinomas is now considered collectively by the International Federation of Gynecology and Obstetrics. The term “high-grade serous ovarian carcinoma” may be used to represent high-grade pelvic serous carcinoma for consistency in language.
High-grade serous ovarian carcinomas have a higher incidence of somatic pathogenic variant. DNA microarray technology suggests distinct molecular pathways of carcinogenesis between , , and sporadic ovarian cancer. Furthermore, data suggest that -related ovarian cancers metastasize more frequently to the viscera, while sporadic ovarian cancers remain confined to the peritoneum.
Unlike high-grade serous carcinomas, low-grade serous ovarian cancers are less likely to be part of the spectrum.
Role of BRCA1 and BRCA2 in sporadic ovarian cancer
Given that germline variants in or lead to a very high probability of developing ovarian cancer, it was a natural assumption that these genes would also be involved in the development of the more common nonhereditary forms of the disease. Although somatic pathogenic variants in and are not common in sporadic ovarian cancer tumors, there is increasing evidence that hypermethylation of the gene promoter (BRCA1) and LOH (BRCA2) are frequent events. Loss of BRCA1 or BRCA2 protein expression is more common in ovarian cancer than in breast cancer, and downregulation of BRCA1 is associated with enhanced sensitivity to cisplatin and improved survival in this disease. Targeted therapies are being developed for tumors with loss of BRCA1 or BRCA2 protein expression.
Other High-Penetrance Syndromes Associated With Breast and/or Gynecologic Cancers
Lynch syndrome is characterized by autosomal dominant inheritance of susceptibility to predominantly right-sided colon cancer, endometrial cancer, ovarian cancer, and other extracolonic cancers (including cancer of the renal pelvis, ureter, small bowel, and pancreas), multiple primary cancers, and a young age of onset of cancer. The condition is caused by germline variants in the mismatch repair (MMR) genes, which are involved in repair of DNA mismatch variants. The and genes are the most common susceptibility genes for Lynch syndrome, accounting for 80% to 90% of observed pathogenic variants, followed by and . (Refer to the Lynch Syndrome section in the PDQ summary on Genetics of Colorectal Cancer for more information about this syndrome.)
After colorectal cancer, endometrial cancer is the second hallmark cancer of a family with Lynch syndrome. Even in the original Family G, described by Dr. Aldred Scott Warthin, numerous family members were noted to have extracolonic cancers including endometrial cancer. Although the first version of the Amsterdam criteria did not include endometrial cancer, in 1999, the Amsterdam criteria were revised to include endometrial cancer as extracolonic tumors associated with Lynch syndrome to identify families at risk. In addition, the Bethesda guidelines in 1997 (revised in 2004) did include endometrial and ovarian cancers as Lynch syndrome–related cancers to prompt tumor testing for Lynch syndrome.
The lifetime risk of ovarian carcinoma in females with Lynch syndrome is estimated to be as high as 12%, and the reported RR of ovarian cancer has ranged from 3.6 to 13, based on families ascertained from high-risk clinics with known or suspected Lynch syndrome. Characteristics of Lynch syndrome–associated ovarian cancers may include overrepresentation of the International Federation of Gynecology and Obstetrics stages 1 and 2 at diagnosis (reported as 81.5%), underrepresentation of serous subtypes (reported as 22.9%), and a better 10-year survival (reported as 80.6%) than reported both in population-based series and in carriers of pathogenic variants.
The issue of breast cancer risk in Lynch syndrome has been controversial. Retrospective studies have been inconsistent, but several have demonstrated microsatellite instability in a proportion of breast cancers from individuals with Lynch syndrome; one of these studies evaluated breast cancer risk in individuals with Lynch syndrome and found that it is not elevated. However, the largest prospective study to date of 446 unaffected carriers of pathogenic variants from the Colon Cancer Family Registry who were followed for up to 10 years reported an elevated SIR of 3.95 for breast cancer (95% CI, 1.59–8.13; = .001). The same group subsequently analyzed data on 764 carriers of MMR gene pathogenic variants with a prior diagnosis of colorectal cancer. Results showed that the 10-year risk of breast cancer following colorectal cancer was 2% (95% CI, 1%–4%) and that the SIR was 1.76 (95% CI, 1.07–2.59). A series from the United Kingdom composed of clinically referred Lynch syndrome kindreds, with efforts to correct for ascertainment, showed a twofold increased risk of breast cancer in 157 carriers but not in carriers of other MMR variants. Results from a meta-analysis of breast cancer risk in Lynch syndrome among 15 studies with molecular tumor testing results revealed that 62 of 122 breast cancers (51%; 95% CI, 42%–60%) in MMR pathogenic variant carriers were MMR-deficient. In addition, breast cancer risk estimates among a total of 21 studies showed an increased risk of twofold to 18-fold in eight studies that compared MMR variant carriers with noncarriers, while 13 studies did not observe statistical evidence for an association of breast cancer risk with Lynch syndrome. However, further studies are needed to define absolute risks and age distribution before surveillance guidelines for breast cancer can be developed for carriers of MMR pathogenic variants.
Li-Fraumeni syndrome (LFS)
Breast cancer is also a component of the rare LFS (OMIM), in which germline variant of the gene (OMIM) on chromosome 17p have been documented. Located on chromosome 17p, encodes a 53kd nuclear phosphoprotein that binds DNA sequences and functions as a negative regulator of cell growth and proliferation in the setting of DNA damage. It is also an active component of programmed cell death. Inactivation of the gene or disruption of the protein product is thought to allow the persistence of damaged DNA and the possible development of malignant cells. Widely used clinical diagnostic criteria for LFS were originally developed by Chompret et al. in 2001 (called the “Chompret Criteria”) and revised in 2009 based on additional emerging data.
LFS is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma.
Germline variants in are thought to account for fewer than 1% of breast cancer cases. -associated breast cancer is often HER2/neu-positive, in addition to being ER-positive, PR-positive, or both. Evidence also exists that patients treated for a -related tumor with chemotherapy or radiation therapy may be at risk of a treatment-related second malignancy.
Historical criteria for defining LFS
The term Li-Fraumeni syndrome was used for the first time in 1982, and the following criteria, which subsequently became the classical definition of the syndrome, were proposed by Li and Fraumeni in 1988 :
Subsequently in 2001, Chompret et al. systematically developed clinical criteria for recommending genetic testing, with the narrow LFS tumor spectrum defined as sarcoma, brain tumors, breast cancer, and adrenocortical carcinoma. The criteria were as follows:
These criteria were revised in 2009 based on additional emerging data as follows:
*The 2009 Chompret criteria defined the LFS tumor spectrum as including the following cancers: soft tissue sarcoma, osteosarcoma, brain tumor, premenopausal breast cancer, adrenocortical carcinoma, leukemia, and lung bronchoalveolar cancer.
In 2015, Bougeard et al. revised the criteria based on data from 415 carriers of pathogenic variants, to include the presence of childhood anaplastic rhabdomyosarcoma and breast cancer before age 31 years as an indication for testing, similar to what is recommended for choroid plexus carcinoma and adrenocortical carcinoma. The criteria were revised as follows:
**The 2015 Chompret criteria defined the LFS tumor spectrum as including the following cancers: premenopausal breast cancer, soft tissue sarcoma, osteosarcoma, central nervous system (CNS) tumor, and adrenocortical carcinoma.
Clinical characteristics of LFS
Germline pathogenic variants were identified in 17% (n = 91) of 525 samples submitted to City of Hope laboratories for clinical testing. All families with a pathogenic variant had at least one family member with a sarcoma, breast cancer, brain cancer, or adrenocortical cancer (core cancers). In addition, all eight individuals with a choroid plexus tumor had a pathogenic variant, as did 14 of the 21 individuals with childhood adrenocortical cancer. In women aged 30 to 49 years who had breast cancer but no family history of other core cancers, no variants were found.
Subsequently, a large clinical series of patients from France who were tested primarily based on the 2009 version of the Chompret criteria included 415 carriers of pathogenic variants from 214 families. In this study, 43% of carriers had multiple malignancies, and the mean age at first tumor onset was 24.9 years. The childhood tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas, CNS tumors, and soft tissue sarcomas (present in 23%–30% collectively), whereas the adult tumor spectrum primarily encompassed breast cancer (79% of females) and soft tissue sarcomas (27% of carriers). The pathogenic variant detection rate was 6% among females younger than 31 years with breast cancer and no additional features suggestive of LFS. Evaluation of genotype-phenotype correlations indicated a gradient of clinical severity, with a significantly lower mean age at onset among those with dominant-negative missense variants (21.3 years), compared with those with all types of loss-of-function variants (28.5 years) or genomic rearrangements (35.8 years). With the exception of adrenocortical carcinoma, affected children mostly harbored dominant-negative missense pathogenic variants. Among 127 female carriers of pathogenic variants with breast cancer, 31% developed CBC. Receptor status information was available for 40 tumors, which indicated 55% were HER2-positive, and 37% were triple-positive (i.e., ER-positive, PR-positive, and HER2-positive). There was an exceptionally high rate of multiple malignancies (43%) among carriers of pathogenic variants, of which 83% were metachronous. Treatment records were available for 64 carriers who received radiation therapy for treatment of their first tumor; of these, 19 (30%) developed 26 secondary tumors within a radiation field, with a latency of 2 to 26 years (mean, 10.7 years).
Similarly, results of 286 pathogenic variant–positive individuals in the National Cancer Institute’s LFS Study indicated a cumulative cancer incidence of almost 100% by age 70 years for both males and females. They reported substantial variations by sex, age, and cancer type. Specifically, cumulative cancer incidence reached 50% by age 31 years in females and age 46 years in males, although male risks were higher in childhood and late adulthood. Cumulative cancer incidence by sex for the top four cancers is included in the table below. Of those with one cancer, 49% developed at least one additional cancer after a median of 10 years. Age-specific risks for developing first and second cancers were comparable.
With the increasing use of multigene (panel) tests, it is important to recognize that pathogenic variants in are unexpectedly being identified in individuals without a family history characteristic of LFS. The clinical significance of finding an isolated pathogenic variant in an individual or family who does not meet the Chompret criteria is uncertain. Consequently, it remains important to interpret cancer risks and determine optimal management strategies for individuals who are unexpectedly found to have a germline variant, while taking into account their personal and family histories.
Screening for breast cancer with annual magnetic resonance imaging is recommended; additional screening for other cancers has been studied and is evolving.
PTEN hamartoma tumor syndromes (including Cowden syndrome)
Cowden syndrome and Bannayan-Riley-Ruvalcaba Syndrome (BRRS) are part of a spectrum of conditions known collectively as hamartoma tumor syndromes. Approximately 85% of patients diagnosed with Cowden syndrome, and approximately 60% of patients with BRRS have an identifiable pathogenic variant. In addition, pathogenic variants have been identified in patients with very diverse clinical phenotypes. The term hamartoma tumor syndromes refers to any patient with a pathogenic variant, irrespective of clinical presentation.
functions as a dual-specificity phosphatase that removes phosphate groups from tyrosine, serine, and threonine. Pathogenic variants of are diverse, including nonsense, missense, frameshift, and splice-site variants. Approximately 40% of variants are found in exon 5, which encodes the phosphatase core motif, and several recurrent pathogenic variants have been observed. Individuals with variants in the 5’ end or within the phosphatase core of tend to have more organ systems involved.
Operational criteria for the diagnosis of Cowden syndrome have been published and subsequently updated. These included major, minor, and pathognomonic criteria consisting of certain mucocutaneous manifestations and adult-onset dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease). An updated set of criteria based on a systematic literature review has been suggested and is currently utilized in the National Comprehensive Cancer Network (NCCN) guidelines. Contrary to previous criteria, the authors concluded that there was insufficient evidence for any features to be classified as pathognomonic. With increased utilization of genetic testing, especially the use of multigene panels, clinical criteria for Cowden syndrome will need to be reconciled with the phenotype of individuals with documented germline pathogenic variants who do not meet these criteria. Until then, whether Cowden syndrome and the other hamartoma tumor syndromes will be defined clinically or based on the results of genetic testing remains ambiguous. The American College of Medical Genetics and Genomics (ACMG) suggests that referral for genetics consultation be considered for individuals with a personal history of or a first-degree relative with 1) adult-onset Lhermitte-Duclos disease or 2) any three of the major or minor criteria that have been established for the diagnosis of Cowden syndrome. Detailed recommendations, including diagnostic criteria for Cowden syndrome, can be found in the NCCN and ACMG guidelines. Additionally, a predictive model that uses clinical criteria to estimate the probability of a pathogenic variant is available; a cost-effectiveness analysis suggests that germline testing is cost effective if the probability of a variant is greater than 10%.
Over a 10-year period, the International Cowden Consortium (ICC) prospectively recruited a consecutive series of adult and pediatric patients meeting relaxed ICC criteria for testing in the United States, Europe, and Asia. The vast majority of individuals did not meet the clinical criteria for a diagnosis of Cowden syndrome or BRRS. Of the 3,399 individuals recruited and tested, 295 probands (8.8%) and an additional 73 family members were found to harbor germline pathogenic variants. In addition to breast, thyroid, and endometrial cancers, the authors concluded that on the basis of cancer risk, melanoma, kidney cancer, and colorectal cancers should be considered part of the cancer spectra arising from germline pathogenic variants. A second study of approximately 100 patients with a germline pathogenic variant confirmed these findings and suggested a cumulative cancer risk of 85% by age 70 years.
Although pathogenic variants, which are estimated to occur in 1 in 200,000 individuals, account for a small fraction of hereditary breast cancer, the characterization of PTEN function will provide valuable insights into the signal pathway and the maintenance of normal cell physiology. Lifetime breast cancer risk is estimated to be between 25% and 50% among women with Cowden syndrome. Other studies have reported risks as high as 85%; however, there are concerns regarding selection bias in these studies. As in other forms of hereditary breast cancer, onset is often at a young age and may be bilateral. Skin manifestations include multiple trichilemmomas, oral fibromas and papillomas, and acral, palmar, and plantar keratoses. History or observation of the characteristic skin features raises a suspicion of Cowden syndrome. CNS manifestations include macrocephaly, developmental delay, and dysplastic gangliocytomas of the cerebellum. (Refer to the PDQ summaries on Genetics of Colorectal Cancer and Genetics of Skin Cancer for more information about hamartoma tumor syndromes [including Cowden syndrome].)
Diffuse gastric and lobular breast cancer syndrome
The gene was first described in 1998 in three Maori families with multiple cases of diffuse gastric cancer (DGC), leading to the designation of hereditary diffuse gastric cancer (HDGC). There have been multiple subsequent reports of an excess of lobular breast cancer in HDGC families. is located on chromosome 16q22.1 and encodes the E-cadherin protein, a calcium-dependent homophilic adhesion molecule that plays a key role in cellular adhesion, cell polarity, cell signaling, and maintenance of cellular differentiation and tissue morphology. E-cadherin binds to various catenins to stabilize the cytoplasmic cell adhesion complex and to maintain the E-cadherin interaction with actin filament. Loss of can occur as a result of somatic variants, LOH, or hypermethylation, and can result in dedifferentiation and invasiveness in human cancers. Classic histopathologic findings in gastrectomy specimens include signet ring cells and/or pagetoid spread of signet ring cells. Of all gastric cancers, 1% to 3% are attributed to inherited gastric cancer syndromes.
HDGC is an autosomal dominant syndrome associated with poorly differentiated invasive adenocarcinoma of the stomach presenting as . It is a highly penetrant and highly fatal syndrome, with a risk of clinical DGC ranging from 40% to 83%. The risk of lobular breast cancer, which is characterized by small uniform cells that tend to invade in “single files,” is also increased in HDGC. Although invasive lobular breast cancer represents only 10% to 15% of all breast cancers, the lifetime risk of lobular breast cancer in carriers of pathogenic variants ranges from 30% to 50%. Guidelines for screening for vary but include multiple cases of DGC in a family, early age of DGC, or lobular breast cancer in a family with DGC. Approximately 25% of families meeting these criteria are found to have a pathogenic variant in . pathogenic variants have been found in some families with lobular breast cancer but no gastric cancer. The management of individuals with pathogenic variants without a family history of gastric cancer is unclear.
Peutz-Jeghers syndrome (PJS)
PJS is an early-onset autosomal dominant disorder characterized by melanocytic macules on the lips, the perioral region, and buccal region; and multiple gastrointestinal polyps, both hamartomatous and adenomatous. Germline pathogenic variants in the gene at chromosome 19p13.3 have been identified in the vast majority of PJS families. The most common cancers in PJS are gastrointestinal. However, other organs are at increased risk of developing malignancies. For example, the cumulative risks have been estimated to be 32% to 54% for breast cancer and 21% for ovarian cancer. A systematic review found a lifetime cumulative cancer risk, all sites combined, of up to 93% in patients with PJS. Table 10 shows the cumulative risk of these tumors. The high cumulative risk of cancers in PJS has led to the various screening recommendations summarized in the table of Published Recommendations for Diagnosis and Surveillance of Peutz-Jeghers Syndrome (PJS) in the PDQ summary on Genetics of Colorectal Cancer.
Females with PJS are also predisposed to the development of cervical adenoma malignum, a rare and very aggressive adenocarcinoma of the cervix. In addition, females with PJS commonly develop benign ovarian sex-cord tumors with annular tubules, whereas males with PJS are predisposed to development of Sertoli-cell testicular tumors; although neither of these two tumor types is malignant, they can cause symptoms related to increased estrogen production.
Although the risk of malignancy appears to be exceedingly high in individuals with PJS based on the published literature, the possibility that selection and referral biases have resulted in overestimates of these risks should be considered.
PJS is caused by pathogenic variants in the (also called ) tumor suppressor gene located on chromosome 19p13. Unlike the adenomas seen in familial adenomatous polyposis, the polyps arising in PJS are hamartomas. Studies of the hamartomatous polyps and cancers of PJS show allelic imbalance (LOH) consistent with the two-hit hypothesis, demonstrating that is a tumor suppressor gene. However, heterozygous knockout mice develop hamartomas without inactivation of the remaining wild-type allele, suggesting that haploinsufficiency is sufficient for initial tumor development in PJS. Subsequently, the cancers that develop in +/- mice do show LOH; indeed, compound mutant mice heterozygous for pathogenic variants in +/- and homozygous for pathogenic variants in -/- have accelerated development of both hamartomas and cancers.
Germline variants of the gene represent a spectrum of nonsense, frameshift, and missense variants, and splice-site variants and large deletions. Approximately 85% of variants are localized to regions of the kinase domain of the expressed protein, and no germline variants have been reported in exon 9. No strong genotype-phenotype correlations have been identified.
has been unequivocally demonstrated to cause PJS. Although earlier estimates using direct DNA sequencing showed a 50% pathogenic variant detection rate in , studies adding techniques to detect large deletions have found pathogenic variants in up to 94% of individuals meeting clinical criteria for PJS. Given the results of these studies, it is unlikely that other major genes cause PJS.
PALB2 (partner and localizer of BRCA2) interacts with the BRCA2 protein and plays a role in homologous recombination and double-stranded DNA repair. Similar to and , biallelic pathogenic variants in have also been shown to cause Fanconi anemia.
pathogenic variants have been screened for in multiple small studies of familial and early-onset breast cancer in multiple populations. Pathogenic variant prevalence has ranged from 0.4% to 3.9%. Similar to and , there was incomplete segregation of pathogenic variants in families with hereditary breast cancer. Among 559 cases with CBC and 565 matched controls with unilateral breast cancer, pathogenic (truncating) pathogenic variants were identified in 0.9% of cases and in none of the controls (RR, 5.3; 95% CI, 1.8–13.2).
Data based on 154 families with loss-of-function variants suggest that this gene may be an important cause of hereditary breast cancer, with risks that overlap with . In this study, analysis of 362 family members from 154 families with pathogenic variants indicated that the absolute risk of female breast cancer by age 70 years ranged from 33% (95% CI, 24%–44%) for those with no family history of breast cancer to 58% (95% CI, 50%–66%) for those with two or more FDRs with early-onset breast cancer. Furthermore, among 63 breast cancer cases in which HER2 status was known, 30% had triple-negative disease. An earlier Finnish study reported on a founder pathogenic variant (c.1592delT) that confers a 40% risk of breast cancer to age 70 years and is associated with a high incidence (54%) of triple-negative disease and lower survival. Pathogenic variants have been observed in early-onset and familial breast cancer in many populations. A large report of 1,824 patients with triple-negative breast cancer unselected for family history, recruited through 12 studies, identified 1.2% with a pathogenic variant. (Refer to BRCA1 pathology section of this summary for more information about this study.)
In a later Polish study of more than 12,529 unselected women with breast cancer and 4,702 controls, pathogenic variants were detected in 116 cases (0.93%; 95% CI, 0.76–1.09) and 10 controls (0.21%; 95% CI, 0.08–0.34), with an odds ratio for breast cancer of 4.39 (95% CI, 2.30–8.37). The study findings confirm a substantially elevated risk of breast cancer (24%–40%) among women with a pathogenic variant up to age 75 years. The 5-year cumulative incidence of CBC was 10% among those with a pathogenic variant, compared with 17% among those with a pathogenic variant and 3% among those without a variant in either gene. Furthermore, the 10-year survival for women with a pathogenic variant and breast cancer was 48% (95% CI, 36.5%–63.2%), compared with 72.0% among those with a pathogenic variant and 74.7% among those without a variant in either gene. Among carriers, breast tumors 2 cm or larger had substantially worse outcomes (32.4% 10-year survival), compared with tumors smaller than 2 cm (82.4% 10-year survival). Approximately one-third of those with a pathogenic variant had triple-negative breast cancer, and the average age at breast cancer diagnosis was 53.3 years.
Male breast cancer has been observed in pathogenic variant–positive breast cancer families. In a study of 115 male breast cancer cases in which 18 men had pathogenic variants, an additional two men had either a pathogenic or predicted pathogenic variant (accounting for about 10% of germline variants in the study and 1%–2% of the total sample). The RR of breast cancer for male carriers of pathogenic variants compared with that seen in the general population was estimated to be 8.30 (95% CI, 0.77–88.56; = .08) in the study of 154 families.
After the identification of pathogenic variants in pancreatic tumors and the detection of germline pathogenic variants in 3% of 96 familial pancreatic patients, numerous studies have pointed to a role for in pancreatic cancer. pathogenic variants were detected in 3.7% of 81 familial pancreatic cancer families and in 2.1% of 94 pathogenic variant–negative breast cancer patients who had either a personal or family history of pancreatic cancer. Two relatively small studies—one of 77 pathogenic variant–negative probands with a personal or family history of pancreatic cancer, one-half of whom were of AJ descent, and another study of 29 Italian pancreatic cancer patients with a personal or family history of breast or ovarian cancer—failed to detect any pathogenic variants. A sixfold increase in pancreatic cancer was observed in the relatives of 33 -negative, pathogenic variant–positive breast cancer probands.
Overall, the observed prevalence of pathogenic variants in familial breast cancer varied depending on ascertainment relative to personal and family history of pancreatic and ovarian cancers, but in all studies, the observed pathogenic variant rate was lower than 4%. Data suggest that the RR of breast cancer may overlap with that of , particularly in those with a strong family history; thus, it remains important to refine cancer risk estimates in larger studies. Furthermore, the risk of other cancers (e.g., pancreatic) is poorly defined. Given the low pathogenic variant prevalence in the population, additional data are needed to define best candidates for testing and appropriate management.
De Novo Pathogenic Variant Rate
Until the 1990s, the diagnosis of genetically inherited breast and ovarian cancer syndromes was based on clinical manifestations and family history. Now that some of the genes involved in these syndromes have been identified, a few studies have attempted to estimate the spontaneous pathogenic variant rate (de novo pathogenic variant rate) in these populations. Interestingly, PJS, hamartoma syndromes, and LFS are all thought to have high rates of spontaneous pathogenic variants, in the 10% to 30% range, while estimates of de novo pathogenic variants in the genes are thought to be low, primarily on the basis of the few case reports published. Additionally, there has been only one case series of breast cancer patients who were tested for pathogenic variants in which a de novo variant was identified. Specifically, in this study of 193 patients with sporadic breast cancer, 17 pathogenic variants were detected, one of which was confirmed to be a de novo pathogenic variant. As such, the de novo pathogenic variant rate appears to be low and fall into the 5% or less range, based on the limited studies performed. Similarly, estimates of de novo pathogenic variants in the MMR genes associated with Lynch syndrome are thought to be low, in the 0.9% to 5% range. However, it is important to note that these estimates of spontaneous pathogenic variant rates in the genes and Lynch syndrome genes seem to overlap with the estimates of nonpaternity rates in various populations (0.6%–3.3%), making the de novo pathogenic variant rate for these genes relatively low.
Moderate-Penetrance Genes Associated With Breast and/or Gynecologic Cancer
Pathogenic variants in , , , and the genes involved in other rare syndromes discussed in the High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes section of this summary account for less than 25% of the familial risk of breast cancer. Despite intensive genetic linkage studies, there do not appear to be other high-penetrance genes that account for a significant fraction of the remaining multiple-case familial clusters. However, several moderate-penetrance genes associated with breast and/or gynecologic cancers have been identified. Genes such as and are associated with a 20% or higher lifetime risk of breast cancer; similarly, genes such as , , and are associated with a 5% to 10% risk of ovarian cancer. Many of these genes are now included on multigene panels, although the clinical actionability of these findings remains uncertain and under investigation.
Breast and Gynecologic Cancer Susceptibility Genes Identified Through Candidate Gene Approaches
There is a very large literature of genetic epidemiology studies describing associations between various loci and breast cancer risk. Many of these studies suffer from significant design limitations. Perhaps as a consequence, most reported associations do not replicate in follow-up studies. This section is not a comprehensive review of all reported associations. This section describes associations that are believed by the editors to be clinically valid, in that they have been described in several studies or are supported by robust meta-analyses. The clinical utility of these observations remains unclear, however, as the risks associated with these variations usually fall below a threshold that would justify a clinical response.
Fanconi anemia genes
Fanconi anemia (FA) is a rare, inherited condition characterized by bone marrow failure, increased risk of malignancy, and physical abnormalities. To date, 16 FA-related genes, including , have been identified (as outlined in Table 11). FA is mainly an autosomal recessive condition, except when caused by pathogenic variants in , which is X-linked recessive. accounts for 60% to 70% of pathogenic variants, accounts for approximately 14%, and the remaining genes each account for 3% or fewer.
Progressive bone marrow failure typically occurs in the first decade, with patients often presenting with thrombocytopenia or leucopenia. The incidence of bone marrow failure is 90% by age 40 to 50 years. The incidence is 10% to 30% for hematologic malignancies (primarily acute myeloid leukemia) and 25% to 30% for nonhematologic malignancies (solid tumors, particularly of the head and neck, skin, gastrointestinal [GI] tract, and genital tract). Physical abnormalities, including short stature, abnormal skin pigmentation, radial ray defects (including malformation of the thumbs), abnormalities of the urinary tract, eyes, ears, heart, GI system, and central nervous system, hypogonadism, and developmental delay are present in 60% to 75% of affected individuals.
Variants in some of the FA genes, most notably and , but also , (in the RAD51 family of genes), and , among others, may predispose to breast cancer in heterozygotes. Given the widespread availability of multigene (panel) tests, genetic testing of many of the FA genes is frequently performed despite uncertain cancer risks and the lack of available evidence-based medical management recommendations for many of these genes.
FA gene pathogenic variant carrier status can have implications for reproductive decision-making because pathogenic variants in these genes can lead to serious childhood onset of disease if both parents are carriers of pathogenic variants in the same gene. Partner testing may be considered.
(also known as ) encodes a helicase that interacts with the C-terminal (BRCT) domain. This gene also has a role in BRCA1-dependent DNA repair and cell cycle checkpoint function. Biallelic pathogenic variants in are a cause of FA, much like such pathogenic variants in . Inactivating variants of are associated with an increased risk of breast cancer. In one study, more than 3,000 individuals from pathogenic variant–negative families were examined for variants. Pathogenic variants were identified in 9 of 1,212 individuals with breast cancer but in only 2 of 2,081 controls ( = .003). The relative risk (RR) of breast cancer was estimated to be 2.0 (95% confidence interval [CI], 1.2–3.2; = .012). Of note, in families with pathogenic variants and multiple cases of breast cancer, there was incomplete segregation of the pathogenic variant with breast cancer, consistent with a low-penetrance allele and similar to that seen with . In a case-control study of 3,236 women with ovarian cancer, pathogenic variants were more frequently associated with ovarian cancer risk (RR, 11.2; 95% CI, 3.2–34.1).
(OMIM) is a gene involved in the DNA damage repair response pathway. Based on numerous studies, a polymorphism, 1100delC, appears to be a rare, moderate-penetrance cancer susceptibility allele. One study identified the pathogenic variant in 1.2% of the European controls, 4.2% of the European -negative familial breast cancer cases, and 1.4% of unselected female breast cancer cases. In a group of 1,479 Dutch women younger than 50 years with invasive breast cancer, 3.7% were found to have the 1100delC pathogenic variant. In additional European and U.S. (where the pathogenic variant appears to be slightly less common) studies, including a large prospective study, the frequency of pathogenic variants detected in familial breast or ovarian cancer cases has ranged from 0% to 11%; overall, these studies have found an approximately 1.5-fold to 3-fold increased risk of female breast cancer. A multicenter combined analysis and reanalysis of nearly 20,000 subjects from ten case-control studies, however, has verified a significant 2.3-fold excess of breast cancer among carriers of pathogenic variants. A subsequent meta-analysis based on 29,154 cases and 37,064 controls from 25 case-control studies found a significant association between 1100delC heterozygotes and breast cancer risk (odds ratio [OR], 2.75; 95% CI, 2.25–3.36). The ORs and CIs in unselected, familial, and early-onset breast cancer subgroups were 2.33 (1.79–3.05), 3.72 (2.61–5.31), and 2.78 (2.28–3.39), respectively. However, study limitations included pooling of populations without subgroup analysis, using a mix of population-based and hospital-based controls, and basing results on unadjusted estimates (as cases and controls were matched on only a few common factors); therefore, results should be interpreted in the context of these limitations.
Two studies have suggested that the risk associated with a 1100delC pathogenic variant was stronger in the families of probands ascertained because of bilateral breast cancer. Furthermore, a meta-analysis of carriers of 1100delC pathogenic variants estimated the risk of breast cancer to be 42% by age 70 years in women with a family history of breast cancer. Similarly, a Polish study reported that truncating pathogenic variants confer breast cancer risks based on a family history of breast cancer as follows: no family history: 20%; one second-degree relative: 28%; one first-degree relative: 34%; and both first- and second-degree relatives: 44%. Moreover, a Dutch study suggested that female homozygotes for the 1100delC variant have a greater-than-twofold increased breast cancer risk compared with heterozygotes. Although there have been conflicting reports regarding cancers other than breast cancer associated with pathogenic variants, this may be dependent on variant type (i.e., missense vs. truncating) or population studied and is not currently of clinical utility. The contribution of variants to breast cancer may depend on the population studied, with a potentially higher variant prevalence in Poland. Carriers of variants in Poland may be more susceptible to ER-positive breast cancer.
Currently, the clinical applicability of variants remains uncertain because of low variant prevalence and lack of guidelines for clinical management.
A large Dutch study of 86,975 individuals reported an increased risk of cancers other than breast and colon for carriers of the 1100delC pathogenic variant, although additional studies are needed to further refine these risks.
(Refer to the section in the PDQ summary on Genetics of Colorectal Cancer for more information.)
Ataxia telangiectasia (AT) (OMIM) is an autosomal recessive disorder characterized by neurologic deterioration, telangiectasias, immunodeficiency states, and hypersensitivity to ionizing radiation. It is estimated that 1% of the general population may be heterozygote carriers of variants (OMIM). More than 300 variants in the gene have been identified, most of which are truncating variants. ATM proteins have been shown to play a role in cell cycle control. , AT-deficient cells are sensitive to ionizing radiation and radiomimetic drugs, and lack cell cycle regulatory properties after exposure to radiation.
Initial studies searching for an excess of pathogenic variants among breast cancer patients provided conflicting results, perhaps due to study design and variant testing strategies. However, two large epidemiologic studies have demonstrated a statistically increased risk of breast cancer among female heterozygote carriers, with an estimated RR of approximately 2.0. Despite this convincing epidemiologic association, the clinical application of testing for variants is unclear due to the wide spectrum of variants and the logistics of testing. Because the presence of a variant could pose a risk in screening-related radiation exposure, further investigation is needed.
CASP8 and TGFB1
The Breast Cancer Association Consortium (BCAC), an international group of investigators, investigated single nucleotide polymorphisms (SNPs) identified in previous studies as possibly associated with excess breast cancer risk in 15,000 to 20,000 cases and 15,000 to 20,000 controls. Two SNPs, D302H and L10P, were associated with invasive breast cancer with RRs of 0.88 (95% CI, 0.84–0.92) and 1.08 (95% CI, 1.04–1.11), respectively.
and the family of -related genes, also known as paralogs, are thought to encode proteins that are involved in DNA damage repair through homologous recombination and interaction with numerous other DNA repair proteins, including BRCA1 and BRCA2. RAD51 protein plays a central role in single-strand annealing in the DNA damage response. RAD51 recruitment to break sites and recombinational DNA repair depend on the paralogs, although their precise cellular functions are poorly characterized. Variants in these genes are thought to result in loss of RAD51 focus formation in response to DNA damage.
One of five -related genes, has been reported to be linked to both FA-like disorders and familial breast and ovarian cancers. The literature, however, has produced contradictory findings. In a study of 480 German families characterized by breast and ovarian cancers who were negative for and pathogenic variants, six monoallelic variants in were found (frequency of 1.3%). Another study screened 286 -negative patients with breast cancer and/or ovarian cancer and found one likely pathogenic variant in -G153D. pathogenic variants have also been reported in Australian, British, Finnish, and Spanish non- ovarian cancer–only and breast/ovarian cancer families, and in unselected ovarian cancer cases, with frequencies ranging from 0% to 3% in these populations. In a sample of 206 high-risk Jewish women (including 79 of Ashkenazi origin) previously tested for the common Jewish pathogenic variants, two previously described and possibly pathogenic missense variants were detected. Four additional studies were unable to confirm an association between the gene and hereditary breast cancer or ovarian cancer.
In addition to carriers of pathogenic variants, there are other paralogs, including , , and , that may be associated with breast and/or ovarian cancer risk, although the clinical significance of these findings is unknown. In a case-control study of 3,429 ovarian cancer patients, and pathogenic variants were more commonly found in ovarian cancer cases (0.82%) than in controls (0.11%, < .001).
In addition to germline variants, different polymorphisms of have been hypothesized to have reduced capacity to repair DNA defects, resulting in increased susceptibility to familial breast cancer. The Consortium of Investigators of Modifiers of (CIMBA) pooled data from 8,512 carriers of and pathogenic variants and found evidence of an increased risk of breast cancer among women who were carriers and who were homozygous for CC at the 135G→C SNP (hazard ratio, 1.17; 95% CI, 0.91–1.51).
Several meta-analyses have investigated the association between the 135G→C polymorphism and breast cancer risk. There is significant overlap in the studies reported in these meta-analyses, significant variability in the characteristics of the populations included, and significant methodologic limitations to their findings. A meta-analysis of nine epidemiologic studies involving 13,241 cases and 13,203 controls of unknown status found that women carrying the CC genotype had an increased risk of breast cancer compared with women with the GG or GC genotype (OR, 1.35; 95% CI, 1.04–1.74). A meta-analysis of 14 case-control studies involving 12,183 cases and 10,183 controls confirmed an increased risk only for women who were known carriers (OR, 4.92; 95% CI, 1.10–21.83). Another meta-analysis of 12 studies included only studies of known -negative cases and found no association between 135G→C and breast cancer.
In summary, among this conflicting data is substantial evidence for a modest association between germline variants in and breast cancer and ovarian cancer. There is also evidence of an association between polymorphisms in 135G→C among women with homozygous CC genotypes and breast cancer, particularly among carriers. These associations are plausible given the known role of in the maintenance of genomic stability.
Pathogenic variants in the -interacting gene were found in three Finnish breast cancer families and no controls. The significance of this finding outside of this population is not yet known.
Through full exome sequencing among high-risk Polish and Quebec-based French Canadian families, the gene was discovered to harbor multiple rare truncating variants in both populations. (Refer to the Clinical Sequencing section in the Cancer Genetics Overview PDQ summary for more information about whole-exome sequencing.) In the same populations, truncating variants in this gene were also identified in two subsequent validation phases among additional breast cancer patients from high-risk families, and among additional breast cancer cases in which the variant frequency was higher than that observed among controls. Although study results suggest that truncating germline pathogenic variants are associated with an increased risk of breast cancer, the exact magnitude of risk remains uncertain, and future studies are needed to determine clinical usefulness. Furthermore, the significance of this finding outside of these two populations is not yet known.
encodes BRG1 and is a catalytic subunit of the SWI/SNF chromatin remodeling complex, which plays a major role in rendering chromatin accessible to regulation of gene expression.
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive tumor that has an early age at onset (before age 40 years) and a poor prognosis. Familial clustering is sometimes present. SCCOHT tumors may be unilateral or bilateral and have been characterized histologically by the presence of small hyperchromatic cells with brisk mitotic activity. A multimodality approach including surgery, chemotherapy, and radiation therapy has been suggested for the treatment of SCCOHT. Given the paraneoplastic phenomenon of hypercalcemia in 60% of cases, tracking calcium levels is useful in monitoring the course of disease. With a wide range of differential diagnoses including germ cell tumors, sex cord–stromal tumors, and undifferentiated carcinomas, SCCOHT remains classified by the World Health Organization as a "miscellaneous tumor" but more recently has been sequenced to be a malignant rhabdoid tumor. Through exome sequencing, most cases of SCCOHT have been found to lack functional /BRG1; in fact, pathogenic variants in may be the sole variants responsible for SCCOHT.
Despite only approximately 300 cases in the literature, three separate research groups showed SCCOHT to be associated with germline and somatic pathogenic variants in the gene. In one study of 12 young women with SCCOHT, sequencing of paired tumor and normal samples identified inactivating biallelic pathogenic variants in each case. Only four additional nonrecurrent somatic genes were identified in any of the other 278 genes sequenced. Immunohistochemistry demonstrated loss of SMARCA4 protein expression in seven of nine tested cases, consistent with a tumor-suppressor gene function. In a second study of another 12 patients, next-generation sequencing also identified as the only recurrently variant gene, with the majority of variants predicted to result in a truncated protein. A third study included three families in whom whole-exome sequencing with Sanger sequencing confirmation identified at least one germline or somatic pathogenic variant in 24 of 26 cases. Overall, 38 of 43 (88%) of SCCOHT tumors showed loss of SMARCA4 expression, in comparison to only 1 of 139 (0.7%) other ovarian tumor types.
Because of the rarity of this tumor, the penetrance of is unknown. There is currently no consensus for management, yet is on the larger multigene panels currently available for genetic testing, and risk-reducing surgery has been offered to pathogenic variant carriers.
Low-Penetrance Genes and Loci
Polymorphisms underlying polygenic susceptibility to breast and gynecologic cancers are considered low penetrance, a term often applied to sequence variants associated with a minimal to moderate risk. This is in contrast to “high-penetrance” variants or alleles that are typically associated with more severe phenotypes, for example pathogenic variants leading to an autosomal dominant inheritance pattern in a family, and “moderate-penetrance” variants such as , , and . (Refer to the High-Penetrance Genes and the Moderate-Penetrance Genes sections of this summary for more information.) Because these types of sequence variants (also called low-penetrance genes, alleles, variants, and polymorphisms) are relatively common in the general population, their overall contribution to cancer risk is estimated to be much greater than the attributable risk in the population from pathogenic variants in and . For example, it is estimated by segregation analysis that half of all breast cancer occurs in 12% of the population that is deemed most susceptible. There are no known low-penetrance variants in . The N372H variation in , initially thought to be a low-penetrance allele, was not verified in a large combined analysis.
Two strategies have attempted to identify low-penetrance polymorphisms leading to breast cancer susceptibility: candidate gene and genome-wide searches. Both involve the epidemiologic case-control study design. The candidate gene approach involves selecting genes based on their known or presumed biological function, relevance to carcinogenesis or organ physiology, and then searching for or testing known genetic variants for an association with cancer risk. This strategy relies on imperfect and incomplete biological knowledge, and, despite some confirmed associations (described below), has been relatively disappointing. The candidate gene approach has largely been replaced by genome-wide association studies (GWAS) in which a very large number of single nucleotide polymorphisms (SNPs) (approximately 1 million to 5 million) are chosen within the genome and tested, mostly without regard to their possible biological function, but instead to more uniformly capture all genetic variation throughout the genome.
In contrast to assessing candidate genes and/or alleles, GWAS involve comparing a very large set of genetic variants spread throughout the genome. The current paradigm uses sets of as many as 5 million SNPs that are chosen to capture a large portion of common variation within the genome based on the HapMap and the 1000 Genomes Project. By comparing allele frequencies between a large number of cases and controls, typically 1,000 or more of each, and validating promising signals in replication sets of subjects, very robust statistical signals of association have been obtained. The strong correlation between many SNPs that are physically close to each other on the chromosome (linkage disequilibrium) allows one to “scan” the genome for susceptibility alleles even if the biologically relevant variant is not within the tested set of SNPs. Although this between-SNP correlation allows one to interrogate the majority of the genome without having to assay every SNP, when a validated association is obtained, it is not usually obvious which of the many correlated variants is causal.
Genome-wide searches are showing great promise in identifying common, low-penetrance susceptibility alleles for many complex diseases, including breast cancer. The first study involved an initial scan in familial breast cancer cases followed by replication in two large sample sets of sporadic breast cancer, the final being a collection of over 20,000 cases and 20,000 controls from the Breast Cancer Association Consortium. Five distinct genomic regions were identified that were within or near the , , , and genes or at the chromosome 8q region. The 8q region and others may harbor multiple independent loci associated with risk. Subsequent genome-wide studies have replicated these loci and identified additional ones. Numerous SNPs identified through large studies of sporadic breast cancer appear to be associated more strongly with estrogen receptor–positive disease; however, some are associated primarily or exclusively with other subtypes, including triple-negative disease. An online catalog is available of SNP-trait associations from published GWAS for use in investigating genomic characteristics of trait/disease-associated SNPs.
Although the statistical evidence for an association between genetic variation at these loci and breast and ovarian cancer risk is overwhelming, the biologically relevant variants and the mechanism by which they lead to increased risk are unknown and will require further genetic and functional characterization. Additionally, these loci are associated with very modest risk (typically, an odds ratio [OR] <1.5), with more risk variants likely to be identified. No interaction between the SNPs and epidemiologic risk factors for breast cancer have been identified. Furthermore, theoretical models have suggested that common moderate-risk SNPs have limited potential to improve models for individualized risk assessment. These models used receiver operating characteristic (ROC) curve analysis to calculate the area under the curve (AUC) as a measure of discriminatory accuracy. A subsequent study used ROC curve analysis to examine the utility of SNPs in a clinical dataset of more than 5,500 breast cancer cases and nearly 6,000 controls, using a model with traditional risk factors compared with a model using both standard risk factors and ten previously identified SNPs. The addition of genetic information modestly changed the AUC from 58% to 61.8%, a result that was not felt to be clinically significant. Despite this, 32.5% of patients were in a higher quintile of breast cancer risk when genetic information was included, and 20.4% were in a lower quintile of risk. Whether such information has clinical utility is unclear.
More limited data are available regarding ovarian cancer risk. Three GWAS involving staged analysis of more than 10,000 cases and 13,000 controls have been carried out for ovarian cancer. As in other GWAS, the ORs are modest, generally about 1.2 or weaker but implicate a number of genes with plausible biological ties to ovarian cancer, such as , whose protein complexes with and may regulate BRCA1, and , which codes for a poly (ADP-ribose) polymerase, molecules that may be important in-deficient cells.
Because the individual and collective influences of these SNPs on cancer risk have not been evaluated prospectively, they are not considered clinically relevant.
In addition to genome-wide studies interrogating common genetic variants, sequencing-based studies involving whole-genome or whole-exome sequencing are also identifying genes associated with breast cancer, such as , a rare, moderate-penetrance, breast cancer susceptibility gene. (Refer to the Clinical Sequencing section in the Cancer Genetics Overview PDQ summary for more information about whole-exome sequencing.)
Clinical Management of Carriers of BRCA Pathogenic Variants
Increasing data are available on the outcomes of interventions to reduce risk in people with a genetic susceptibility to breast cancer or ovarian cancer. As outlined in other sections of this summary, uncertainty is often considerable regarding the level of cancer risk associated with a positive family history or genetic test. In this setting, personal preferences are likely to be an important factor in patients’ decisions about risk reduction strategies.
Screening and Prevention Strategies
Refer to the PDQ summary on Breast Cancer Screening for information on screening in the general population, and to the PDQ summary Levels of Evidence for Cancer Genetics Studies for information on levels of evidence related to screening and prevention.
In the general population, evidence for the value of breast self-examination (BSE) is limited. Preliminary results have been reported from a randomized study of BSE being conducted in Shanghai, China. At 5 years, no reduction in breast cancer mortality was seen in the BSE group compared with the control group of women, nor was a substantive stage shift seen in breast cancers that were diagnosed. (Refer to the PDQ summary on Breast Cancer Screening for more information.)
Little direct prospective evidence exists regarding BSE in individuals with an increased risk of breast cancer. In the Canadian National Breast Screening Study, women with first-degree relatives (FDRs) with breast cancer had statistically significantly higher BSE competency scores than those without a family history. In a study of 251 high-risk women at a referral center, five breast cancers were detected by self-examination less than a year after a previous screen (as compared with one cancer detected by clinician exam and 11 cancers detected as a result of mammography). Women in the cohort were instructed in self-examination, but it is not stated whether the interval cancers were detected as a result of planned self-examination or incidental discovery of breast masses. In another series of carriers of pathogenic variants, four of nine incident cancers were diagnosed as palpable masses after a reportedly normal mammogram, further suggesting the potential value of self-examination. A task force convened by the Cancer Genetics Studies Consortium has recommended “monthly self-examination beginning early in adult life (e.g., by age 18–21 years) to establish a regular habit and allow familiarity with the normal characteristics of breast tissue. Education and instruction in self-examination are recommended.”
Clinical breast examination
Few prospective data exist regarding clinical breast examination (CBE).
The Cancer Genetics Studies Consortium task force concluded, “As with self-examination, the contribution of clinical examination may be particularly important for women at inherited risk of early breast cancer.” They recommended that female carriers of a or high-risk pathogenic variant undergo annual or semiannual clinical examinations beginning at age 25 to 35 years.
In the general population, strong evidence suggests that regular mammography screening of women aged 50 to 59 years leads to a 25% to 30% reduction in breast cancer mortality. (Refer to the PDQ summary on Breast Cancer Screening for more information.) For women who begin mammographic screening at age 40 to 49 years, a 17% reduction in breast cancer mortality is seen, which occurs 15 years after the start of screening. Observational data from a cohort study of more than 28,000 women suggest that the sensitivity of mammography is lower for young women. In this study, the sensitivity was lowest for younger women (aged 30–49 years) who had a FDR with breast cancer. For these women, mammography detected 69% of breast cancers diagnosed within 13 months of the first screening mammography. By contrast, sensitivity for women younger than 50 years without a family history was 88% ( = .08). For women aged 50 years and older, sensitivity was 93% at 13 months and did not vary by family history. Preliminary data suggest that mammography sensitivity is lower in and carriers than in noncarriers. Subsequent observational studies have found that the positive predictive value (PPV) of mammography increases with age and is highest among older women and among women with a family history of breast cancer. Higher PPVs may be due to increased breast cancer incidence, higher sensitivity, and/or higher specificity. One study found an association between the presence of pushing margins and false-negative mammograms in 28 women, 26 of whom had a pathogenic variant and two of whom had a pathogenic variant. Pushing margins, characteristic of medullary histology, are associated with an absence of fibrotic reaction. In addition, rapid tumor doubling times may lead to tumors presenting shortly after an apparently normal study. In one study, mean tumor doubling time in carriers was 45 days, compared with 84 days in noncarriers. Another study that evaluated mammographic breast density in women with pathogenic variants found no association between pathogenic variant status and mammographic density; however, in both carriers and noncarriers, increased breast density was associated with increased breast cancer risk.
The randomized Canadian National Breast Screening Study-2 compared annual CBE plus mammography to CBE alone in women aged 50 to 59 years from the general population. Both groups were given instruction in BSE. Although mammography detected smaller primary invasive tumors, more invasive cancers, and more ductal carcinoma (DCIS) than CBE, the breast cancer mortality rates in the CBE-plus-mammography group and the CBE-alone group were nearly identical, and compared favorably with other breast cancer screening trials. After a mean follow-up of 13 years (range 11.3–16.0 years), the cumulative breast cancer mortality ratio was 1.02 (95% confidence interval [CI], 0.78–1.33). One possible explanation of this finding was the careful training and supervision of the health professionals performing CBE.
Digital mammography refers to the use of a digital detector to find and record x-ray images. This technology improves contrast resolution and has been proposed as a potential strategy for improving the sensitivity of mammography. A screening study comparing digital with routine mammography in 6,736 examinations of women aged 40 years and older found no difference in cancer detection rates; however, digital mammography resulted in fewer recalls. In another study () comparing digital mammography to plain-film mammography in 42,760 women, the overall diagnostic accuracy of the two techniques was similar. When receiver operating characteristic curves were compared, digital mammography was more accurate in women younger than 50 years, in women with radiographically dense breasts, and in premenopausal or perimenopausal women.
In a prospective study of 251 individuals with pathogenic variants who received uniform recommendations regarding screening and risk-reducing surgery, annual mammography detected breast cancer in six women at a mean of 20.2 months after receipt of results. The Cancer Genetics Studies Consortium task force has recommended for female carriers of a or high-risk pathogenic variant, “annual mammography, beginning at age 25 to 35 years. Mammograms should be done at a consistent location when possible, with prior films available for comparison.” Data from prospective studies on the relative benefits and risks of screening with an ionizing radiation tool versus CBE or other nonionizing radiation tools would be useful.
Certain observations have led to the concern that carriers of pathogenic variants may be more prone to radiation-induced breast cancer than women without pathogenic variants. The BRCA1 and BRCA2 proteins are known to be important in cellular mechanisms of DNA damage repair, including those involved in repairing radiation-induced damage. Some studies have suggested intermediate radiation sensitivity in cells that are heterozygous for a variant, but this is not consistent and varies by experimental system and endpoint.
Three studies have failed to find convincing evidence of an association between ionizing radiation exposure and breast cancer risk in carriers of and pathogenic variants. In contrast, two large international studies found evidence of an increased breast cancer risk due to chest x-rays or estimates of total exposure to diagnostic radiation. A large, international, case-control study of 1,601 carriers of pathogenic variants described an increased risk of breast cancer (hazard ratio [HR], 1.54) among women who were ever exposed to chest x-rays, with risk being highest in women aged 40 years and younger, born after 1949, and exposed to x-rays only before age 20 years. Some of the subjects in this study were also included in a larger, more comprehensive analysis of carriers of pathogenic variants from three European centers. In that study of 1,993 carriers of and pathogenic variants from the United Kingdom, France, and the Netherlands, age-specific total diagnostic radiation exposure (e.g., chest x-rays, mammography, fluoroscopy, and computed tomography) estimates were derived from self-reported questionnaires. Women exposed before age 30 years had an increased risk (HR, 1.90; 95% CI, 1.20–3.00), compared with those never exposed. This risk was primarily driven by nonmammographic radiation exposure in women younger than 20 years (HR, 1.62; 95% CI, 1.02–2.58). Subsequently, a prospective study of 1,844 carriers and 502 carriers without a breast cancer diagnosis at study entry, with an average follow-up time of 5.3 years, observed no significant association between prior mammography exposure and breast cancer risk. Additional subgroup analyses in women younger than 30 years demonstrated no association with breast cancer risk.
With the routine use of magnetic resonance imaging (MRI) in carriers of and pathogenic variants, any potential benefit of mammographic screening must be carefully weighed against potential risks, particularly in young women. One study has suggested that the most cost-effective screening strategy in carriers of and pathogenic variants may be annual MRI beginning at age 25 years, with alternating MRI and digital mammography (so that each test is done annually but screening occurs every 6 months) beginning at age 30 years. The National Comprehensive Cancer Network (NCCN) currently recommends annual MRI screening between ages 25 and 29 years and annual MRI and mammography between ages 30 and 75 years.
Because of the relative insensitivity of mammography in women with an inherited risk of breast cancer, a number of screening modalities have been proposed and investigated in high-risk women, including carriers of pathogenic variants. Many studies have described the experience with breast MRI screening in women at risk of breast cancer, including descriptions of relatively large multi-institutional trials.
Despite some limitations of these studies, they consistently demonstrate that breast MRI is more sensitive than either mammography or ultrasound for the detection of hereditary breast cancer. The results of six large studies are presented in Table 12, Summary of MRI Screening Studies in Women at Hereditary Risk of Breast Cancer. Most cancers in these programs were screen detected, with only 6% of cancers presenting in the interval between screenings. The sensitivity of MRI (as defined by the study methodology) ranged from 71% to 100%. Of the combined studies, 77% of cancers were identified by MRI, and 42% were identified by mammography.
Concerns have been raised about the reduced specificity of MRI compared with other screening modalities. In one study, after the initial MRI screen, 16.5% of patients were recalled for further evaluation and an additional 7.6% of patients were recommended to undergo a short-interval follow-up examination at 6 months. These rates declined significantly during later screening rounds, with fewer than 10% of the subjects recalled for more detailed MRI and fewer than 3% recommended to have short interval follow-up. In a second study, Magnetic Resonance Imaging for Breast Screening (MARIBS), the recall rate for additional evaluation was 10.7% per year. The benign biopsy rates in the first study were 11% at first round, 6.6% at second round, and 4.7% at third round. In the MARIBS study, the aggregate surgical biopsy rate was 9 per 1,000 screening episodes, though this may underestimate the burden because follow-up ultrasounds, core-needle biopsies, and fine-needle aspirations have not been included in the numerator of the MARIBS calculation. The PPV of MRI has been calculated differently in the various series and fluctuates somewhat, depending on whether all abnormal examinations or only the examinations that result in a biopsy are counted in the denominator. Generally, the PPV of a recommendation for tissue sampling (as opposed to further investigation) is in the range of 50% in most series.
These trials appear to establish that MRI is superior to mammography in the detection of hereditary breast cancer, and that women participating in these trials including annual MRI screening were less likely to have a cancer missed by screening. However, mammography may identify some cancers, particularly DCIS, that are not identified by MRI.
Regarding downstaging, one screening study demonstrated that patients at risk of hereditary breast cancer were more likely to be diagnosed with small tumors and node-negative disease than were women in two nonrandomized control groups. However, a randomized study of screening with or without MRI using tumor stage or mortality as an endpoint has not been performed. Despite the apparent sensitivity of MRI screening, some women in MRI-based programs will develop life-threatening breast cancer. In a prospective study of 51 carriers of pathogenic variants and 41 carriers of pathogenic variants screened with yearly mammograms and MRIs (of whom 80 had risk-reducing oophorectomy), 11 breast cancers (9 invasive and 2 DCIS) were detected. Six cancers were first detected on MRI; three were first detected by mammogram; and two were interval cancers. All breast cancers occurred in carriers of pathogenic variants, suggesting a continued high risk of -related breast cancer after oophorectomy in the short term. These results suggest that surveillance and prevention strategies may have differing outcomes in carriers of and pathogenic variants.
A publication combining results from three large studies (MARIBS, a Canadian study, and a Dutch MRI screening study) demonstrated that when MRI was added to mammography, 80% of cancers detected in carriers of pathogenic variants were either DCIS or invasive cancers smaller than 1 cm. In carriers of pathogenic variants, 49% of cancers were DCIS or small invasive cancers. In addition, the authors predicted mortality benefits with the addition of MRI for both carriers of and pathogenic variants. The model predicted breast cancer mortality reductions of 42% to 47% for mammography, 48% to 61% for MRI, and 50% to 62% for combined screening. An additional study examining carriers of pathogenic variants undergoing MRI between 1997 and 2006 has demonstrated that 97% of incident cancers were stage 0 or stage I. The American Cancer Society and NCCN have recommended the use of annual MRI screening for women at hereditary risk of breast cancer.
An additional question regarding the timing of mammography and MRI is whether they should be done simultaneously or in an alternating fashion (so that while each test is done annually, screening occurs every 6 months). One study has suggested that the most cost-effective screening strategy in carriers of and pathogenic variants may be annual MRI beginning at age 25 years, with alternating MRI and digital mammography beginning at age 30 years.
In summary, evidence strongly supports the integral role of breast MRI in breast cancer surveillance for carriers of pathogenic variants.
Several studies have reported instances of breast cancer detected by ultrasound that were missed by mammography, as discussed in one review. In a pilot study of ultrasound as an adjunct to mammography in 149 women with moderately increased risk based on family history, one cancer was detected, based on ultrasound findings. Nine other biopsies of benign lesions were performed. One was based on abnormalities on both mammography and ultrasound, and the remaining eight were based on abnormalities on ultrasound alone. A large study of 2,809 women with dense breast tissue (ACRIN-6666) demonstrated that ultrasound increased the detection rate due to breast cancer screening from 7.6 per 1,000 with mammography alone to 11.8 per 1,000 for combined mammography and ultrasound. However, ultrasound screening increases false-positive rates and appears to have a limited benefit in combination with MRI. In a multicenter study of 171 women (92% of whom were carriers of pathogenic variants) undergoing simultaneous mammography, MRI, and ultrasound, no cancers were detected by ultrasound alone. Uncertainties about ultrasound include the effect of screening on mortality, the rate and outcome of false-positive results, and access to experienced breast ultrasonographers.
Level of evidence: None assigned
Other screening modalities
A number of other techniques are under active investigation, including tomosynthesis, contrast-enhanced mammography, thermography, and radionuclide scanning. Additional evidence is needed before these techniques can be incorporated into clinical practice.
Level of evidence: None assigned
In the general population, both subcutaneous mastectomy and simple (total) mastectomy have been used for prophylaxis. Between 90% and 95% of breast tissue is removed with subcutaneous mastectomy. In a total or simple mastectomy, removal of the nipple-areolar complex increases the proportion of breast tissue removed compared with subcutaneous mastectomy. However, some breast tissue is usually left behind with both procedures.
Because there are no randomized, prospective trials of risk-reducing mastectomy (RRM) versus observation in patients who are considered to be at high risk of developing breast cancer, data are limited to cohort and case-control studies. The available data demonstrate that RRM does decrease breast cancer incidence in high-risk patients, and overall survival (OS) correlates more closely with the overall risk from the primary incidence of breast cancer. In carriers of pathogenic variants with a diagnosis of breast cancer, the risk of a second, unrelated breast cancer is related to age at initial diagnosis, biology, and systemic therapies used. The timing of genetic testing and knowledge of pathogenic variant status may influence surgical decision making and may prevent subsequent surgeries. Therefore, it is important to consider genetic testing in advance of surgery when possible in individuals at increased risk of carrying a pathogenic variant. Although contralateral mastectomy decreases the incidence of contralateral breast cancer, the contralateral surgery itself does not improve mortality, but may decrease morbidity from future local and systemic therapies in cohorts of patients at a high risk of developing breast cancer. However, carriers of pathogenic variants have an even higher risk of developing a subsequent breast cancer. Therefore, in carriers of pathogenic variants whose first cancer has an excellent prognosis, estimating the risk of a second, unrelated breast cancer event is important for informing their decision for risk-reducing surgery and has been described in this setting to improve survival. (Refer to the Contralateral breast cancer in carriers of BRCA pathogenic variants section of this summary for more information about the risk of contralateral breast cancer in this population.)
Several studies have analyzed the impact of RRM on recurrence, contralateral breast cancer risk, and mortality. In one retrospective cohort study of 214 women considered to be at hereditary risk by virtue of a family history suggesting an autosomal dominant predisposition, three women were diagnosed with breast cancer after bilateral RRM, with a median follow-up of 14 years. As 37.4 cancers were expected, the calculated risk reduction was 92% (95% CI, 76.6%–98.3%). In a follow-up subset analysis, 176 of the 214 high-risk women in this cohort study underwent genetic testing for pathogenic variants in and . Variants were found in 26 women (18 deleterious, eight variants of unknown significance). None of those women had developed breast cancer after a median follow-up of 13.4 years. Two of the three women diagnosed with breast cancer after RRM were tested, and neither carried a pathogenic variant. The calculated risk reduction among carriers of pathogenic variants was 89.5% to 100% (95% CI, 41.4%–100%), depending on the assumptions made about the expected numbers of cancers among carriers of pathogenic variants and the status of the untested woman who developed cancer despite mastectomy. The result of this retrospective cohort study has been supported by a prospective analysis of 76 carriers of pathogenic variants undergoing RRM and monitored prospectively for a mean of 2.9 years. No breast cancers were observed in these women, whereas eight were identified in women undergoing regular surveillance (HR for breast cancer after RRM, 0 [95% CI, 0–0.36]).
The Prevention and Observation of Surgical Endpoints study group estimated the degree of breast cancer risk reduction after RRM in carriers of pathogenic variants. The rate of breast cancer in 105 carriers of pathogenic variants who underwent bilateral RRM was compared with that in 378 carriers who did not choose surgery. Bilateral mastectomy reduced the risk of breast cancer by approximately 90% after a mean follow-up of 6.4 years.
Studies of the effectiveness of RRM in women with a unilateral breast cancer, among subsets of women with hereditary breast cancer or significant family histories, have shown a decrease in the rate of contralateral breast cancer. In a group of 148 carriers of and pathogenic variants, 79 of whom underwent RRM, the risk of contralateral cancer was reduced by 91% and was independent of the effect of risk-reducing oophorectomy. Survival was better among women undergoing RRM, but this result was apparently associated with higher mortality due to the index cancer or metachronous ovarian cancer in the group not undergoing surgery. Data from ten European centers on 550 women indicated that RRM was highly effective. A retrospective study of 593 carriers of and pathogenic variants included 105 women with unilateral breast cancer who underwent contralateral RRM and had a 10-year survival rate of 89%, compared with 71% in the group who did not undergo contralateral risk-reducing surgery ( < .001). This study was limited by several factors, such as no information regarding breast cancer screening, grade, and estrogen receptor status in a large portion of this sample.
A meta-analysis of 14 studies evaluated the use of contralateral RRM in women with unilateral breast cancer. The overall analysis demonstrated a synchronous contralateral breast cancer rate of 4.8%, improved OS (1.09; 95% CI, 1.06–1.11), and decreased breast cancer mortality in patients who underwent RRM. When evaluating the rate of metachronous contralateral breast cancer (MCBC) in women who underwent contralateral RRM, the relative risk (RR) of MCBC was 0.04 (95% CI, 0.02–0.09), but it did not reach an absolute reduction in rates of MCBC in this pooled analysis or improve OS. These findings suggest that the rate of MCBC is very low and that the OS difference in the meta-analysis of patients who underwent contralateral RRM is likely due to multiple other confounding and/or selection biases, such as earlier stages of disease, overall health status, survival bias, and potentially the influence of systemic therapies. Two of the studies included confirmed carriers of pathogenic variants only, and several studies included the influence of a family history of breast cancer. Among women with a familial and/or genetic risk of MCBC, there was a decrease in MCBC in patients who underwent contralateral RRM in this meta-analysis, but there was no improvement in OS.
A Dutch cohort of 583 patients identified between 1980 and 2011, who had both a pathogenic variant and a diagnosis of unilateral breast cancer, were evaluated for the effect of contralateral RRM. With a median follow-up of 11.4 years, 242 (42%) of the patients underwent RRM (193 carriers of pathogenic variants and 49 carriers of pathogenic variants) at differing times after their diagnoses. Improved OS was observed in the RRM group compared with the surveillance group (HR, 0.49; 95% CI, 0.29–0.82), with improvements most pronounced in those diagnosed before age 40 years, with low tumor grade, and non–triple-negative subtype. In an attempt to control for the bias of time to surgery, the authors included a separate evaluation of women who were known to be disease free 2 years after the primary cancer diagnosis (HR, 0.55; 95% CI, 0.32–0.95). Additionally, the group who underwent RRM was more likely to undergo bilateral salpingo-oophorectomy and systemic chemotherapy, which may influence the significance of these survival findings.
A retrospective study of 390 women with early-stage breast cancer who were from families with a known pathogenic variant found a significant improvement in survival for women who underwent bilateral mastectomy compared with those who chose unilateral mastectomy. A multivariate analysis controlling for age at diagnosis, year of diagnosis, and treatment and other prognostic factors found that contralateral mastectomy was associated with a 48% reduction in death from breast cancer. This was a relatively small study with a high potential for confounding of prognostic factors.
Studies describing histopathologic findings in RRM specimens from women with or pathogenic variants have been somewhat inconsistent. In two series, proliferative lesions associated with an increased risk of breast cancer (lobular carcinoma , atypical lobular hyperplasia, atypical ductal hyperplasia, DCIS) were noted in 37% to 46% of women with pathogenic variants undergoing either unilateral or bilateral RRM. In these series, 13% to 15% of patients were found to have previously unsuspected DCIS in the prophylactically removed breast. Among 47 cases of risk-reducing bilateral or contralateral mastectomies performed in known carriers of or pathogenic variants from Australia, three (6%) cancers were detected at surgery. In a study from Sweden among 100 women with a hereditary risk of breast cancer, unsuspected lesions were found in 13 out of 50 carriers of pathogenic variants. These findings were not replicated in a third retrospective cohort study. In this study, proliferative fibrocystic changes were noted in none of 11 bilateral mastectomies from patients with pathogenic variants and in only two of seven contralateral RRMs in affected carriers of pathogenic variants.
All of these studies are limited by the biases introduced in relatively small, retrospective studies among very select populations. There is often limited data on potential confounding variables such as socioeconomic status, comorbidities, and access to care. It has been suggested that women who elect to undergo RRM are healthier by virtue of being able to tolerate more-extensive surgery. This theory is supported by one study that used Surveillance, Epidemiology, and End Results Program data to examine the association of contralateral RRM with outcome among women with unilateral breast cancer stages I through III. Results showed a reduction in all-cause mortality and breast cancer-specific mortality, and also in noncancer event mortality, a finding that would not be expected to be related to contralateral RRM.
Although data are sparse, the evidence indicates that while a substantial proportion of women with a strong family history of breast cancer are interested in discussing RRM as a treatment option, uptake varies according to culture, geography, health care system, insurance coverage, provider attitudes, and other social factors. For example, in one setting where the providers made one or two field trips to family gatherings for family information sessions and individual counseling, only 3% of unaffected carriers obtained RRM within 1 year of follow-up. Among women at increased risk of breast cancer due to family history, fewer than 10% opted for mastectomy. Selection of this option was related to breast cancer–related worry as opposed to objective risk parameters (e.g., number of relatives with breast cancer). In contrast, in a Dutch study of highly motivated women being followed up every 6 months at a high-risk center, more than half (51%) of unaffected carriers opted for RRM. Almost 90% of the RRM surgeries were performed within 1 year of DNA testing. In this study, those most likely to have RRM were women younger than 55 years and with children. In addition, self-perceived risk has been closely linked to interest in RRM.
Assuming risk reduction in the range of 90%, a theoretical model suggests that for a group of 30-year-old women with or pathogenic variants, RRM would result in an average increased life expectancy of 2.9 to 5.3 years. While these data are useful for public policy decisions, they cannot be individualized for clinical care as they include assumptions that cannot be fully tested. Another study of at-risk women showed a 70% time-tradeoff value, indicating that the women were willing to sacrifice 30% of life expectancy in order to avoid RRM. A cost-effectiveness analysis study estimated that risk-reducing surgery (mastectomy and oophorectomy) is cost-effective compared with surveillance with regard to years of life saved, but not for improved quality of life.
A computer-simulated survival analysis using a Monte Carlo model included breast MRI, mammography, RRM, and risk-reducing salpingo-oophorectomy (RRSO) and examined the impact of each of these separately on carriers of and pathogenic variants. The most effective strategy was found to be RRSO at age 40 years and RRM at age 25 years, in which case survival at age 70 years approached that of the general population. However, delaying mastectomy until age 40 years, or substituting RRM with screening with breast MRI and mammogram, had little impact on survival estimates. For example, replacing RRM with MRI-based screening in women with RRSO at age 40 years led to a 3% to 5% decrement in survival compared with RRM at age 25 years. The authors have developed an online tool. As with any model, uncertainty remains due to numerous assumptions; however, this provides additional information for women and their providers who are making these difficult decisions.
The option of nipple-sparing mastectomy (NSM) in carriers of pathogenic variants undergoing risk-reducing procedures has been controversial because of concerns of increased breast tissue left behind at surgery to keep the nipple-areolar complex (NAC) viable. Additionally, the ability to leave behind minimal residual tissue may be related to experience and technique. In a retrospective review of NSM in carriers of pathogenic variants performed at two hospitals between 2007 and 2014, NSM was performed on 397 breasts in 201 carriers of pathogenic variants. Incidental cancers were found in 4 of 150 RRM patients (2.7%) and 2 of 51 cancer patients (3.9%). With a mean follow-up of 32.6 months (range, 1–76 months), there were four subsequent cancer events that included two patients with axillary recurrences, one with a local and distant recurrence 11 months after her original NSM, and one patient who developed a new cancer in the inferior portion of her breast, with no recurrences at the NAC. A study of 177 NSMs in 89 carriers of pathogenic variants performed between 2005 and 2013 reported similar, excellent local control rates. Sixty-three patients had risk-reducing NSM (median follow-up, 26 months; range, 11–42 months), and 26 patients had NSM and a diagnosis of breast cancer (median follow-up, 28 months; range, 15–43 months). Five patients required further nipple excision. There were no local recurrences or newly diagnosed breast cancers.
The Society of Surgical Oncology has endorsed RRM as an option for women with pathogenic variants or strong family histories of breast cancer.
Individual psychological factors have an important role in decision-making about RRM by unaffected women. Research is emerging about psychosocial outcomes of RRM. (Refer to the Psychosocial Outcome Studies section of this summary for more information.)
Risk-reducing salpingo-oophorectomy (RRSO)
In the general population, removal of both ovaries has been associated with a reduction in breast cancer risk of up to 75%, depending on parity, weight, and age at time of artificial menopause. (Refer to the PDQ summary on Breast Cancer Prevention for more information.) A Mayo Clinic study of 680 women at various levels of familial risk found that in women younger than 60 years who had bilateral oophorectomy, the likelihood of breast cancers developing was reduced for all risk groups. Ovarian ablation, however, is associated with important side effects such as hot flashes, impaired sleep habits, vaginal dryness, dyspareunia, and increased risk of osteoporosis and heart disease. A variety of strategies may be necessary to counteract the adverse effects of ovarian ablation.
The evidence for the effect of RRSO on breast cancer has evolved. Early small studies suggested a protective benefit. Initial retrospective studies supported breast cancer and ovarian cancer risk reduction after RRSO in pathogenic variant–positive women. In support of early small studies, a retrospective study of 551 women with disease-associated or variants found a significant reduction in risk of breast cancer (HR, 0.47; 95% CI, 0.29–0.77) and ovarian cancer (HR, 0.04; 95% CI, 0.01–0.16) after RRSO. A prospective, single-institution study of 170 women with or pathogenic variants showed a similar trend. With RRSO, the HR was 0.15 (95% CI, 0.02–1.31) for ovarian, fallopian tube, or primary peritoneal cancer, and 0.32 (95% CI, 0.08–1.2) for breast cancer; the HR for either cancer was 0.25 (95% CI, 0.08–0.74). A prospective, multicenter study of 1,079 women followed up for a median of 30 to 35 months found that while RRSO was associated with reductions in breast cancer risk in both carriers of and pathogenic variants, the risk reduction was more pronounced in carriers (HR, 0.28; 95% CI, 0.08–0.92). A meta-analysis of all reports of RRSO and breast and ovarian/fallopian tube cancer in carriers of pathogenic variants confirmed that RRSO was associated with a significant reduction in breast cancer risk (overall: HR, 0.49; 95% CI, 0.37–0.65; : HR, 0.47; 95% CI, 0.35–0.64; : HR, 0.47; 95% CI, 0.26–0.84). However, a cohort study of 822 carriers of pathogenic variants conducted in the Netherlands, where carrier screening is performed nationwide, did not observe a reduced risk of breast cancer after RRSO (HR, 1.09; 95% CI, 0.67–1.77). The authors argued that the previous findings were driven by methodological issues including cancer-induced testing bias and immortal person time, and empirically evaluated this by using their own cohort and applying the same assumptions about counting person time from previous studies. In a response, investigators from the U.S. studies analyzed their data using the assumptions of the Dutch study but still observed an inverse association with RRSO and breast cancer risk. In a retrospective cohort of 676 women, carriers having an RRSO at the time of breast cancer diagnosis had a reduced risk of breast cancer–specific mortality (HR, 0.38; 95% CI, 0.19–0.77 for carriers and HR, 0.57; 95% CI, 0.23–1.43 for carriers). A subsequent international, multi-institutional study of 3,722 and carriers using a similar methodology showed that oophorectomy performed before age 50 years was beneficial for preventing breast cancer in carriers (HR, 0.18; 95% CI, 0.05–0.63; = .007) but not in carriers.
A prospective, multicenter, cohort study of 2,482 carriers of pathogenic variants has reported an association of RRSO with a reduction in all-cause mortality (HR, 0.40; 95% CI, 0.26–0.61), breast cancer–specific mortality (HR, 0.44; 95% CI, 0.26–0.76), and ovarian cancer–specific mortality (HR, 0.21; 95% CI, 0.06–0.80). A subsequent meta-analysis confirmed the impact of RRSO on all-cause mortality (HR, 0.32; 95% CI, 0.27–0.38) in carriers of and pathogenic variants, including those with and without a personal history of breast cancer.
Despite discordant findings regarding RRSO and breast cancer risk in the existing literature, aggregate data suggest that there is a benefit, although the magnitude of this benefit may not be fully understood. Further prospective studies are needed to confirm these findings.
Refer to the RRSO section in the Ovarian cancer section of this summary for more information about the effect of RRSO on ovarian cancer risk in carriers of pathogenic variants.
Tamoxifen (a synthetic antiestrogen) increases breast-cell growth inhibitory factors and concomitantly reduces breast-cell growth stimulatory factors. The National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (NSABP-P-1), a prospective, randomized, double-blind trial, compared tamoxifen (20 mg/day) with placebo for 5 years. Tamoxifen was shown to reduce the risk of invasive breast cancer by 49%. The protective effect was largely confined to ER-positive breast cancer, which was reduced by 69%. The incidence of ER-negative cancer was not significantly reduced. Similar reductions were noted in the risk of preinvasive breast cancer. Reductions in breast cancer risk were noted both among women with a family history of breast cancer and in those without a family history. An increased incidence of endometrial cancers and thrombotic events occurred among women older than 50 years. Interim data from two European tamoxifen prevention trials did not show a reduction in breast cancer risk with tamoxifen after a median follow-up of 48 months or 70 months, respectively. In one trial, however, reduction in breast cancer risk was seen among a subgroup who also used hormone replacement therapy (HRT). These trials varied considerably in study design and populations. (Refer to the PDQ summary on Breast Cancer Prevention for more information.)
Subsequently, the International Breast Cancer Intervention Study 1 (IBIS-1) breast cancer prevention trial randomly assigned 7,154 women between the ages of 35 and 70 years to receive tamoxifen or placebo for 5 years. Eligibility for the trial was based on family history or abnormal benign breast disease. At a median follow-up of 16 years, there was a 29% reduction in risk of breast cancer in the tamoxifen arm (HR, 0.71; 95% CI, 0.60–0.83). There was a 43% reduction in risk for invasive ER-positive breast cancer (HR, 0.66; 95% CI, 0.54–0.81) and a 35% reduction in risk for DCIS (HR, 0.65; 95% CI 0.43–1.00). There was no reduction in risk of invasive ER-negative breast cancer. These findings confirm those of the Breast Cancer Prevention Trial (P-1).
A substudy of the NSABP-P-1 trial evaluated the effectiveness of tamoxifen in preventing breast cancer in carriers of pathogenic variants older than 35 years. -positive women benefited from tamoxifen to the same extent as pathogenic variant–negative participants; however, tamoxifen use among healthy women with pathogenic variants did not appear to reduce breast cancer incidence. These data must be viewed with caution in view of the small number of carriers of pathogenic variants in the sample (8 carriers and 11 carriers).
In contrast to the very limited data on primary prevention in carriers of and pathogenic variants with tamoxifen, several studies have found a protective effect of tamoxifen on the risk of contralateral breast cancer. In one study involving approximately 600 carriers of pathogenic variants, tamoxifen use was associated with a 51% reduction in contralateral breast cancer. An update to this report examined 285 carriers of pathogenic variants with bilateral breast cancer and 751 carriers of pathogenic variants with unilateral breast cancer (40% of these patients were included in their initial study). Tamoxifen was associated with a 50% reduction in contralateral breast cancer risk in carriers of pathogenic variants and a 58% reduction in carriers of pathogenic variants. Tamoxifen did not appear to confer benefit in women who had undergone an oophorectomy, although the numbers in this subgroup were quite small. Another study that involved 160 carriers of pathogenic variants demonstrated that tamoxifen use after the treatment of breast cancer with lumpectomy and radiation was associated with a 69% reduction in the risk of contralateral breast cancer. In another study, 2,464 carriers of pathogenic variants with a personal history of breast cancer were identified from three family cohorts. Using both retrospective and prospective data, researchers found a significant decrease in the risk of contralateral breast cancer among women who received adjuvant tamoxifen therapy after their diagnosis. This association persisted after researchers adjusted for age at diagnosis and the ER status of the first cancer. A major limitation of this study is the lack of information on ER status of the first breast cancer in 56% of the women. These studies are limited by their retrospective, case-control designs and the absence of information regarding ER status in the primary tumor.
The (NSABP-P-2) included more than 19,000 women and compared 5 years of raloxifene versus tamoxifen in reducing the risk of invasive breast cancer. There was no difference in incidence of invasive breast cancer at a mean follow-up of 3.9 years; however, there were fewer noninvasive cancers in the tamoxifen group. The incidence of thromboembolic events and hysterectomy was significantly lower in the raloxifene group. Detailed quality-of-life data demonstrate slight differences between the two arms. Data regarding efficacy in carriers of or pathogenic variants are not available. (Refer to the PDQ summary on Breast Cancer Prevention for more information about the use of selective ER modulators and aromatase inhibitors in the general population, including postmenopausal women.)
Another case-control study of carriers of pathogenic variants and noncarriers identified through ascertainment of women with bilateral breast cancer found that systemic adjuvant chemotherapy reduced CBC risk among carriers of pathogenic variants (RR, 0.5; 95% CI, 0.2–1.0). Tamoxifen was associated with a nonsignificant risk reduction (RR, 0.7; 95% CI, 0.3–1.8). Similar risk reduction was seen in noncarriers; however, given the higher absolute CBC risk in carriers, there is potentially a greater impact of adjuvant treatment in risk reduction.
The effect of tamoxifen on ovarian cancer risk was studied in 714 carriers of pathogenic variants. All subjects had a prior history of breast cancer; use of tamoxifen was not associated with an increased risk of subsequent ovarian cancer (odds ratio [OR], 0.78; 95% CI, 0.46–1.33).
In the general population, breast cancer risk increases with early menarche and late menopause, and is reduced at early first full-term pregnancy. (Refer to the PDQ summary on Breast Cancer Prevention for more information.) In the Nurses’ Health Study, these were risk factors among women who did not have a mother or sister with breast cancer. Among women with a family history of breast cancer, pregnancy at any age appeared to be associated with an increase in risk of breast cancer, persisting to age 70 years.
One study evaluated risk modifiers among 333 female carriers of a high-risk pathogenic variant. In women with known pathogenic variants of the gene, early age at first live birth and parity of three or more have been associated with a lowered risk of breast cancer. A RR of 0.85 was estimated for each additional birth, up to five or more; however, increasing parity appeared to be associated with an increased risk of ovarian cancer. In a case-control study from New Zealand, investigators noted no difference in the impact of parity on the risk of breast cancer between women with a family history of breast cancer and those without a family history.
Studies of the effect of pregnancy on breast cancer risk have revealed complex results and the relationship with parity has been inconsistent and may vary between carriers of and pathogenic variants. Parity has more consistently been associated with a reduced risk of breast cancer in carriers of pathogenic variants. Of note, neither therapeutic nor spontaneous abortions appear to be associated with an increased breast cancer risk.
In the general population, breastfeeding has been associated with a slight reduction in breast cancer risk in a few studies, including a large collaborative reanalysis of multiple epidemiologic studies, and at least one study suggests that it may be protective in carriers of pathogenic variants. In a multicenter, case-control study of 685 carriers of pathogenic variants with breast cancer and 280 carriers of pathogenic variants with breast cancer and 965 carriers without breast cancer drawn from multiple-case families, among carriers of pathogenic variants, breastfeeding for 1 year or more was associated with approximately a 45% reduced risk of breast cancer. No such reduced risk was observed among carriers of pathogenic variants. A second study failed to confirm this association.
There is no consistent evidence that the use of oral contraceptives (OCs) increases the risk of breast cancer in the general population. (Refer to the PDQ summary on Breast Cancer Prevention for more information.)
Although several smaller studies have reported a slightly increased risk of breast cancer with OC use in carriers of pathogenic variants, a meta-analysis concluded that the associated risk is not significant with more recent OC formulations. However, OCs formulated before 1975 were associated with an increased risk of breast cancer. A large proportion of patients on whom this meta-analysis was based were drawn from three large studies summarized in Table 13.
When patients are counseled about contraceptive options and preventive actions, the potential impact of OC use on the risk of breast cancer and ovarian cancer and other health-related effects of OCs need to be considered. A number of important issues remain unresolved, including the potential differences between carriers of or pathogenic variants, effect of age and duration of exposure, and effect of OCs on families with highly penetrant early-onset breast cancer.
(Refer to the Oral contraceptives section in the Chemoprevention section of this summary for a discussion of OC use and ovarian cancer in this population.)
Hormone replacement therapy (HRT)
Both observational and randomized clinical trial data suggest an increased risk of breast cancer associated with HRT in the general population. The Women’s Health Initiative (WHI) was a randomized controlled trial of approximately 160,000 postmenopausal women that investigated the risks and benefits of dietary interventions and hormone therapy to reduce the incidence of heart disease, breast cancer, colorectal cancer, and fractures. The estrogen-plus-progestin arm of the study, in which more than 16,000 women were randomly assigned to receive combined hormone therapy or placebo, was halted early because health risks exceeded benefits. One of the adverse outcomes prompting closure was a significant increase in both total (245 vs. 185 cases) and invasive (199 vs. 150) breast cancers (RR, 1.24; 95% CI, 1.02–1.50; < .001) in women randomly assigned to receive estrogen and progestin. Results of a follow-up study suggest that the recent reduction in breast cancer incidence, especially among women aged 50 to 69 years, is predominantly related to decrease in use of combined estrogen plus progestin HRT. HRT-related breast cancers had adverse prognostic characteristics (more advanced stages and larger tumors) compared with cancers occurring in the placebo group, and HRT was also associated with a substantial increase in abnormal mammograms.
Breast cancer risk associated with postmenopausal HRT has been variably reported to be increased or unaffected by a family history of breast cancer; risk did not vary by family history in the meta-analysis. The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for pathogenic variants. Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk in the general population.
HRT in carriers of BRCA1/BRCA2 pathogenic variants
The effect of HRT on breast cancer risk among carriers of a or pathogenic variant has been examined in two studies. In a prospective study of 462 carriers of and pathogenic variants, bilateral RRSO (n = 155) was significantly associated with breast cancer risk-reduction overall (HR, 0.40; 95% CI, 0.18–0.92). When carriers of pathogenic variants without bilateral RRSO or HRT were used as the comparison group, HRT use (n = 93) did not significantly alter the reduction in breast cancer risk associated with bilateral RRSO (HR, 0.37; 95% CI, 0.14–0.96). In a matched case-control study of 472 postmenopausal women with pathogenic variants, HRT use was associated with an overall reduction in breast cancer risk (OR, 0.58; 95% CI, 0.35–0.96; = .03). A nonsignificant reduction in risk was observed both in women who had undergone bilateral oophorectomy and in those who had not. Women taking estrogen alone had an OR of 0.51 (95% CI, 0.27–0.98; = .04), while the association with estrogen and progesterone was not statistically significant (OR, 0.66; 95% CI, 0.34–1.27; = .21). A case-control study of 432 matched pairs of postmenopausal women with a pathogenic variant who had a personal history of cancer were compared with unaffected carriers. The use of HRT was not associated with an increased risk of developing breast cancer (OR, 0.80; = .24). Especially given the differences in estimated risk associated with HRT between observational studies and the WHI, these findings should be confirmed in randomized prospective studies, but they suggest that HRT in carriers of pathogenic variants neither increases breast cancer risk nor negates the protective effect of oophorectomy.
Refer to the PDQ summary on Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Screening for information on screening in the general population and to the PDQ summary Levels of Evidence for Cancer Genetics Studies for information about levels of evidence related to screening and prevention. The latter also outlines the five requirements that must be met before it is considered appropriate to screen for a particular medical condition as part of routine medical practice.
In the general population, clinical examination of the ovaries has neither the specificity nor the sensitivity to reliably identify early ovarian cancer. No data exist regarding the benefit of clinical examination of the ovaries (bimanual pelvic examination) in women at inherited risk of ovarian cancer.
Level of evidence: None assigned
In the general population, transvaginal ultrasound (TVUS) appears to be superior to transabdominal ultrasound in the preoperative diagnosis of adnexal masses. Both techniques have lower specificity in premenopausal women than in postmenopausal women due to the cyclic menstrual changes in premenopausal ovaries (e.g., transient corpus luteum cysts) that can cause difficulty in interpretation. The randomized prospective Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial () found no reduction in mortality with the annual use of combined TVUS and cancer antigen 125 (CA-125) in screening asymptomatic postmenopausal women at general-population risk of ovarian cancer.
Data are limited regarding the potential benefit of TVUS in screening women at inherited risk of ovarian cancer. A number of retrospective studies have reported experience with ovarian cancer screening in high-risk women using TVUS with or without CA-125. However, there is little uniformity in the definition of high-risk criteria and compliance with screening, and in whether cancers detected were incident or prevalent. One of the largest reported studies included 888 carriers of pathogenic variants who were screened annually with TVUS and CA-125. Ten women developed ovarian cancer; five of the ten developed interval cancers after normal screening results within 3 to 10 months before diagnosis. Five of the ten ovarian cancers were screen-detected incident cases, which had normal screening results within 6 to 14 months before diagnosis. Of these five cases, four were stage IIIB or IV.
A similar study reported the results of annual TVUS and CA-125 in a cohort of 312 high-risk women (152 carriers of pathogenic variants). Of the four cancers that were detected due to abnormal TVUS and CA-125, all four patients were symptomatic, and three had advanced-stage disease. Annual screening of carriers of pathogenic variants with pelvic ultrasound, TVUS, and CA-125 failed to detect early-stage ovarian cancer among 241 carriers of pathogenic variants in a study from the Netherlands. Three cancers were detected over the course of the study, all advanced stage IIIC disease. Finally, a study of 1,100 moderate- and high-risk women who underwent annual TVUS and CA-125 reported that ten of 13 ovarian tumors were detected due to screening. Only five of ten were stage I or II. There are limited data related to the efficacy of semiannual screening with TVUS and CA-125.
In the United Kingdom Familial Ovarian Cancer Screening Study, 3,563 women with an estimated 10% or higher lifetime risk of ovarian cancer were screened with annual ultrasound and serum CA-125 measurements for a mean of 3.2 years. Four of 13 screen-detected cancers were stage I or II. Women screened within the previous year were less likely to have higher than stage IIIC disease; there was also a trend towards better rates of optimal cytoreduction and improved OS. Furthermore, most of the cancers occurred in women with known ovarian cancer susceptibility genes, identifying a cohort at highest cancer risk for consideration of screening. Phase II of this study increased the frequency of screening to every 4 months; the impact of this is not yet available.
The first prospective study of TVUS and CA-125 with survival as the primary outcome was completed in 2009. Of the 3,532 high-risk women screened, 981 were carriers of pathogenic variants, 49 of whom developed ovarian cancer. The 5- and 10-year survival was 58.6% (95% CI, 50.9%–66.3%) and 36% (95% CI, 27–45), respectively, and there was no difference in survival between carriers and noncarriers. A major limitation of the study was the absence of a control group. Despite limitations, this study suggests that annual surveillance by TVUS and CA-125 level appear to be ineffective in detecting tumors at an early stage to substantially influence survival.
Serum CA-125 screening for ovarian cancer in high-risk women has been evaluated in combination with TVUS in a number of retrospective studies, as described in the previous section.
The National Institutes of Health (NIH) Consensus Statement on Ovarian Cancer recommended against routine screening of the general population for ovarian cancer with serum CA-125. (Refer to the Combined CA-125 and TVU section in the PDQ summary on Ovarian Cancer Screening for more information.) The NIH Consensus Statement did, however, recommend that women at inherited risk of ovarian cancer undergo TVUS and serum CA-125 screening every 6 to 12 months, beginning at age 35 years. The Cancer Genetics Studies Consortium task force has recommended that female carriers of a pathogenic variant undergo annual or semiannual screening using TVUS and serum CA-125 levels, beginning at age 25 to 35 years. Both recommendations are based solely on expert opinion and best clinical judgment.
Other candidate ovarian cancer biomarkers
The need for effective ovarian cancer screening is particularly important for women carrying and pathogenic variants, and the mismatch repair (MMR) genes (e.g., , , , ), disorders in which the risk of ovarian cancer is high. There is a special sense of urgency for carriers of pathogenic variants, in whom cumulative lifetime risks of ovarian cancer may exceed 40%.
Thus, it is expected that many new ovarian cancer biomarkers (either singly or in combination) will be proposed as ovarian cancer screening strategies during the next 5 to 10 years. While this is an active area of research with a number of promising new biomarkers in early development, at present, none of these biomarkers alone or in combination have been sufficiently well studied to justify their routine clinical use for screening purposes, either in the general population or in women at increased genetic risk.
Before information related to emerging ovarian cancer biomarkers is addressed, it is important to consider the several steps that are required to develop and, more importantly, validate a new biomarker. One useful framework is that published by the National Cancer Institute Early Detection Research Network investigators. They indicated that the goal of a cancer-screening program is to detect tumors at an early stage so that treatment is likely to be successful. The gold standard by which such programs are judged is whether the death rate from the cancer for which screening is performed is reduced among those being screened. In addition, the screening test must be sufficiently noninvasive and inexpensive to allow widespread use in the population to be screened. Maintaining high test specificity (i.e., few false-positive results) is essential for a population screening test, because even a low false-positive rate results in many people having to undergo unnecessary and costly diagnostic procedures and psychological stress. It is likely that the use of several such cancer biomarkers in combination will be required for a screening test to be both sensitive and specific.
Furthermore, a clinically useful test must have a high PPV (a parameter derived from sensitivity, specificity, and disease prevalence in the screened population). Practically speaking, a biomarker with a PPV of 10% implies that ten surgical procedures would be required to identify one case of ovarian cancer; the remaining nine surgeries would represent false-positive test findings. In general, the ovarian cancer research community considers biomarkers with a PPV less than 10% to be clinically unacceptable, given the morbidity related to bilateral salpingo-oophorectomy. Finally, it is important to keep in mind that while novel biomarkers may be present in the sera of women with advanced ovarian cancer (who represent most cases analyzed in the early phases of biomarker development), they may or may not be detectable in women with early-stage disease, which is essential if the screening test is to be clinically useful.
It has been suggested that there are five general phases in biomarker development and validation are currently suggested:
- Identify potentially discriminating biomarkers.
- Usually done by comparing gene over- or underexpression in the tumor compared with normal tissue.
- Because many exploratory analyses in large numbers of genes are performed at this stage, one or more may seem to have good discriminating ability between cancers and normal tissue by random chance alone.
- Develop a clinical assay that can be obtained on noninvasively obtained samples (e.g., a blood specimen).
- Often the test targets the protein product of one of the genes found to be of interest in phase I.
- The goal is to describe the performance characteristics of the assay for distinguishing between subjects with and without cancer. At this point, the assay should be in its final configuration and remain stable throughout the following phases.
- IMPORTANT: Because the case subjects in a phase 2 study already have cancer, with assay results obtained at the time of disease diagnosis, one cannot determine whether disease can be detected early with a given biomarker.
- Compare clinical specimens collected from cancer case subjects before their clinical diagnosis with specimens from subjects who have not developed cancer.
- Evaluate, as a function of time before clinical diagnosis, the biomarker’s ability to detect preclinical disease.
- Define the criteria for a positive screening test in preparation for phase 4.
- Explore the influence of other patient characteristics (e.g., age, gender, smoking status, medication use) on the ability of the biomarker to discriminate between those with and without preclinical disease.
- Determine the operating characteristics of the biomarker-based screening test in a population for which the test is intended.
- Measure the detection rate (number of abnormal tests among all those with the disease) and the false-positive rate (the number of abnormal tests among all those who do not have the disease).
- Evaluate whether the cancers detected by the test are being found at an early stage, a point at which treatment is more likely to be curative.
- Assess whether the test is acceptable in a population of persons for whom it is intended. Will subjects comply with the test schedule and results?
- Ideally, conduct randomized controlled clinical trials in clinically relevant populations, in which one arm is subjected to screening and appropriate intervention if screen-positive, while the other arm is not screened.
- Determine whether the death rate of the cancer being screened for is reduced among those who use the screening test.
- Obtain information about the costs of screening and treatment of screen-detected cancers.
Finally, for a validated biomarker test to be considered appropriate for use in a particular population, it must have been evaluated in that specific population without prior selection of known positives and negatives. In addition, the test must demonstrate clinical utility, that is, a positive net balance of benefits and risks associated with the application of the test. These may include improved health outcomes and net psychosocial and economic benefits.
Ovarian cancer poses a unique challenge relative to the potential impact of false-positive test results. There are no reliable noninvasive diagnostic tests for early-stage disease, and clinically significant early-stage cancer may not be grossly visible at the time of exploratory surgery. Consequently, it is likely that some patients will be reassured that their abnormal test does not indicate the presence of cancer only by having their ovaries and fallopian tubes surgically removed and examined microscopically. High test specificity (i.e., a very low false-positive rate) is required to avoid unnecessary surgery and induction of premature menopause women with in false-positive results.
Variations on CA-125
CA-125 plus an ovarian cancer symptom index
An ovarian cancer symptom index for predicting the presence of cancer was evaluated in 75 cases and 254 high-risk controls (carriers of pathogenic variants or women with a strong family history of breast and ovarian cancer). Women had a positive symptom index if they reported any of the predefined symptoms (bloating or increase in abdominal size, abdominal or pelvic pain, and difficulty eating or feeling full quickly) more than 12 times per month, occurring only within the prior 12 months. CA-125 values greater than 30 U/mL were considered abnormal. The symptom index independently predicted the presence of ovarian cancer, after controlling for CA-125 levels ( < .05). The combination of an elevated CA-125 and a positive-symptom index correctly identified 89.3% of the cases. The symptom index correlated with the presence of cancer in 50% of the affected women who did not have elevated CA-125 levels, but 11.8% of the high-risk controls without cancer also had a positive-symptom index. The authors suggested that a composite index that included both CA-125 and the symptom index had better performance characteristics than either test used alone, and that this strategy might be used as a first screen in a multistep screening program. Additional test performance validation and determination of clinical utility are required in unselected screening populations.
Risk of ovarian cancer algorithm
A novel modification of CA-125 screening is based on the hypothesis that rising CA-125 levels over time may provide better ovarian cancer screening performance characteristics than simply classifying CA-125 as normal or abnormal based on an arbitrary cut-off value. This has been implemented in the form of the risk of ovarian cancer algorithm (ROCA), an investigational statistical model that incorporates serial CA-125 test results and other covariates into a computation that produces an estimate of the likelihood that ovarian cancer is present in the screened subject. The first report of this strategy, based on reanalysis of 5,550 average-risk women from the Stockholm Ovarian Cancer screening trial, suggested that ovarian cancer cases and controls could be distinguished with 99.7% sensitivity, 83% specificity, and a PPV of 16%. That PPV represents an eightfold increase over the 2% PPV reported with a single measure of CA-125. This report was followed by applying the ROCA to 33,621 serial CA-125 values obtained from the 9,233 average-risk postmenopausal women in a prospective British ovarian cancer screening trial. The area under the receiver operator curve increased from 84% to 93% ( = .01) for ROCA compared with a fixed CA-125 cutoff. These observations represented the first evidence that preclinical detection of ovarian cancer might be improved using this screening strategy. A prospective study of 13,000 normal volunteers aged 50 years and older in England used serial CA-125 values and the ROCA to stratify participants into low, intermediate, and elevated risk subgroups. Each had its own prescribed management strategy, including TVUS and repeat CA-125 either annually (low risk) or at 3 months (intermediate risk). Using this protocol, ROCA was found to have a specificity of 99.8% and a PPV of 19%.
Two prospective trials in England utilized the ROCA. The United Kingdom Collaborative Trial of Ovarian Cancer Screening () randomly assigned normal-risk women to either (1) no screening, (2) annual ultrasound, or (3) multimodal screening (N = 202,638; accrual completed; follow-up ends in 2014), and the U.K. Familial Ovarian Cancer Screening Study () targeted high-risk women (accrual completed). There are also two high-risk cohorts using the ROCA under evaluation in the United States: the Cancer Genetics Network ROCA Study (N = 2,500; follow-up complete; analysis underway) and the Gynecologic Oncology Group Protocol 199 (; enrollment complete; follow-up ended in 2011). Thus, additional data regarding the utility of this currently investigational screening strategy will become available within the next few years.
Miscellaneous new markers
A wide array of new candidate ovarian cancer biomarkers has been described during the past decade, e.g., HE4; mesothelin; kallikreins 6, 10, and 11; osteopontin; prostasin; M-CSF; OVX1; lysophosphatidic acid; vascular endothelial growth factor B7-H4; and interleukins 6 and 8. These have been singly studied, in combination with CA-125, or in various other permutations. Most of the study populations are relatively small and comprise highly selected, known ovarian cancer cases and healthy controls of the type evaluated in early biomarker development phases 1 and 2. Results have not been consistently replicated in multiple studies; presently, none are considered ready for widespread clinical application.
Initially, mass spectroscopy of serum proteins was combined with complex analytic algorithms to identify protein patterns that might distinguish between ovarian cancer cases and controls. This approach assumed that pattern recognition alone would be sufficient to permit such discrimination, and that identification of the specific proteins responsible for the patterns identified was not required. This strategy was modified, using similar laboratory tools, to identify finite numbers of specific known serum markers that may be used in place of, or in conjunction with, CA-125 measurements for the early detection of cancer. These studies have generally been small case-control studies that are limited by sample size and the number of early-stage cancer cases included. Further evaluation is needed to determine whether any additional markers identified in this fashion have clinical utility for the early detection of ovarian cancer in the unselected clinical population of interest.
Because individual biomarkers have not met the criteria for an effective screening test, it has been suggested that it may be necessary to combine multiple ovarian cancer biomarkers to obtain satisfactory screening test results. This strategy was employed to quantitatively analyze six serum biomarkers (leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, and CA-125), using a multiplex, bead-based platform. A similar assay was available commercially under the trade name OvaSure until its voluntary withdrawal from the market by the manufacturer.[Response to FDA Warning Letter]
The cases in this study were newly diagnosed ovarian cancer patients who had blood collected just before surgery: 36 were stage I and II; 120 were stage III and IV. The controls were healthy age-matched individuals who had not developed ovarian cancer within 6 months of blood draw. Neither cases nor controls in this study were well characterized regarding their familial and/or genetic risk status, but they have been suggested to comprise a high-risk population. First, 181 controls and 113 ovarian cancer cases were tested to determine the initial panel of biomarkers that best discriminated between cases and controls (training set). The resulting panel was applied to an additional 181 controls and 43 ovarian cancer cases (test set). Pooling both early- and late-stage ovarian cancer across the combined training and test sets, performance characteristics were reported as a sensitivity of 95.3% and a specificity of 99.4%, with a PPV of 99.3% and a negative predictive value of 99.2%, using a formula that assumed an ovarian cancer prevalence of about 50%, as seen in the highly selected research population.
To avoid biases that may make test performance appear to be better than it really is, combining training populations and test populations in analyses of this sort is generally not recommended. The most appropriate prevalence to use is the disease prevalence in the unselected population to be screened. The prevalence of ovarian cancer in the general population is 1 in 2,500. In a correction to their manuscript, the authors assumed that the prevalence of ovarian cancer in the screened population was 1 in 2,500 (0.04%) and recalculated the PPV to be only 6.5%. On that basis, the investigators have retracted their claim that this test is suitable for population screening. If this test were used in patients at increased risk of ovarian cancer, the actual prevalence in such a target population is likely to be higher than that observed in the general population, but well below the assumed 50% figure used in the published analysis. This revised PPV of 6.5% indicates that approximately 1 in 15 women with a positive test would in fact have ovarian cancer, and only a fraction of those with ovarian cancer would be stages I or II. The remaining 14 positive tests would represent false-positives, and these women would be at risk of exposure to needless anxiety and potentially morbid diagnostic procedures, including bilateral salpingo-oophorectomy.
Viewed in the context of the criteria previously described, this assay would be classified as phase 2 in its development. While this appears to be a promising avenue of ovarian cancer screening research, additional validation is required, particularly in an unselected population representative of the clinical screening population of interest. A position statement by the Society of Gynecologic Oncologists regarding this assay indicated “it is our opinion that additional research is needed to validate the test’s effectiveness before offering it to women outside of the context of a research study conducted with appropriate informed consent under the auspices of an institutional review board.”
Numerous studies have found that women with an inherited risk of breast and ovarian cancer have a decreased risk of ovarian cancer after RRSO. A retrospective study of 551 women with or pathogenic variants found a significant reduction in risk of breast cancer (HR, 0.47; 95% CI, 0.29–0.77) and ovarian cancer (HR, 0.04; 95% CI, 0.01–0.16) after bilateral oophorectomy. A prospective, single-institution study of 170 women with or pathogenic variants showed a similar trend. With oophorectomy, the HR was 0.15 (95% CI, 0.02–1.31) for ovarian, fallopian tube, or primary peritoneal cancer, and 0.32 (95% CI, 0.08–1.2) for breast cancer; the HR for either cancer was 0.25 (95% CI, 0.08–0.74). A prospective multicenter study of 1,079 women who were followed up for a median of 30 to 35 months found that RRSO is highly effective in reducing ovarian cancer risk in carriers of and pathogenic variants. This study also showed that RRSO was associated with reductions in breast cancer risk in both carriers of and pathogenic variants; however, the breast cancer risk reduction was more pronounced in carriers (HR, 0.28; 95% CI, 0.08–0.92). In a case-control study in Israel, bilateral oophorectomy was associated with reduced ovarian/peritoneal cancer risks (OR, 0.12; 95% CI, 0.06–0.24). A meta-analysis of all reports of RRSO and breast and ovarian/fallopian tube cancer in carriers of pathogenic variants confirmed that RRSO was associated with a significant reduction in risk of ovarian or fallopian tube cancer (HR, 0.21; 95% CI, 0.12–0.39). The study also found a significant reduction in risk of breast cancer (overall: HR, 0.49; 95% CI, 0.37–0.65; : HR, 0.47; 95% CI, 0.35–0.64; : HR, 0.47; 95% CI, 0.26–0.84). Subsequently, a matched case-control study of 2,854 pairs of women with a or pathogenic variant with or without breast cancer showed a greater breast cancer risk reduction with surgical menopause (OR, 0.52; 95% CI, 0.40–0.66) than with natural menopause (OR, 0.81; 95% CI, 0.62–1.07). This study also reported a highly significant reduction in breast cancer risk among women who had an oophorectomy after natural menopause (OR, 0.13; 95% CI, 0.02–0.54; = .006). Another study of 5,783 women with or pathogenic variants who were followed up for an average of 5.6 years reported that 68 of 186 women who developed either ovarian, fallopian, or peritoneal cancer had died. The HR for these cancers with bilateral oophorectomy was 0.20 (95% CI, 0.13–0.30; = .001). In carriers of pathogenic variants without a history of cancer, the HR for all-cause mortality to age 70 years associated with oophorectomy was 0.23 (95% CI, 0.13–0.39; < .001). Among studies with 50 or more subjects, prevalence ranged from 2.3% to 11%. Some of the variation in prevalence is likely due to differences in surgical technique, pathologic handling of the tissues, and age at RRSO. In the GOG 199 study of 966 high-risk women, the incidence of occult cancer was highest among carriers of pathogenic variants (4.6%), followed by carriers of pathogenic variants (3.5%), versus only 0.5% of noncarriers. The odds of an occult pathologic finding was fourfold higher among postmenopausal women.
In addition to a reduction in risk of ovarian and breast cancer, RRSO may also significantly improve OS and breast and ovarian cancer–specific survival. A prospective cohort study of 666 women with germline pathogenic variants in and found an HR for overall mortality of 0.24 (95% CI, 0.08–0.71) in women who had RRSO compared with women who did not. This study provides the first evidence to suggest a survival advantage among women undergoing RRSO.
Studies on the degree of risk reduction afforded by RRSO have begun to clarify the spectrum of occult cancers discovered at the time of surgery. Primary fallopian tube cancers, primary peritoneal cancers, and occult ovarian cancers have all been reported. Several case series have reported a prevalence of malignant findings among carriers of pathogenic variants undergoing risk-reducing oophorectomy. Among studies with 50 or more subjects, prevalence ranged from 2.3% to 11%. Some of the variation in prevalence probably results from differences in surgical technique, pathologic handling of the tissues, and age at RRSO. In the GOG 199 study of 966 high-risk women, the incidence of occult cancer was highest in carriers of pathogenic variants (4.6%), followed by carriers of pathogenic variants (3.5%), versus only 0.5% of noncarriers. The odds of an occult pathologic finding was fourfold higher among postmenopausal women.
In addition to occult cancers, premalignant lesions have also been described in fallopian tube tissue removed for prophylaxis. In one series of 12 women with pathogenic variants undergoing risk-reducing surgery, 11 had hyperplastic or dysplastic lesions identified in the tubal epithelium. In several of the cases the lesions were multifocal. These pathologic findings are consistent with the identification of germline and pathogenic variants in women affected with both tubal and primary peritoneal cancers. One study suggests a causal relationship between early tubal carcinoma, or tubal intraepithelial carcinoma, and subsequent invasive serous carcinoma of the fallopian tube, ovary, or peritoneum. (Refer to the Pathology of ovarian cancer section of this summary for more information.)
These findings support the inclusion of fallopian tube cancers, which account for less than 1% of all gynecologic cancers in the general population, as a component of hereditary ovarian cancer syndrome and necessitate removal of the fallopian tubes at the time of risk-reducing surgery. There is clear evidence that RRSO must include routine collection of peritoneal washings and careful adherence to comprehensive pathologic evaluation of the entire adnexa with the use of serial sectioning.
The peritoneum, however, appears to remain at low risk for the development of a Müllerian-type adenocarcinoma, even after oophorectomy. Of the 324 women from the Gilda Radner Familial Ovarian Cancer Registry who underwent risk-reducing oophorectomy, 6 (1.8%) subsequently developed primary peritoneal carcinoma. No period of follow-up was specified. Among 238 individuals in the Creighton Registry with pathogenic variants who underwent risk-reducing oophorectomy, 5 subsequently developed intra-abdominal carcinomatosis (2.1%). Of note, all five of these women had pathogenic variants. A study of 1,828 women with a or pathogenic variant found a 4.3% risk of primary peritoneal cancer at 20 years after RRSO.
Data are limited regarding outcomes of carriers of and pathogenic variants who are found to have occult lesions at the time of RRSO. In a multi-institution study of 32 women with either invasive carcinoma (n = 15) or serous tubal intraepithelial carcinoma (STIC) (n = 17), 47% of women with invasive cancer had a recurrence at a median time of 32.5 months, with an OS rate of 73%. For women with intraepithelial lesions, one patient (approximately 6%) had a recurrence at 43 months, suggesting a different disease process between the two entities. Another study confirmed the malignant potential of STIC lesions. While 3 of 243 women (1.2%) with benign pathology at RRSO subsequently developed primary peritoneal carcinoma, 2 of 9 women (22%) with STIC developed high-grade pelvic serous carcinoma after a median follow-up time of 63 months.
Given the current limitations of screening for ovarian cancer and the high risk of the disease in carriers of and pathogenic variants, NCCN Guidelines recommend RRSO between the ages of 35 and 40 years or upon completion of childbearing, as an effective risk-reduction option. Optimal timing of RRSO must be individualized, but evaluating a woman's risk of ovarian cancer based on pathogenic variant status can be helpful in the decision-making process. In a large study of U.S. and families, age-specific cumulative risk of ovarian cancer at age 40 years was 4.7% for carriers of pathogenic variants and 1.9% for carriers of pathogenic variants. In a combined analysis of 22 studies of carriers of and pathogenic variants, risk of ovarian cancer for carriers of pathogenic variants increased most sharply from age 40 years to age 50 years, while the risk for carriers of pathogenic variants was low before age 50 years but increased sharply from age 50 years to age 60 years. In a population-based study of pathogenic variants in ovarian cancer patients, patients with variants had a significantly later age of onset than patients with variants (57.3 years [range, 40–72] vs. 52.6 years [range, 31–78]). In summary, women with pathogenic variants may consider RRSO for ovarian cancer risk reduction at a somewhat earlier age than women with pathogenic variants; however, women with variants may still consider early RRSO for breast cancer risk reduction.
The role of concomitant hysterectomy at the time of RRSO in carriers of pathogenic variants is controversial. There is concern that a small portion of the proximal fallopian tube remains when hysterectomy is not performed, thereby resulting in a residual increased risk of fallopian tube cancer. However, several studies that have examined fallopian tube cancers indicate that the vast majority of these cancers occur in the distal or midportion of the fallopian tube, suggesting that the occurrence of proximal fallopian tube cancer would be a very unlikely event. Some reports have suggested an increased incidence of uterine carcinoma in carriers of pathogenic variants, whereas others have not confirmed an elevated risk of serous uterine cancer. A prospective study of 857 women suggested that any increased incidence of uterine cancer appeared to be among carriers of pathogenic variants who used tamoxifen; this was confirmed by the same group in a later study of 4,456 carriers of pathogenic variants. Even with tamoxifen use, the excess risk of endometrial cancer was small, with a 10-year cumulative risk of 2%. In addition, the use of tamoxifen can now be minimized, given the options of raloxifene (which does not increase the risk of uterine cancer) and aromatase inhibitors for breast cancer prevention in postmenopausal women. Therefore, on the basis of the current understanding of the risk of uterine cancer in carriers of pathogenic variants, there is not a singularly compelling reason to consider hysterectomy at the time of RRSO to reduce the risk of uterine cancer. Concomitant hysterectomy does offer the advantage of simplifying the hormone replacement regimen for carriers of pathogenic variants who choose to take hormones. After hysterectomy, women can take estrogen alone (which does not increase the risk of breast cancer), without progestins, thereby eliminating the risk of postmenopausal bleeding.
Studies indicate that removal of the uterus is not necessary as a risk-reducing procedure. No increased pathogenic variant prevalence was seen among 200 Jewish women with endometrial carcinoma or 56 unselected women with uterine papillary serous carcinoma. However, small studies have reported that uterine papillary serous carcinoma may be part of the -associated spectrum of disease. The cumulative risk of endometrial cancer among carriers of pathogenic variants with ER-positive breast cancer treated with tamoxifen may be an additional factor to consider when counseling this population about risk-reducing hysterectomy. Hysterectomy might also be considered in young, unaffected carriers of pathogenic variants who may want to use HRT but for whom hysterectomy would offer a simplified regimen of estrogen alone. In counseling a carrier of a pathogenic variant about optimal risk-reducing surgical options, aggregate data suggest that the risk from residual tubal tissue after RRSO is the least compelling reason to suggest hysterectomy. Therefore, in the absence of tamoxifen use or other underlying uterine or cervical problems, hysterectomy is not a routine component of RRSO for carriers.
For women who are premenopausal at the time of surgery, the symptoms of surgical menopause (e.g., hot flashes, mood swings, weight gain, and genitourinary complaints) can cause a significant impairment in their quality of life. To reduce the impact of these symptoms, providers have often prescribed a time-limited course of systemic HRT after surgery. (Refer to the Hormone replacement therapy in carriers of BRCA1/BRCA2 pathogenic variants section of this summary for more information.)
Studies have examined the effect of RRSO on quality of life (QOL). One study examined 846 high-risk women of whom 44% underwent RRSO and 56% had periodic screening. Of the 368 carriers of pathogenic variants, 72% underwent RRSO. No significant differences were observed in QOL scores (as assessed by the Short Form-36) between those with RRSO or screening or compared with the general population; however, women with RRSO had fewer breast and ovarian cancer worries ( < .001) and more favorable cancer risk perception ( < .05) but more endocrine symptoms ( < .001) and worse sexual functioning ( < .05). Of note, 37% of women used HRT after RRSO, although 62% were either perimenopausal or postmenopausal. Researchers then examined 450 premenopausal high-risk women who had chosen either RRSO (36%) or screening (64%). Of those in the RRSO group, 47% used HRT. HRT users (n = 77) had fewer vasomotor symptoms than did nonusers (n = 87; < .05), but they had more vasomotor symptoms than did women in the screening group (n = 286). Likewise, women who underwent RRSO and used HRT had more sexual discomfort due to vaginal dryness and dyspareunia than did those in the screening group ( < .01). Therefore, while such symptoms are improved via HRT use, HRT is not completely effective, and additional research is warranted to address these important issues.
The long-term nononcologic effects of RRSO in carriers of pathogenic variants are unknown. In the general population, RRSO has been associated with increased cardiovascular disease, dementia, death from lung cancer, and overall mortality. When age at oophorectomy has been analyzed, the most detrimental effect has been seen in women who undergo RRSO before age 45 years and do not take estrogen replacement therapy. Carriers of pathogenic variants undergoing RRSO may have an increased risk of metabolic syndrome. RRSO has also been associated with an improvement in short-term mortality in this population. The benefits related to cancer risk reduction after RRSO are clear, but further data on the long-term nononcologic risks and benefits are needed.
Bilateral salpingectomy has been suggested as an interim procedure to reduce risk in carriers of pathogenic variants. There are no data available on the efficacy of salpingectomy as a risk-reducing procedure. The procedure preserves ovarian function and spares the premenopausal patient the adverse effects of a premature menopause. The procedure can be performed using a minimally invasive approach, and a subsequent bilateral oophorectomy could be deferred until the patient approaches menopause. While the data make a compelling argument that some pelvic serous cancers in carriers of pathogenic variants originate in the fallopian tube, some cancers clearly arise in the ovary. Furthermore, bilateral salpingectomy could give patients a false sense of security that they have eliminated their cancer risk as completely as if they had undergone a bilateral salpingo-oophorectomy. A small study of 14 young carriers of pathogenic variants documented the procedure as feasible. However, efficacy and impact on ovarian function was not assessed in this study. Future prospective trials are needed to establish the validity of the procedure as a risk-reducing intervention.
OCs have been shown to have a protective effect against ovarian cancer in the general population. Several studies, including a large, multicenter, case-control study, showed a protective effect, while one population-based study from Israel failed to demonstrate a protective effect.
There has been great interest in determining whether a similar benefit extends to women who are at increased genetic risk of ovarian cancer. A multicenter study of 799 ovarian cancer patients with or pathogenic variants, and 2,424 control patients without ovarian cancer but with a or pathogenic variant, showed a significant reduction in ovarian cancer risk with use of OCs (OR, 0.56; 95% CI, 0.45–0.71). Compared with never-use of OCs, duration up to 1 year was associated with an OR of 0.67 (95% CI, 0.50–0.89). The OR for each year of OC use was 0.95 (95% CI, 0.92–0.97), with a maximum observed protection at 3 years to 5 years of use. This study included women from a prior study by the same authors and confirmed the results of that prior study. A population-based case-control study of ovarian cancer did not find a protective benefit of OC use in carriers of or pathogenic variants (OR, 1.07 for ≥5 years of use), although they were protective, as expected, among noncarriers (OR, 0.53 for ≥5 years of use). A small, population-based, case-control study of 36 carriers of pathogenic variants, however, observed a similar protective effect in both carriers of pathogenic variants and noncarriers (OR, approximately 0.5). A larger case-control study of women with pathogenic variants in demonstrated maximum benefit after 5 years of OC use, while women with pathogenic variants in seemed to reach maximum benefit after 3 years of OC use. A multicenter study of subjects drawn from numerous registries observed a protective effect of OCs among the 147 carriers of or pathogenic variants, with ovarian cancer compared with the 304 matched carriers of pathogenic variants without cancer (OR, 0.62 for ≥6 years of use). Finally, a meta-analysis of 18 studies that included 13,627 carriers of pathogenic variants, 2,855 of whom had breast cancer and 1,503 of whom had ovarian cancer, reported a significantly reduced risk of ovarian cancer (summary RR, 0.50; 95% CI, 0.33–0.75) associated with OC use. The authors also reported significantly higher risk reductions with longer duration of OC use (36% reduction in risk for each additional 10 years of OC use). There was no association with breast cancer risk and use of OC pills formulated after 1975.
(Refer to the Oral contraceptives section in the Reproductive factors section of this summary for a discussion of OC use and breast cancer in this population.)
It has been suggested that incessant ovulation, with repetitive trauma and repair to the ovarian epithelium, increases the risk of ovarian cancer. In epidemiologic studies in the general population, physiologic states that prevent ovulation have been associated with decreased risk of ovarian cancer. It has also been suggested that chronic overstimulation of the ovaries by luteinizing hormone plays a role in ovarian cancer pathogenesis. Most of these data derive from studies in the general population, but some information suggests the same is true in women at high risk due to genetic predisposition.
Among the general population, parity decreases the risk of ovarian cancer by 45% compared with nulliparity. Subsequent pregnancies appear to decrease ovarian cancer risk by 15%. Earlier studies of women with pathogenic variants showed that parity decreases the risk of ovarian cancer. In a large case-control study, parity was associated with a significant reduction in ovarian cancer risk in women with pathogenic variants, OR 0.67 (CI, 0.46–0.96). For each birth, carriers of pathogenic variants had an OR of 0.87 (CI, 0.79–0.95). In this same study, parity was associated with an increase in ovarian cancer risk in carriers of pathogenic variants; however, there was no significant trend for each birth, OR 1.08 (CI, 0.90–1.29). Further studies are necessary to define the association of parity and risk of ovarian cancer in carriers of pathogenic variants, but for carriers, each live birth significantly decreases risk of ovarian cancer, as it does in sporadic ovarian cancer.
Lactation and tubal ligation
In the general population, breastfeeding is associated with a decrease in ovarian cancer risk. In carriers of pathogenic variants, data are limited. One study found no protective effect with breastfeeding. A case-control study among women with or pathogenic variants demonstrates a significant reduction in risk of ovarian cancer (OR, 0.39) for women who have had a tubal ligation. This protective effect was confined to those women with pathogenic variants in and persists after controlling for OC use, parity, history of breast cancer, and ethnicity. A case-control study of ovarian cancer in Israel found a 40% to 50% reduced risk of ovarian cancer among women undergoing gynecologic surgeries (tubal ligation, hysterectomy, unilateral oophorectomy, ovarian cystectomy, excluding bilateral oophorectomy). The mechanism of protection is uncertain. Proposed mechanisms of action include decreased blood flow to the ovary, resulting in interruption of ovulation and/or ovarian hormone production; occlusion of the fallopian tube, thus blocking a pathway for potential carcinogens; or a reduction in the concentration of uterine growth factors that reach the ovary. (Refer to the PDQ summary on Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Prevention for information relevant to the general population.)
Refer to the Oral contraceptives section in the Chemoprevention section of this summary for more information.
Management of Male Carriers of BRCA Pathogenic Variants
There are data to suggest that men with pathogenic variants have an increased risk of various cancers including male breast cancer and prostate cancer (see Table 6). However, clinical guidelines to manage male carriers with pathogenic variants are based on consensus statements and expert opinions because information is limited.
There have been suggestions that -associated prostate cancers are associated with aggressive disease phenotype. Specifically, two recent studies have reported the median survival of male carriers with prostate cancer in the range of 4 to 5 years. Furthermore, mortality rate was reported as 60% at 5 years in one of these studies, compared with 2% to 8% reported in the recent European and North American prostate-specific antigen (PSA) screening trials after comparable follow-up. The data have been more limited in -associated prostate cancers, however a number of recent studies have suggested an aggressive disease phenotype as well.
The benefits of PSA screening in carriers are unknown; however, there have been suggestions (based on very small studies) that PSA levels at prostate cancer diagnosis may be higher in carriers than noncarriers. These findings suggest that PSA screening may be of potential utility in men with pathogenic variants, especially in view of the aggressive phenotype. Preliminary results of the IMPACT PSA screening study reported a PPV of 47.6% in 21 carriers undergoing biopsy on the basis of elevated PSA. Because screening these men detected clinically significant prostate cancer, the authors suggest that these findings provide rationale for continued screening in such men; however, a survival benefit from such screening has not been shown. Ultimately, it is possible that information on pathogenic variant status in men may inform optimal screening and treatment strategies. Furthermore, recent data that the presence of a germline pathogenic variant is an independent prognostic factor for survival in prostate cancer led these authors to conclude that active surveillance may not be the optimal management strategy due to the aggressive disease phenotype.
Screening for male breast cancer in carriers of pathogenic variants as suggested by the NCCN clinical practice guidelines includes breast self-exam training and education and clinical breast exam every 12 months starting at age 35 years. Furthermore, beginning at age 45 years, NCCN recommends prostate cancer screening for carriers and the consideration of prostate cancer screening for carriers.
Reproductive Considerations in Carriers of BRCA Pathogenic Variants
Refer to the Prenatal diagnosis and preimplantation genetic diagnosis section in the Psychosocial Issues in Inherited Breast and Ovarian Cancer Syndromes section of this summary for more information.
Prognosis of BRCA1- and BRCA2-related breast cancer
BRCA1-related breast cancer
The distinct features of -associated breast tumors are important in prognosis. In addition, there appears to be accelerated growth in -associated breast cancer, which is suggested by high-proliferation indices and absence of the expected correlation of tumor size with lymph node status. These pathological features are associated with a worse prognosis in breast cancer, and early studies suggested that carriers of pathogenic variants with breast cancer may have a poorer prognosis compared with sporadic cases. These studies particularly noted an increase in ipsilateral and contralateral second primary breast cancers in carriers of and pathogenic variants. (Refer to the Contralateral breast cancer in carriers of BRCA pathogenic variants section of this summary for more information.) A retrospective cohort study of 496 Ashkenazi Jewish (AJ) breast cancer patients from two centers compared the relative survival among 56 carriers of pathogenic variants followed up for a median of 116 months. pathogenic variants were independently associated with worse disease-specific survival. The poorer prognosis was not observed in women who received chemotherapy. A large population-based study of incident cases of breast cancer among women in Israel failed to find a difference in OS for carriers of founder pathogenic variants (n = 76) compared with noncarriers (n = 1,189). Similar findings were seen in a European cohort with no differences in disease-free survival in -associated breast cancers. Subsequently, a prospective cohort study of 3,220 women from North America and Australia with incident breast cancer (including 93 carriers and 71 carriers) who were followed up for a mean of 7.9 years reported similar outcomes among carriers and those with sporadic disease. However, results were based on chemotherapy regimens used in the late 1990s and did not adjust for surgical approach (lumpectomy vs. mastectomy) and effect of oophorectomy.
A group of researchers reported the results of testing in 77 unselected patients with triple-negative breast cancer. Of these, 15 (19.5%) had either a germline (n = 11; 14%) or (n = 3; 4%) pathogenic variant or a somatic (n = 1) pathogenic variant. The median age at cancer diagnosis was 45 years in carriers of pathogenic variants and 53 years in noncarriers ( = .005). Interestingly, this study also demonstrated a lower risk of relapse in those with triple-negative breast cancer associated with a pathogenic variant than in non--associated triple-negative breast cancer, although this study was limited by its size. Another study examining clinical outcome in -associated versus non–-associated triple-negative breast cancer showed no difference, although there was a trend toward more brain metastases in those with -associated breast cancer. In both of these studies, all but one carrier of a pathogenic variant received chemotherapy. Subsequently, in a study of 89 carriers and 175 noncarriers with triple-negative breast cancer, pathogenic variant status was not an independent predictor of survival after adjusting for age, oophorectomy, and risk-reducing mastectomy. However, carriers who underwent oophorectomy had a significantly lower rate of breast cancer–related death.
A Polish study of 3,345 patients younger than 50 years with stages I through III breast cancer studied the impact of a pathogenic variant on prognosis. In this cohort, 233 patients (7%) carried one of three Polish founder pathogenic variants (5382insC, C61G, or 4154delA). carriers were younger and more frequently ER-negative and HER2/neu-negative. Ten-year survival was similar (80.9% in carriers and 82.2% in noncarriers). Oophorectomy was associated with improved survival in carriers (HR, 0.30; 95% CI 0.12–0.75).
In summary, -associated tumors appear to have a prognosis similar to sporadic tumors despite having clinical, histopathologic, and molecular features that indicate a more aggressive phenotype. Carriers of pathogenic variants who do not receive chemotherapy may have a worse prognosis. However, because most -associated breast cancers are triple negative, they are usually treated with adjuvant chemotherapy. Work is ongoing to determine whether -associated breast cancers should receive different therapy than do sporadic tumors. (Refer to the Role of BRCA1 and BRCA2 in response to systemic therapy section of this summary for more information.)
BRCA2-related breast cancer
Early studies of the prognosis of -associated breast cancer have not shown substantial differences in comparison with sporadic breast cancer. A small study reported statistically significant higher OS in carriers of pathogenic variants with metastatic breast cancer.
Role of BRCA1 and BRCA2 in response to systemic therapy
A growing body of preclinical and clinical literature suggests a differential response of -related breast cancers to systemic chemotherapy. This is based on the emerging understanding of the functions of these genes in response to DNA damage and mitotic spindle machinery control. As several chemotherapeutic agents target either DNA or mitotic spindle structural integrity, the lack of functions could alter response to these agents. Intact and are important in DNA repair by homologous recombination. Preclinical studies of - and -deficient cell lines have suggested increased sensitivity to drugs that cause DNA damage that is repaired by homologous recombination, such as cisplatin, carboplatin and mitomycin C. Conversely, intact may be important for spindle poisons, such as taxanes, to be effective. Preclinical models suggest decreased sensitivity to these drugs in mutated cell lines.
Evidence of the role of pathogenic variants in humans is evolving. A number of small studies have suggested increased clinical response rates, particularly in carriers of pathogenic variants, but design limitations make it difficult to use these studies to guide clinical recommendations.
Retrospective and prospective studies have suggested a higher-than-expected response rate to chemotherapy in carriers of pathogenic variants receiving neoadjuvant chemotherapy for breast cancer, especially when using cisplatin. Several studies regarding the Polish experience on the use of preoperative chemotherapy in carriers of pathogenic variants have been published. The largest report includes data on 102 carriers of pathogenic variants of which 51 were described in two prior studies. Women were identified from a registry of 6,903 patients. Those with a Polish founder pathogenic variant in (5382insC, C61G, or 4153delA) who had also received preoperative chemotherapy were included. Of these 102 women, 22% had a pathologic complete response (pCR). Twelve women received cisplatin chemotherapy as part of a clinical trial, ten of whom had a pCR (83%). All other patients were examined retrospectively. Of these, 14 received cyclophosphamide, methotrexate, and fluorouracil with one pCR (7%), 25 received doxorubicin and docetaxel with two pCRs (8%), and 51 received doxorubicin and cyclophosphamide with 11 pCRs (22%). To place this in the context of other available data, several retrospective studies in carriers of and pathogenic variants typically treated with anthracycline-based chemotherapy have demonstrated clinical complete response rates of 46% to 90% after preoperative chemotherapy, particularly in carriers of pathogenic variants. A trial of preoperative cisplatin in triple-negative breast cancer patients demonstrated a pCR of 22%; however, both carriers of pathogenic variants in the study had a pCR.
A small study reported a statistically significant higher sensitivity to first-line treatment in carriers of pathogenic variants with metastatic breast cancer than in those with sporadic metastatic cancer; conversely, no statistically significant differences were observed for carriers with metastatic breast cancer. No data directly compare different types of chemotherapy in and carriers of pathogenic variants. However, in a small study of 20 carriers of pathogenic variants with metastatic breast cancer, there was an overall response rate of 80% to cisplatin therapy. Further studies are evaluating the role of platinums in - and -associated metastatic cancer.
Thus, the preclinical and clinical data suggesting improved chemotherapy response rates in -associated breast cancer are consistent with the emerging understanding of function in DNA-damage response and cell-cycle regulation. While these findings raise the possibility that germline status may influence treatment choices, there is insufficient evidence at this time to support treating carriers of pathogenic variants with different regimens in the adjuvant and neoadjuvant setting.
Another specific process to exploit in -deficient tumors is the poly (ADP-ribose) polymerase (PARP) pathway. Whereas and are active in the repair of double-stranded DNA breaks by homologous recombination, PARP is involved in the repair of single-stranded breaks by base excision repair. It was hypothesized that inhibiting base excision repair in - or -deficient cells would lead to enhanced cell death as two separate repair mechanisms would be compromised—the concept of synthetic lethality. studies have shown that PARP inhibition kills variant cells with high specificity.
PARP inhibitors quickly entered clinical trials. A phase I study of an oral PARP inhibitor called olaparib has demonstrated tolerability (with minimal side effects) and activity in carriers of and pathogenic variants with breast cancer, ovarian cancer, and prostate cancer. Phase II trials in breast cancer have confirmed tolerability and efficacy of olaparib in carriers of pathogenic variants. Two sequential cohorts of 27 patients, each receiving 400 mg twice daily of olaparib and 100 mg twice daily of olaparib were examined. The women had received a median of three prior chemotherapeutic regimens. Responses were seen in both groups. In the group that received 400 mg twice daily, 41% (11 of 27) of patients had a RECIST-defined response, and another 44% (12 of 27) had stable disease. In the group that received 100 mg twice daily group, 22% (6 of 27) had responses, and 44% (12 of 27) had stable disease. Although the two dose levels cannot be directly compared because they were not randomized, more responses were seen in the higher-dose cohort. Several other PARP inhibitors are in development.
Preclinical models suggest that the combination of PARP inhibitors and chemotherapy may be synergistic; however, such synergy may come at the expense of toxicity. The results of ongoing and recently completed clinical trials are awaited with interest.
(Refer to the Systemic therapy section in the Ovarian cancer section of this summary for more information about treatment strategies for -associated ovarian cancer.)
Breast conservation therapy for carriers of BRCA1/BRCA2 pathogenic variants
While lumpectomy plus radiation therapy has become standard local-regional therapy for women with early-stage breast cancer, its use in women with a hereditary predisposition for breast cancer who do not choose immediate bilateral mastectomy is more complicated. Initial concerns about the potential for therapeutic radiation to induce tumors or cause excess toxicity in carriers of pathogenic variants were unfounded. Despite this, an increased rate of second primary breast cancer exists, which could impact treatment decisions.
Because of the established increased risk of second primary breast cancers, which may be up to 60% in younger women with pathogenic variants, some carriers of pathogenic variants choose bilateral mastectomy at the time of their initial cancer diagnosis. (Refer to the Contralateral breast cancer in carriers of BRCA pathogenic variants section of this summary for more information.) However, several studies support the use of breast conservation therapy as a reasonable option to treat the primary tumor. The risk of ipsilateral recurrence at 10 years has been estimated to be between 10% to 15% and is similar to that seen in noncarriers. Studies with longer periods of follow-up demonstrate risks of ipsilateral breast events at 15 years to be as high as 24%, largely resulting from ipsilateral second breast cancers (rather than relapse of the primary tumor). Although not entirely consistent across studies, radiation therapy, chemotherapy, oophorectomy, and tamoxifen are associated with a decreased risk of ipsilateral events, as is the case in sporadic breast cancer. The risk of contralateral breast cancer does not appear to differ in women undergoing breast conservation therapy versus unilateral mastectomy, suggesting no added risk of contralateral breast cancer from scattered radiation. This finding is supported by a population-based case-control study of women diagnosed with breast cancer before the age of 55 years. All women were genotyped for . Although there was a significant fourfold risk of contralateral breast cancer in carriers compared with noncarriers, carriers who were exposed to radiation therapy for the first primary were not at increased risk of contralateral breast cancer compared with carriers who were not exposed. (Refer to the Mammography section for more information about radiation and breast cancer risk.) Finally, no difference in OS at 15 years has been seen between carriers of pathogenic variants choosing breast conservation therapy and carriers choosing mastectomy.
Prognosis of BRCA1- and BRCA2-related ovarian cancer
Despite generally poor prognostic factors, several studies have found an improved survival among ovarian cancer patients with pathogenic variants. A nationwide, population-based, case-control study in Israel found 3-year survival rates to be significantly better for ovarian cancer patients with founder pathogenic variants, compared with controls. Five-year follow-up in the same cohort showed improved survival for carriers of both and pathogenic variants (54 months) versus noncarriers (38 months), which was most pronounced for women with stages III and IV ovarian cancer and for women with high-grade tumors. In a U.S. study of AJ women with ovarian cancer, those with pathogenic variants had a longer median time to recurrence and an overall improved survival, compared with both AJ women with ovarian cancer who did not have a pathogenic variant and two large groups of advanced-stage ovarian cancer clinical trial patients. In a retrospective U.S. hospital-based study, AJ carriers of pathogenic variants had a better response to platinum-based chemotherapy, as measured by response to primary therapy, disease-free survival, and OS, compared with sporadic cases. Similarly, a significant survival advantage was seen in a case-control study among women with non-AJ pathogenic variants. A study from the Netherlands also showed a better response to platinum-based primary chemotherapy in 112 carriers than in 220 sporadic ovarian cancer patients. A U.S. population-based study showed improvement in OS in , but not in , carriers. However, the study included only 12 carriers of pathogenic variants and 20 carriers of pathogenic variants. Significantly better OS and progression-free survival (PFS) were observed in 29 high-grade serous ovarian cancer cases with a known pathogenic variant (20 germline, 9 somatic) from The Cancer Genome Atlas study compared with cases negative for a pathogenic variant. pathogenic variants were not significantly associated with prognosis. Furthermore, a pooled analysis of 26 observational studies that included 1,213 carriers of pathogenic variants and 2,666 noncarriers with epithelial ovarian cancer showed more favorable survival in carriers of pathogenic variants (: HR, 0.73; 95% CI, 0.64–0.84; < .001;: HR, 0.49; 95% CI, 0.39–0.61; < .001). Thus, 5-year survival in both and carriers with epithelial ovarian cancers was better than that observed in noncarriers, with carriers having the best prognosis. A study in Japanese patients found a survival advantage in stage III -associated ovarian cancers treated with cisplatin regimens compared with nonhereditary cancers treated in a similar manner.
In contrast, several studies have not found improved OS among ovarian cancer patients with pathogenic variants. The largest of these studies involved a large series of unselected Canadian and U.S. patients who were tested for and pathogenic variants. At 3 years, the presence of a pathogenic variant was associated with a better prognosis, but at 10 years, there was no longer a difference seen in prognosis. Furthermore, one study suggested that there was worse survival in ovarian cancer patients with a family history.
Compelling data suggest a short-term survival advantage in carriers of pathogenic variants. However, long-term outcomes are yet to be established. Survival in AJ ovarian cancer patients with or founder pathogenic variants does seem to be improved; however, further large studies in other populations with appropriate controls are needed to determine whether this survival advantage applies more broadly to all cancers.
The molecular mechanisms that explain the improved prognosis in hereditary -associated ovarian cancer are unknown but may be related to the function of genes. genes play an important role in cell-cycle checkpoint activation and in the repair of damaged DNA via homologous recombination. Deficiencies in homologous repair can impair the cells’ ability to repair DNA cross-links that result from certain chemotherapy agents, such as cisplatin. Preclinical data has demonstrated BRCA1 impacts chemosensitivity in breast cancer and ovarian cancer cell lines. Reduced BRCA1 protein expression has been shown to enhance cisplatin chemosensitivity. Patients with -associated ovarian cancer have shown improved responses to both first-line and subsequent platinum-based chemotherapy, compared with patients with sporadic cancers, which may contribute to their better outcome.
PARP pathway inhibitors are currently being studied for the treatment of - or -deficient ovarian cancers. (Refer to the Role of BRCA1 and BRCA2 in response to systemic therapy section in the Treatment Strategies section of this summary for more information about PARP inhibitors.) While PARP is involved in the repair of single-stranded breaks by base excision repair, and are active in the repair of double-stranded DNA breaks by homologous combination. Therefore, it was hypothesized that inhibiting base excision repair with PARP inhibition in - or -deficient tumors leads to enhanced cell death, as two separate repair mechanisms would be compromised—the concept of synthetic lethality.
A phase I study of olaparib, an oral PARP inhibitor, demonstrated tolerability (with minimal side effects) and activity in carriers of and pathogenic variants with ovarian, breast, and prostate cancers. A phase II trial of two different doses of olaparib demonstrated tolerability and efficacy in recurrent ovarian cancer patients with or pathogenic variants. The overall response rate was 33% (11 of 33 patients) in the cohort receiving 400 mg twice daily and 13% (3 of 24 patients) in the cohort receiving 100 mg twice daily. The most frequent side effects were mild nausea and fatigue. In addition to ovarian cancer patients with germline or pathogenic variants, PARP inhibitors also may be useful in ovarian cancer patients with somatic or pathogenic variants or with epigenetic silencing of the genes.
Studies have used PARP inhibitors in ovarian cancer, as both treatment and maintenance, after platinum-based chemotherapy. Several phase II treatment studies have explored the efficacy of olaparib in patients with recurrent ovarian cancer, in both platinum-sensitive and platinum-resistant disease. Olaparib at 400 mg twice daily was used in a single-arm study to treat a spectrum of 298 -associated cancers, including breast, pancreas, prostate, and ovarian. Of the 193 women with ovarian cancer treated with olaparib, 31% had a response, and 40.4% had stable disease that persisted for at least 8 weeks. Among the 154 women previously treated with at least three lines of chemotherapy, a similar overall response rate of 30% was seen, with comparable median durations of response of 8.2 months for platinum-sensitive disease and 8.0 months for platinum-resistant disease. Another study of 173 patients with platinum-sensitive disease were treated with paclitaxel/carboplatin plus olaparib versus paclitaxel/carboplatin alone. The PFS was significantly longer in the olaparib group than the control group (12.2 vs. 9.6 months) (HR, 0.51; 95% CI, 0.34–0.77), especially in the subgroup of patients with pathogenic variants (HR, 0.21; 95% CI, 0.08–0.55). There were no differences in OS between the olaparib and control groups.
In contrast, another study observed a survival advantage among wild-type patients. A randomized open-label trial assigned 90 women with recurrent platinum-sensitive ovarian cancer to either olaparib or cediranib and olaparib. Median PFS was significantly longer with the combination (17.7 months vs. 9 months) (HR, 0.42; 95% CI, 0.23–0.76). Subset analysis showed that combination cediranib and olaparib resulted in significantly longer PFS in the 43 wild-type/unknown patients than did single agent olaparib (16.5 months vs. 5.7 months) (HR, 0.32; =.008) and a smaller trend toward increased PFS in 47 women with pathogenic variants (19.4 vs. 16.5 months) (HR, 0.55; = 0.16).
In another study, women with pathogenic variants and recurrent ovarian cancer within 12 months of a prior platinum-based regimen were randomly assigned to receive liposomal doxorubicin (Doxil) (n = 33), versus olaparib at 200 mg twice daily (n = 32), versus olaparib at 400 mg twice daily (n = 32). This study did not show a difference in PFS between the groups, which was the primary endpoint. Of interest, the liposomal doxorubicin arm had a higher response rate than anticipated, consistent with other studies demonstrating that -associated ovarian cancers may be more sensitive to liposomal doxorubicin than are sporadic ovarian cancers. Another study demonstrated significant responses to olaparib in recurrent ovarian cancer patients, including patients with a pathogenic variant (objective response rate [ORR], 41%) and patients without a pathogenic variant (ORR, 24%). This study emphasizes that certain sporadic ovarian cancers, particularly those of high-grade serous histology, may have properties similar to tumors related to a pathogenic variant.
As maintenance treatment, olaparib has shown significantly improved PFS in platinum-sensitive recurrent ovarian cancer. In a randomized controlled study of 256 patients, those who received olaparib had a PFS of 8.4 months compared with 4.8 months in those who received the placebo (HR, 0.35; 95% CI, 0.25–0.49). Within the cohort, the 136 patients with pathogenic variants demonstrated the most benefit with olaparib compared with placebo, with a PFS of 11.2 versus 4.3 months (HR, 0.18; 95% CI, 0.1–0.31). There was no OS difference observed in the entire cohort, or in the carriers of pathogenic variants. A subsequent post-hoc exploratory analysis excluded patients with pathogenic variants who received a PARP inhibitor at the time of progression to minimize the confounding influence on OS. In this group of 97 patients, an improved OS HR of 0.52 (95% CI, 0.28–0.97) was associated with olaparib, compared with placebo. More mature data are necessary to determine whether platinum sensitivity is a marker of response to PARP inhibitors in women with pathogenic variants, and the optimal timing of PARP inhibitors as treatment or as maintenance therapy.
Available Clinical Practice Guidelines for Hereditary Breast and Ovarian Cancer
Table 14 lists several organizations that have published recommendations for cancer risk assessment and genetic counseling, genetic testing, and/or management for hereditary breast and ovarian cancer.
Clinical Management of Other Hereditary Breast and/or Gynecologic Cancer Syndromes
As mismatch repair genes were identified as the genetic basis of Lynch syndrome, microsatellite instability was identified as a common molecular marker of mismatch repair deficiency. Approximately 15% of sporadic colorectal cancers show microsatellite instability, while up to 28% of sporadic endometrial cancers have this molecular change. Most frequently, sporadic tumors with microsatellite instability have hypermethylation of the promoter. In Lynch syndrome–related tumors showing microsatellite instability, there is typically loss of one or more of the proteins associated with the mismatch repair genes.
Certain histopathologic features are also strongly suggestive of a microsatellite instability phenotype, including the presence of tumor infiltrating lymphocytes, peritumoral lymphocytes, undifferentiated carcinomas, and lower uterine segment tumors. Use of clinical criteria is one strategy of selection criteria for tumor testing. Computer models have also been used to predict the probability of a mismatch repair genetic variant and can be used in the absence of microsatellite instability or immunohistochemistry information. Overall, however, there is a move towards universal testing of colorectal and endometrial tumors when tumor tissue is available. (Refer to the Universal tumor testing to screen for Lynch syndrome section in the PDQ summary on Genetics of Colorectal Cancer for more information.)
Psychosocial Issues in Inherited Breast and Ovarian Cancer Syndromes
Psychosocial research in the context of cancer genetic testing helps to define psychological outcomes, interpersonal and familial effects, and cultural and community responses. This type of research also identifies behavioral factors that encourage or impede screening and other health behaviors. It can enhance decision-making about risk-reduction interventions, evaluate psychosocial interventions to reduce distress and/or other negative sequelae related to risk notification and genetic testing, provide data to help resolve ethical concerns, and predict the interest in testing of various groups.
This section addresses psychosocial issues in hereditary breast and ovarian cancer syndromes. Psychosocial and screening issues related to gynecologic cancers associated with Lynch syndrome are discussed in the Psychosocial Issues in Hereditary Colon Cancer Syndromes section in the PDQ summary on Genetics of Colorectal Cancer.
Uptake of Genetic Counseling and Genetic Testing
Degree of uptake of genetic counseling and genetic testing
Comparison of uptake rates across studies is challenging because of differences in methodologies, including the sampling strategy used, the recruitment setting, and testing through a research protocol with high-risk cohorts or kindreds. In a systematic review of 40 studies conducted before 2002 that had assessed genetic testing utilization, uptake rates varied widely and ranged from 25% to 96%, with an average uptake rate of 59%. Results of multivariate analysis found that genetic testing uptake was associated with having a personal or family history of breast or ovarian cancer, and with methodological features of the studies, including sampling strategies, recruitment settings, and how studies defined actual uptake versus the intention to have testing.
Other factors have been positively correlated with uptake of genetic testing, although these findings are not consistent across all studies. Psychological factors that have been positively correlated with testing uptake include greater cancer-specific distress and greater perceived risk of developing breast or ovarian cancer. Having more cancer-affected relatives also has been correlated with greater testing uptake.
Table 15 summarizes the uptake of genetic testing in clinical and research cohorts in the United States.
Several studies conducted in non-U.S. settings have examined the uptake of genetic testing. In studies examining the uptake of testing among at-risk relatives of carriers of / pathogenic variants, uptake rates have averaged below 50% (range, 36%–48%), with higher uptake reported among female relatives than in male relatives. Other factors associated with higher uptake of testing were not consistently reported among studies but have most commonly included being a parent and wanting to learn information about a child’s risk.
Factors influencing uptake of genetic counseling and genetic testing
In reviews that have examined the cumulative evidence concerning the predictors of uptake of / genetic testing, important predictors of testing uptake include older age, Ashkenazi Jewish (AJ) heritage, unmarried status, a personal history of breast cancer, and a family history of breast cancer. Studies recruiting participants in hospital settings had significantly higher recruitment rates than did studies recruiting participants in community settings. Studies that required an immediate decision to test, rather than allowing delayed decision making, tended to report higher uptake rates. However, there is evidence that women diagnosed with breast cancer are equally satisfied with genetic counseling (including information received and strength and timing of physician recommendations for counseling), whether they received genetic counseling before or after their definitive surgery for breast cancer. Another review found that uptake of genetic testing for pathogenic variants was related to psychological factors (e.g., anxiety about breast cancer and perceived risk of breast cancer) and demographic and medical factors (e.g., history of breast cancer or ovarian cancer, presence of children, and higher number of affected first-degree relatives [FDRs]). Family members with a known pathogenic variant were more likely to pursue testing; those with more extensive knowledge of testing, heightened risk perceptions, beliefs that mammography would promote health benefit, and high intentions to undergo testing were more likely to follow through with testing.
In a review of racial/ethnic differences that affect uptake of testing, intention to undergo genetic testing in African American women was related to having at least one FDR with breast cancer or ovarian cancer, higher perceived risk of being a carrier, and less anticipatory guilt about the possibility of being a gene carrier.
Reasons cited for following through with testing included a desire to learn about a child's risk, to feel relief from uncertainty, to inform screening or risk-reducing surgery decisions, and to inform important life decisions such as marriage and childbearing. Among African American women, the most important reason for testing included motivation to help other relatives decide on genetic testing.
Physician recommendation may be another motivator for testing. In a retrospective study of 335 women considering genetic testing, 77% reported that they wanted the opinion of a genetics physician about whether they should be tested, and 49% wanted the opinion of their primary care provider. However, there is some evidence of referral bias favoring those with a maternal family history of breast cancer or ovarian cancer. In a Canadian retrospective review of 315 patients, those with a maternal family history of breast cancer or ovarian cancer were 4.9 times (95% confidence interval, 3.6–6.7) more likely to be referred for a cancer genetics consultation by their physician than were those with a paternal family history ( < .001). Studies have found that physicians may not adequately assess paternal family history or may underestimate the significance of a paternal family history for genetic risk.
Insurance coverage is an important consideration for individuals deciding whether to undergo genetic testing. (Refer to the Insurance coverage section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)
Uptake of genetic counseling and genetic testing in diverse populations
Degree of uptake of genetic counseling and genetic testing in diverse populations
There are limited data on uptake of genetic counseling and testing among nonwhite populations, and further research will be needed to define factors influencing uptake in these populations. The uptake of testing appears to vary across some racial/ethnic groups. A few studies have compared uptake rates between African American and white women. In a case-control study of women who had been seen in a university-based primary care system, African American women with family histories of breast cancer or ovarian cancer were less likely to undergo testing than were white women who had similar histories. In another study among breast cancer patients who were counseled about risk in a clinical setting, lower uptake was reported among African American women than among white women.
Notably, the racial differences observed in these studies do not appear to be explained by factors related to cost, access to care, risk factors for carrying a or pathogenic variant, or differences in psychosocial factors, including risk perceptions, worry, or attitudes toward testing.
Factors influencing uptake of genetic counseling and genetic testing in diverse populations
Several studies have examined uptake or “acceptance” of testing among African Americans enrolled in genetic research programs. Among study enrollees from an African American kindred in Utah, 83% underwent testing. Age, perceived risk of being a carrier, and more extensive cancer knowledge predicted testing acceptance. Another study that recruited African American women through physician and community referrals reported a testing acceptance rate of 22%. Predictors of test acceptance included having a higher probability of having a pathogenic variant, being married, and being less certain about one’s cancer risk. Finally, a third study that recruited at-risk African American women from an urban cancer screening clinic found that acceptors of testing were more knowledgeable about breast cancer genetics and perceived fewer barriers to testing, including negative emotional reactions, stigmatization concerns, and family-related guilt. While these are independent predictors of genetic testing uptake, they do not explain the disparities in testing uptake across different ethnic groups. What may explain these differences are several attitudes and beliefs held about testing by individuals from diverse populations.
Recent work examining attitudes toward breast cancer genetic testing in Latino and African American populations indicates limited knowledge and awareness about testing but a generally receptive view once they are informed; in comparison with whites, Latino and African American populations have relatively more concerns about testing.
For example, in a qualitative study with 51 Latino individuals unselected for risk status, important findings included the fact that participants were highly interested in genetic testing for inherited cancer susceptibility, despite very limited knowledge about genetics. One important barrier involved secrecy or embarrassment about family discussions of cancer and genetics, which could be addressed in intervention strategies. Another qualitative study with 54 Latina women at risk of hereditary breast cancer showed that knowledge about counseling was low, although the women were interested in learning more about counseling to gain risk information for family members. Barriers to counseling included life demands, cost, and language issues.
A telephone survey of 314 patients from an inner-city network of Pittsburgh, Pennsylvania, health centers, 50% of whom were African American, found that most participants (57%) (both African Americans and whites) felt that genetic testing to evaluate disease risk was a good idea; however, more African Americans than whites thought that genetic testing would lead to racial discrimination (37% vs. 22%, respectively) and that genetics research was unethical and tampered with nature (20% vs. 11%, respectively). Finally, in a study of 222 women in Savannah, Georgia, where most had neither a personal history (70%) nor a family history (60%) of breast cancer, African American women (who comprised 26% of the sample) were less likely to be aware of breast cancer genes and genetic testing. Awareness was also related to higher income, higher education level, and having a family breast cancer history. However, 74% of the entire sample expressed willingness to be tested for breast cancer susceptibility.
In a sample of 146 African American women meeting criteria for pathogenic variant testing, women born outside the United States reported higher levels of anticipated negative emotional reactions (e.g., fear, hopelessness, and lack of confidence that they could emotionally handle testing). Higher levels of breast cancer–specific distress were associated with anticipated negative emotional reactions, confidentiality concerns, and anticipated guilt regarding the family impact of breast cancer genetic testing. A future orientation (e.g., "I often think about how my actions today will affect my health when I am older") was associated with overall perceived benefits of breast cancer genetic testing in this population (n = 140); however, future orientation was also found to be positively associated with family-related cons of testing, including family guilt and worry regarding the impact of testing on the family.
Factors associated with declining genetic counseling and testing
There is evidence that primary reasons for declining testing involves being childless, which reduces any family motivations for testing; and concerns about the negative ramifications of testing, including difficulty retaining insurance or concerns about personal health.
Limited data are available about the characteristics of at-risk individuals who decline to be tested or have never been tested. It is difficult to access samples of test decliners because they may be reluctant to participate in research studies. Studies of genetic testing uptake are difficult to compare because people may decline at different points and with different amounts of pretest education and counseling. One study found that 43% of affected and unaffected individuals from hereditary breast/ovarian cancer families who completed a baseline interview regarding testing declined to be tested. Most individuals who declined testing chose not to participate in educational sessions. Decliners were more likely to be male and be unmarried, and have fewer relatives with breast cancer. Decliners who had high levels of cancer-related stress had higher levels of depression. Decliners lost to follow-up were significantly more likely to be affected with cancer.
Another study looked at a small number (n = 13) of women decliners who carried a 25% to 50% probability of harboring a pathogenic variant; these nontested women were more likely to be childless and to have higher levels of education. This study showed that most women decided not to undergo the test after serious deliberation about the risks and benefits. Satisfaction with frequent surveillance was given as one reason for nontesting by most of these women. Other reasons for declining included having no children and becoming acquainted with breast/ovarian cancer in the family relatively early in their lives.
A third study evaluated characteristics of 34 individuals who declined testing in a large multicenter study in the United Kingdom. Decliners were younger than a national sample of test acceptors, and female decliners had lower mean scores on a measure of cancer worry. Although 78% of test decliners/deferrers felt that their health was at risk, they reported that learning about their pathogenic variant status would cause them to worry about the following:
- Their children's health (76%).
- Their life insurance (60%).
- Their own health (56%).
- Loss of their job (5%).
- Receiving less screening if they did not carry a pathogenic variant (62%).
Apprehension about the impact of the test result was a more important factor in the decision to decline testing than were concrete burdens such as time required to travel to a genetics clinic and time spent away from work, family, and social obligations. In 15% (n = 31) of individuals from 13 hereditary breast and ovarian cancer families who underwent genetic education and counseling and declined testing for a documented pathogenic variant in the family, positive changes in family relationships were reported—specifically, greater expressiveness and cohesion—compared with those who pursued testing.
Genetic counseling and testing in children
Testing for pathogenic variants has been almost universally limited to adults older than 18 years. The risks of testing children for adult-onset disorders, such as breast and ovarian cancers, as inferred from developmental data on children’s medical understanding and ability to provide informed consent, have been outlined in several reports.
Studies suggest that persons who have undergone genetic testing or who are adult offspring of persons who have had testing are generally not in favor of testing minors. Although the data are limited, research suggests that males, pathogenic variant noncarriers, and those whose mothers did not have personal histories of breast cancer may be more likely to favor genetic testing in minors in general. Of those who had minor children at the time the study was conducted, only 17% stated a preference for having their own children tested. Concerns regarding testing of minors included psychological risks and insufficient maturity. Potential benefits included the ability to influence health behaviors.
No data exist on the testing of children for pathogenic variants, although some researchers believe it is necessary to test the validity of assumptions underlying the general prohibition of testing children for genetic variants associated with breast and ovarian cancers and other adult-onset diseases. In one study, 20 children (aged 11–17 years) of a selected group of mothers undergoing genetic testing (80% of whom previously had breast cancer and all of whom had discussed testing with their children) completed self-report questionnaires on their health beliefs and attitudes toward cancer, feelings related to cancer, and behavioral problems. Ninety percent of children thought they would want cancer risk information as adults; half worried about themselves or a family member developing cancer. There was no evidence of emotional distress or behavioral problems.
What People Bring to Genetic Testing: Impact of Risk Perception, Health Beliefs, and Personality Characteristics
The emerging literature in this area suggests that risk perceptions, health beliefs, psychological status, and personality characteristics are important factors in decision-making about breast/ovarian cancer genetic testing. Many women presenting at academic centers for testing arrive with a strong belief that they have a pathogenic variant, having decided they want genetic testing, but possessing little information about the risks or limitations of testing. Most mean scores of psychological functioning at baseline for subjects in genetic counseling studies were within normal limits. Nonetheless, a subset of subjects in many genetic counseling studies present with elevated anxiety, depression, or cancer worry. Identification of these individuals is essential to prevent adverse outcomes. In a study of 205 women pursuing genetic counseling, interactions among cancer worry, breast cancer risk perception, and perceived severity of having a breast cancer genetic variant were found such that those with high worry, high breast cancer risk perception, and low perceived severity were twice as likely to follow through with testing than others.
A general tendency to overestimate inherited risk of breast and ovarian cancer has been noted in at-risk populations, in cancer patients, in spouses of breast and ovarian cancer patients, and among women in the general population. but underestimation of breast cancer risk in higher-risk and average-risk women also has been reported. This overestimation may encourage a belief that genetic testing will be more informative than it is currently thought to be. Some evidence exists that even counseling does not dissuade women at low to moderate risk from the belief that testing could be valuable. Overestimation of both breast and ovarian cancer risk has been associated with nonadherence to physician-recommended screening practices. A meta-analysis of 12 studies of outcomes of genetic counseling for breast/ovarian cancer showed that counseling improved the accuracy of risk perception.
Women appear to be the prime communicators within families about the family history of breast cancer. Higher numbers of maternal versus paternal transmission cases are reported, likely due to family communication patterns, to the misconception that breast cancer risk can only be transmitted through the mother, and to the greater difficulty in recognizing paternal family histories because of the need to identify more distant relatives with cancer. In an analysis of 2,505 women participating in the Family Healthware Impact Trial, not only was evidence of underreporting of paternal family history identified, but also women reported a lower level of perceived breast cancer risk with a paternal versus maternal breast cancer family history. Physicians and counselors taking a family history are encouraged to elicit paternal and maternal family histories of breast, ovarian, or other associated cancers.
The accuracy of reported family history of breast or ovarian cancer varies; some studies found levels of accuracy above 90%, with others finding more errors in the reporting of cancer in second-degree or more distant relatives or in age of onset of cancer. Less accuracy has been found in the reporting of cancers other than breast cancer. Ovarian cancer history was reported with 60% accuracy in one study compared with 83% accuracy in breast cancer history. Providers should be aware that there are a few published cases of Munchausen syndrome in reporting of false family breast cancer history. Much more common is erroneous reporting of family cancer history due to unintentional errors or gaps in knowledge, related in some cases to the early death of potential maternal informants about cancer family history. (Refer to the Taking a Family History section of the Cancer Genetics Risk Assessment and Counseling summary for more information.)
Targeted written, video, CD-ROM, interactive computer program, and culturally targeted educational materials may be effective and efficient methods of increasing knowledge about the pros and cons of genetic testing. Such supplemental materials may allow more efficient use of the time allotted for pretest education and counseling by genetics and primary care providers and may discourage individuals without appropriate indication of risk from seeking genetic testing.
Genetic Counseling for Hereditary Predisposition to Breast Cancer
Counseling for breast cancer risk typically involves individuals with family histories that are potentially attributable to or . It also, however, may include individuals with family histories of Li-Fraumeni syndrome, ataxia-telangiectasia, Cowden syndrome, or Peutz-Jeghers syndrome. (Refer to the High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes section of this summary for more information.)
Management strategies for carriers may involve decisions about the nature, frequency, and timing of screening and surveillance procedures, chemoprevention, risk-reducing surgery, and use of hormone replacement therapy (HRT). The utilization of breast conservation and radiation as cancer therapy for women who are carriers may be influenced by knowledge of pathogenic variant status. (Refer to the Clinical Management of Carriers of BRCA Pathogenic Variants section of this summary for more information.)
Counseling also includes consideration of related psychosocial concerns and discussion of planned family communication and the responsibility to warn other family members about the possibility of having an increased risk of breast, ovarian, and other cancers. Data suggest that individual responses to being tested as adults are influenced by the results status of other family members. Management of anxiety and distress are important not only as quality-of-life factors, but also because high anxiety may interfere with the understanding and integration of complex genetic and medical information and adherence to screening. Formal, objective evaluation of these outcomes are well documented. (Refer to the Emotional Outcomes and Behavioral Outcomes sections of this summary for more information.)
Published descriptions of counseling programs for (and subsequently for ) testing include strategies for gathering a family history, assessing eligibility for testing, communicating the considerable volume of relevant information about breast/ovarian cancer genetics and associated medical and psychosocial risks and benefits, and discussion of specialized ethical considerations about confidentiality and family communication. Participant distress, intrusive thoughts about cancer, coping style, and social support were assessed in many prospective testing candidates. The psychosocial outcomes evaluated in these programs have included changes in knowledge about the genetics of breast/ovarian cancer after counseling, risk comprehension, psychological adjustment, family and social functioning, and reproductive and health behaviors. A Dutch study of communication processes and satisfaction levels of counselees going through cancer genetic counseling for inherited cancer syndromes indicated that asking more medical questions (by the counselor), providing more psychosocial information, and longer eye contact by the counselor were associated with lower satisfaction levels. The provision of medical information by the counselor was most highly related to satisfaction and perception that needs have been fulfilled.
Many of the psychosocial outcome studies involve specialized, highly selected research populations, some of which were utilized to map and clone and . One such example is K2082, an extensively studied kindred of more than 800 members of a Utah Mormon family in which a pathogenic variant accounts for the observed increased rates of breast and ovarian cancer. A study of the understanding that members of this kindred have about breast/ovarian cancer genetics found that, even in breast cancer research populations, there was incomplete knowledge about associated risks of colon and prostate cancer, the existence of options for risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), and the complexity of existing psychosocial risks. A meta-analysis of 21 studies found that genetic counseling was effective in increasing knowledge and improved the accuracy of perceived risk. Genetic counseling did not have a statistically significant long-term impact on affective outcomes including anxiety, distress, or cancer-specific worry and the behavioral outcome of cancer surveillance activities. These prospective studies, however, were characterized by a heterogeneity of measures of cancer-specific worry and inconsistent findings in effects of change from baseline.
Although there were initial concerns about the possibility of adverse emotional consequences from testing, most studies conducted over the years have shown low levels of psychological distress among both carriers and noncarriers, particularly over the longer term. In a meta-analysis examining cancer-specific distress over short (0–4 weeks), moderate (5–24 weeks), and long (25–52 weeks) periods of time since the receipt of testing results, carriers were found to demonstrate increased levels of distress shortly after receiving results, with levels returning to baseline within moderate and long periods of time. In contrast, noncarriers and those with inconclusive results showed reduced levels of distress over time. Psychological distress patterns were found to vary as a function of several factors, including the cancer history of the individual and the country within which the study was conducted. Carriers with a personal history of cancer experienced small decreases in distress over time, whereas no changes were observed among carriers without a personal history of cancer. Among individuals with inconclusive results, greater decreases in distress were observed among those without a cancer history than among those with a cancer history. Among noncarriers, those in the United States experienced significantly greater decreases in psychological distress than noncarriers from Europe and Australia. A study conducted in Austria noted that certain subgroups of counselees experienced greater distress, including those who were older, had a more recent cancer diagnosis, or those who had received counseling but declined testing.
Several studies have reported on emotional outcomes over longer follow-up periods (i.e., greater than 12 months after disclosure) than those reported in the meta-analysis described above. In a U.K. study, cancer-related worry did not differ between carriers and noncarriers at 3 years of follow-up. Two U.S.-based studies published since the meta-analytic review have reported similar findings among women who were surveyed more than 3 years after receipt of test results. In a cross-sectional study, 167 women who were surveyed more than 4 years after receiving test results reported low levels of genetic testing–specific concerns, as measured using the Multidimensional Impact of Cancer Risk Assessment Scale. In multivariate regression models, carriers of pathogenic variants were significantly more likely to experience distress than were noncarriers. In a second study, 464 women were followed prospectively for a median of 5 years (range: 3.4–9.1 years) after testing. Among both affected and unaffected participants, carriers reported significantly higher levels of distress, uncertainty (affected only), perceived stress (affected only), and lower positive testing experiences (unaffected only) than women who received negative results for a known pathogenic variant in the family. Although both studies reported greater distress among carriers than among noncarriers, the level of distress was not reflective of clinically significant dysfunction.
Although most studies have reported that a positive test result has a relatively minimal impact on psychological distress, many of these studies were conducted among families with a strong family history of breast or ovarian cancer who underwent extensive pretest genetic counseling. Therefore, emotional responses may not generalize to individuals who test under different contexts. For example, individuals who are tested with population screening may not have a family history of cancer. Although pretest genetic counseling is recommended, this is not always done when genetic testing is ordered by nongenetic providers or directly through commercial companies.
For example, in a Canadian study of 2,080 Jewish women who participated in a population-based genetic screening study to test for three pathogenic variants common in families of Jewish heritage, women were not offered in-person genetic counseling but were given a pamphlet on genetic testing for before they provided a DNA sample. One year after genetic testing, women who were positive for a pathogenic variant (n = 18) showed significant increases in cancer-specific distress, whereas no changes in distress were observed among women who were negative for a pathogenic variant. The mean distress score on the Impact of Event Scale for the 18 women with a known pathogenic variant was 25.3 (range, 2–51); 10 of 18 women (56%) scored within moderate (26–43) (n = 7) or severe (44+) (n = 3) ranges. It is unclear from this study whether the increase in distress observed at 1 year of follow-up was due to the lack of in-person genetic counseling, or whether the lower levels of distress at baseline observed were because the women in the study were low risk but eligible for testing because of their ancestry. A follow-up study with this cohort found that distress decreased between 1 to 2 years after testing and that changes in distress varied by risk-reduction options undertaken by carriers. Specifically, those who had undergone risk-reducing mastectomy or oophorectomy experienced significant decreases in distress compared with those who did not have either surgery. Another smaller qualitative study also supports these findings.
Similarly, the impact of direct-to-consumer (DTC) testing through commercial companies requires further evaluation. Case studies have reported adverse emotional responses after receipt of a positive result from DTC genetic testing, suggesting the need for further evaluation of the emotional outcomes of women undergoing genetic testing through commercial companies. Only one study, conducted by a commercial company, has attempted to evaluate the impact of testing in this context. A total of 32 individuals (16 women and 16 men) who tested positive for one of three founder pathogenic variants common in Ashkenazi Jews completed semi-structured interviews. None of the carriers reported extreme anxiety, although some experienced moderate anxiety (13%) or initial disappointment and anxiety that dissipated over time (28%). These findings should be interpreted with caution given that only 24% (32 of 136) of invited carriers of pathogenic variants participated in the study, raising concerns about selection bias.
Despite evidence of a short-term increase in distress after the receipt of genetic testing results, any adverse responses to a positive carrier status dissipate within 12 months. Additional research is needed to examine emotional outcomes for those who are not provided genetic counseling before testing.
Emotional outcomes of recently diagnosed individuals
testing, when offered to women newly diagnosed with breast cancer, has been shown to influence surgical decision making. Although some studies have raised concerns about the adverse psychological implications of offering rapid genetic counseling and testing between diagnosis and surgery, other studies, including a randomized trial and a qualitative study have provided evidence indicating no additional adverse psychological effects.
Family communication about genetic testing and hereditary risk
Family communication about genetic testing for cancer susceptibility, and specifically about the results of genetic testing, is complex; there are few systematic data available on this topic. Gender appears to be an important variable in family communication and psychological outcomes. One study documented that female carriers are more likely to disclose their status to other family members (especially sisters and children aged 14–18 years) than are male carriers. Among males, noncarriers were more likely than carriers to tell their sisters and children the results of their tests. carriers who disclosed their results to sisters had a slight decrease in psychological distress, compared with a slight increase in distress for carriers who chose not to tell their sisters. One study found that men reported greater difficulty disclosing a known pathogenic variant to family members than women (90% vs. 70%).
Family communication of test results to relatives is another factor affecting participation in testing. There have been more studies of communication with FDRs and second-degree relatives than with more distant family members. One study investigated the process and content of communication among sisters about test results. Study results suggest that both carriers of pathogenic variants and women with uninformative results communicate with sisters to provide them with genetic risk information. Among relatives with whom genetic test results were not discussed, the most important reason given was that the affected women were not close to their relatives. Studies found that women with a pathogenic variant more often shared their results with their mother and adult sisters and daughters than with their father and adult brothers and sons. A study that evaluated communication of test results to FDRs at 4 months postdisclosure found that women aged 40 years or older were more likely to inform their parents of test results compared with younger women. Participants also were more likely to inform brothers of their results if the pathogenic variant was inherited through the paternal line. Another study found that disclosure was limited mainly to FDRs, and dissemination of information to distant relatives was problematic. Age was a significant factor in informing distant relatives with younger patients being more willing to communicate their genetic test result.
A few in-depth qualitative studies have looked at issues associated with family communication about genetic testing. Although the findings from these studies may not be generalizable to the larger population of at-risk persons, they illustrate the complexity of issues involved in conveying hereditary cancer risk information in families. On the basis of 15 interviews conducted with women attending a familial cancer genetics clinic, the authors concluded that while women felt a sense of duty to discuss genetic testing with their relatives, they also experienced conflicting feelings of uncertainty, respect, and isolation. Decisions about whom in the family to inform and how to inform them about hereditary cancer and genetic testing may be influenced by tensions between women's need to fulfill social roles and their responsibilities toward themselves and others. Another qualitative study of 21 women who attended a familial breast and ovarian cancer genetics clinic suggested that some women may find it difficult to communicate about inherited cancer risk with their partners and with certain relatives, especially brothers, because of those persons’ own fears and worries about cancer. This study also suggested that how genetic risk information is shared within families may depend on the existing norms for communicating about cancer in general. For example, family members may be generally open to sharing information about cancer with each other, may selectively avoid discussing cancer information with certain family members to protect themselves or other relatives from negative emotional reactions, or may ask a specific relative to act as an intermediary to disclosure of information to other family members. The potential importance of persons outside the family, such as friends, as both confidantes about inherited cancer risk information and as sources of support for coping with this information was also noted in the study.
A study of 31 mothers with a documented pathogenic variant explored patterns of dissemination to children. Of those who chose to disclose test results to their children, age of offspring was the most important factor. Fifty percent of the children who were told were aged 20 to 29 years and slightly more than 25% of the children were aged 19 years or younger. Sons and daughters were notified in equal numbers. More than 70% of mothers informed their children within a week of learning their test result. Ninety-three percent of mothers who chose not to share their results with their children indicated that it was because their children were too young. These findings were consistent with three other studies showing that children younger than 13 years were less likely to be informed about test results compared with older children. Another study of 187 mothers undergoing testing evaluated their need for resources to prepare for a facilitated conversation about sharing their testing results with their children. Seventy-eight percent of mothers were interested in three or more resources, including literature (93%), family counseling (86%), talk to prior participants (79%), and support groups (54%).
A longitudinal study of 153 women self-referred for genetic testing for and pathogenic variants and 118 of their partners evaluated communication about genetic testing and distress before testing and at 6 months posttesting. The study found that most couples discussed the decision to undergo testing (98%), most test participants felt their partners were supportive, and most women disclosed test results to their partners (97%, n = 148). Test participants who felt their partners were supportive during pretest discussions experienced less distress after disclosure, and partners who felt more comfortable sharing concerns with test participants pretest experienced less distress after disclosure. Six-month follow-up revealed that 22% of participants felt the need to talk about the testing experience with their partners in the week before the interview. Most participants (72%, n = 107) reported comfort in sharing concerns with their partners, and 5% (n = 7) reported relationship strain as a result of genetic testing. In couples in which the woman had a positive genetic test result, more relationship strain, more protective buffering of their partners, and more discussion of related concerns were reported than in couples in which the woman had a true-negative or uninformative result.
There is a small but growing body of literature regarding psychological effects in men who have a family history of breast cancer and who are considering or have had testing. A qualitative study of 22 men from 16 high-risk families in Ireland revealed that more men in the study with daughters were tested than men without daughters. These men reported little communication with relatives about the illness, with some men reporting being excluded from discussion about cancer among female family members. Some men in the study also reported actively avoiding open discussion with daughters and other relatives. In contrast, a study of 59 men testing positive for a pathogenic variant found that most men participated in family discussions about breast and/or ovarian cancer. However, fewer than half of the men participated in family discussions about risk-reducing surgery. The main reason given for having testing was concern for their children and a need for certainty about whether they could have transmitted the pathogenic variant to their children. In this study, 79% of participating men had at least one daughter. Most of these men described how their relationships had been strengthened after receipt of results, helping communication in the family and greater understanding. Men in both studies expressed fears of developing cancer themselves. Irish men especially reported fear of cancer in sexual organs.
One study assessed 212 individuals from 13 hereditary breast and ovarian cancer families who received genetic counseling and were offered testing for documented pathogenic variants in the family. Individuals who were not tested were found 6 to 9 months later to have significantly greater increases in family expressiveness and cohesiveness compared with those who were tested. Persons who were randomly assigned to a client-centered versus problem-solving genetic counseling intervention had a significantly greater reduction in conflict, regardless of the test decision.
Partners of high-risk women
Many studies have looked at the psychological effects in women of having a high risk of developing cancer, either on the basis of carrying a pathogenic variant or having a strong family history of cancer. Some studies have also examined the effects on the partners of such women.
A Canadian study assessed 59 spouses of women found to have a pathogenic variant. All were supportive of their spouses’ decision to undergo genetic testing and 17% wished they had been more involved in the genetic testing process. Spouses who reported that genetic testing had no impact on their relationship had long-term relationships (mean duration 27 years). Forty-six percent of spouses reported that their major concern was of their partner dying of cancer. Nineteen percent were concerned their spouse would develop cancer and 14% were concerned their children would also be carriers of pathogenic variants.
In a U.S. study, 118 partners of women who underwent genetic testing for pathogenic variants in and completed a survey before testing and then again 6 months after result disclosure. At 6 months, only 10 partners reported that they had not been told of the test result. Ninety-one percent reported that the testing had not caused strain on their relationship. Partners who were comfortable sharing concerns before testing experienced less distress after testing. Protective buffering was not found to impact distress levels of partners.
An Australian study of 95 unaffected women at high risk of developing breast and/or ovarian cancer (13 carriers of pathogenic variants and 82 with unknown variant status) and their partners showed that although the majority of male partners had distress levels comparable to a normative population sample, 10% had significant levels of distress that indicated the need for further clinical intervention. Men with a high monitoring coping style and greater perceived breast cancer risk for their wives reported higher levels of distress. Open communication between the men and their partners and the occurrence of a cancer-related event in the wife’s family in the last year were associated with lower distress levels. When men were asked what kind of information and support they would like for themselves and their partners, 57.9% reported that they would like more information about breast and ovarian cancer, and 32.6% said they would like more support in dealing with their partner's risk. Twenty-five percent of men had suggestions on how to improve services for partners of high-risk women, including strategies on how to best support their partner, greater encouragement from health care professionals to attend appointments, and meeting with other partners.
A review of this literature reported that the testing process may be distressing for male partners, particularly for those with spouses identified as carriers. Male partner distress appears to be associated with their beliefs about the woman’s breast cancer risk, lack of couple communication, and feelings of alienation from the testing process.
A review of the literature on the experiences of males in families with a known and pathogenic variant reported that while the data are limited, men from variant-positive families are less likely than females to participate in communication regarding genetics at every level, including the counseling and testing process. Men are less likely to be informed of genetic test results received by female relatives, and most men from these families do not pursue their own genetic testing.
A study of Dutch men at increased risk of having inherited a pathogenic variant reported a tendency for the men to deny or minimize the emotional effects of their risk status, and to focus on medical implications for their female relatives. Men in these families, however, also reported considerable distress in relation to their female relatives. In another study of male psychological functioning during breast cancer testing, 28 men belonging to 18 different high-risk families (with a 25% or 50% risk of having inherited a pathogenic variant) participated. The study purpose was to analyze distress in males at risk of carrying a pathogenic variant who applied for genetic testing. Of the men studied, most had low pretest distress; scores were lowest for men who were optimistic or who did not have daughters. Most carriers of pathogenic variants had normal levels of anxiety and depression and reported no guilt, though some anticipated increased distress and feelings of responsibility if their daughters developed breast or ovarian cancer. None of the noncarriers reported feeling guilty. In one study, adherence to recommended screening guidelines after testing was analyzed. In this study, more than half of male carriers of pathogenic variants did not adhere to the screening guidelines recommended after disclosure of genetic test results. These findings are consistent with those for female carriers of pathogenic variants.
A multicenter U.K. cohort study examined prospective outcomes of testing in 193 individuals, of which 20% were men aged 28 to 86 years. Men’s distress levels were low, did not differ among carriers and noncarriers, and did not change from baseline (before genetic testing) to the 3-year follow-up. Twenty-two percent of male carriers of pathogenic variants received colorectal cancer screening and 44% received prostate cancer screening; however, it is unclear whether men in this study were following age-appropriate screening guidelines.
Several studies have explored communication of test results to at-risk children. Across all studies, the rate of disclosure to children ranging in age from 4 to 25 years is approximately 50%. In general, age of offspring was the most important factor in deciding whether to disclose test results. In one study of 31 mothers disclosing their test results, 50% of the children who were informed of the results were aged 20 to 29 years and slightly more than 25% of the children were aged 19 years or younger. Sons and daughters were notified in equal numbers. Similarly, in another study of 42 female carriers of pathogenic variants, 83% of offspring older than age 18 years were told of the results, while only 21% of offspring aged 13 years or younger were told.
Several studies have also looked at the timing of disclosure to children after parents receive their test results. Although the majority of children were told within a week to several months after results disclosure, some parents chose to delay disclosure. Reasons for delaying disclosure included waiting for the child to get older, allowing time for the parent to adjust to the information, and waiting until results could be shared in person (in the case of adult children living away from home).
In one study, participants who told children younger than 13 years about their carrier status had increased distress, and those who did not tell their young children experienced a slight decrease in distress. Communication with young children was found to be influenced by developmental variables such as age and style of parent/child communication.
One study looked at the reaction of children to results disclosure or the effect on the parent-child relationship of communicating the results. With regard to offspring’s understanding of the information, almost half of parents from one study reported that their child did not appear to understand the significance of a positive test result, although older children were reported to have a better understanding. This same study also showed that 48% of parents reported at least one negative reaction in their child, ranging from anxiety or concern (22%) to crying and fear (26%). It should be noted, however, that in this study children's level of understanding and reactions to the test result were measured qualitatively and based only on the parents' perception. Also, given the retrospective design of the study, there was a potential for recall bias. There were no significant differences in emotional reaction depending on age or gender of the child. Lastly, 65% of parents reported no change in their relationship with their child, while 5 parents (22%) reported a strengthening of their relationship.
Interestingly, a large multicenter study of 869 mother-daughter pairs (the daughters were aged 6 to 13 years) found that girls with a family history of breast cancer or a familial pathogenic variant (BCFH+) compared with those without such family histories had better psychosocial adjustment by maternal report. However, based on a combination of maternal report and direct assessment of girls aged 10 to 13 years, BCFH+ girls experienced greater breast cancer–specific distress and a higher perceived risk of breast cancer than their peers without such family histories. Moreover, higher daughter distress was associated with higher maternal distress. A similarly designed study in older girls, aged 11 to 19 years, found that higher breast cancer–specific distress in daughters was associated with perceived risk and maternal distress. This older age group had higher self-esteem than did their peers without a family history of breast cancer.
Another study of 187 mothers undergoing testing evaluated their need for resources to prepare for a facilitated conversation about sharing their testing results with their children. Seventy-eight percent of mothers were interested in three or more resources, including literature (93%), family counseling (86%), talking to prior participants (79%), and support groups (54%).
Testing for has been almost universally limited to adults older than 18 years. The risks of testing children for adult-onset disorders (such as breast and ovarian cancer), as inferred from developmental data on children’s medical understanding and ability to provide informed consent, have been outlined in several reports. Surveys of parental interest in testing children for adult-onset hereditary cancers suggest that parents are more eager to test their children than to be tested themselves for a breast cancer gene, suggesting potential conflicts for providers. In a general population survey in the United States, 71% of parents said that it was moderately, very, or extremely likely that if they carried a breast-cancer predisposing pathogenic variant, they would test a 13-year-old daughter now to determine her breast cancer gene status. To date, no data exist on the testing of children for , though some researchers believe it is necessary to test the validity of assumptions underlying the general prohibition of testing of children for breast/ovarian cancer and other adult-onset disease genes. In one study, 20 children (aged 11–17 years) of a selected group of mothers undergoing genetic testing (80% of whom previously had breast cancer and all of whom had discussed testing with their children) completed self-report questionnaires on their health beliefs and attitudes toward cancer, feelings related to cancer, and behavioral problems. Ninety percent of children thought they would want cancer risk information as adults; half worried about themselves or a family member developing cancer. There was no evidence of emotional distress or behavioral problems. Another study by this group found that 1 month after disclosure of genetic test results, 53% of 42 enrolled mothers of children aged 8 to 17 years had discussed their result with one or more of their children. Age of the child rather than pathogenic variant status of the mother influenced whether they were told, as did family health communication style.
Prenatal diagnosis and preimplantation genetic diagnosis
The possibility of transmitting a pathogenic variant to a child may pose a concern to families affected by history of breast/ovarian cancer (HBOC), perhaps to the extent that some carriers may avoid childbearing. These concerns also may prompt women to consider using prenatal diagnosis methods to help reduce the risk of transmission. Prenatal diagnosis is an encompassing term used to refer to any medical procedure conducted to assess the presence of a genetic disorder in a fetus. Methods include amniocentesis and chorionic villous sampling (CVS). Both procedures carry some risk of miscarriage and some evidence suggests fetal defects may result from using these tests. Moreover, discovering the fetus is a carrier for a genetic defect may impose a difficult decision for couples regarding pregnancy continuation or termination. An alternative to these tests is preimplantation genetic diagnosis (PGD), a procedure used to test fertilized embryos for genetic disorders before uterine implantation, thereby avoiding the potential dangers associated with amniocentesis and CVS and the decision to terminate a pregnancy. Using the information obtained from the genetic testing, potential parents can decide whether or not to implant. PGD can be used to detect pathogenic variants in hereditary cancer predisposing genes, including .
In the United States, a series of studies has evaluated awareness, interest (e.g., would consider using PGD), and attitudes related to PGD among members of Facing Our Risk of Cancer Empowered (FORCE), an advocacy organization focused on persons at increased risk of HBOC. The first study was a Web-based survey of 283 members, the second included 205 attendees of the 2007 annual FORCE conference, and the third was a Web-based survey of 962 members. These studies have documented low levels of awareness, with 20% to 32% of study respondents reporting having heard of PGD before study participation. With respect to interest in PGD, the first study found only 13% of women would be likely to use PGD, whereas, 33% of respondents in the subsequent FORCE studies reported that they would consider using PGD. In the third FORCE-based study (n = 962), multivariable analysis revealed PGD interest was associated with the desire to have more children, having previously had any prenatal genetic test, and previous awareness of PGD. Attitudinal predictors of interest in PGD included agreement that others at risk of HBOC should be offered PGD; the belief that PGD is acceptable for persons at risk of HBOC; the belief that PGD information should be given to individuals at risk of HBOC; and endorsement of PGD benefits of having children without genetic variants and eliminating genetic diseases. Conversely, those who indicated that PGD was “too much like playing God” and reported that they considered PGD in the context of religion, had less interest in PGD.
It is unknown whether the attitudes of FORCE members toward PGD are representative of the majority of carriers. One study of 171 clinic-based patients from a single U.S. institution who tested positive for a pathogenic variant found that approximately 20% (33 of 168) were aware of PGD; 72% (122 of 169) thought PGD should be offered; and 41% (65 of 158) would consider PGD.
The U.K. Human Fertilization and Embryology authority has approved the use of PGD for hereditary breast and ovarian cancer. In a sample of 102 women with a pathogenic variant, most were supportive of PGD but only 38% of the women who had completed their families would consider it for themselves had PGD been available, and only 14% of women who were contemplating a future pregnancy would consider PGD. In a study of 77 individuals undergoing testing as part of a multicenter cohort study in Spain, 61% of respondents reported they would consider PGD. Factors associated with PGD interest were age 40 years and older and had a prior cancer diagnosis.
In France, couples who obtain authorization from a multidisciplinary prenatal diagnosis team may access PGD free of charge as a benefit of their national health care system. However, no carriers have been authorized to use PGD. In a national study of 490 unaffected carriers of pathogenic variants of childbearing age (women aged 18–49 years; men aged 18–69 years), 16% stated that test results had altered their ongoing plans for childbearing. Upon qualitative analysis of written comments provided by some respondents, the primary impact was related to accelerating the timing of pregnancy, feelings of guilt about possibly passing on the pathogenic variant to offspring, and having future children. In response to a hypothetical scenario in which PGD was readily available, 33% of participants reported that they would undergo PGD. Factors associated with this intention were having no future reproductive plans at the time of the survey, feeling pregnancy termination was an acceptable option in the context of identifying a pathogenic variant, and having fewer cases of breast and/or ovarian cancer in the family. When presented with questions about expectations about delivery of PGD or prenatal diagnosis (PND) information, 85% of respondents felt it should be provided along with test results; 45% felt that it should be provided when carriers decide to have children. Respondents stated that they would expect this information to be delivered by cancer geneticists (92%), obstetrician/gynecologists (76%), and general practitioners (48%).
A small (N = 25) qualitative study of women of reproductive age positive for a pathogenic variant who underwent genetic testing before having children evaluated how their status influenced their attitudes about reproductive genetic testing (both PGD and PND) and decisions about having children. In this study, the decision to undergo testing was primarily motivated by the desire to manage one’s personal cancer risk, rather than a desire to inform future reproductive decisions. The perceived severity of HBOC influenced concerns about passing on a pathogenic variant to children and also influenced willingness to consider PGD or PND and varied based on personal experience. Most did not believe that a known pathogenic variant was a reason to terminate a pregnancy. As observed in prior studies, knowledge of reproductive options varied; however, there was a tendency among participants to view PGD as more acceptable than PND with regard to termination of pregnancy. Decisions regarding the pros and cons of PGD versus PND with termination of pregnancy were driven primarily by personal preferences and experiences, rather than by morality judgments. For example, women were deterred from PGD based on the need to undergo fertilization and to take hormones that might increase cancer risk and based on the observed experiences of others who underwent this procedure.
One study has examined these issues among high-risk men recruited from FORCE and Craigslist (a bulletin board website) (N = 228). Similar to the previous studies of women, only 20% of men were aware of PGD before survey participation. In a multivariate analysis, those who selected the “other” option for possible benefits of PGD compared with those who selected from several predetermined options (e.g., having children without genetic variants) and those who considered PGD in the context of religion (as opposed to health and safety) were less likely to report that they would ever consider using PGD.
The recognition that pathogenic variants are prevalent, not only in breast/ovarian cancer families but also in some ethnic groups, has led to considerable discussion of the ethical, psychological, and other implications of having one’s ethnicity be a factor in determination of disease predisposition. Concerns that people will think everything is solely determined by genetic factors and the creation of a genetic underclass have been voiced. Questions about the impact on the group of being singled out as having genetic vulnerability to breast cancer have been raised. There is also confusion about who gives or withholds permission for the group to be involved in studies of their genetic identity. These issues challenge traditional views on informed consent as a function of individual autonomy.
A growing literature on the unique factors influencing a variety of cultural subgroups suggests the importance of developing culturally specific genetic counseling and educational approaches. The inclusion of members within the community of interest (e.g., breast cancer survivors, advocates, and community leaders) may enhance the development of culturally tailored genetic counseling materials. One study showed that participation in any genetic counseling (culturally mediated or standard approaches) reduced perceived risk of developing breast cancer.
The human implications of the ethical issues raised by the advent of genetic testing for breast/ovarian cancer susceptibility are described in case studies, essays, and research reports. Issues about rights and responsibilities in families concerning the spread of information about genetic risk promise to be major ethical and legal dilemmas in the coming decades.
Studies have shown that 62% of studied family members were aware of the family history and that 88% of hereditary breast/ovarian cancer family members surveyed have significant concerns about privacy and confidentiality. Expressed concern about cancer in third-degree relatives, or relatives farther removed, was about the same as that for first- or second-degree relatives of the proband. Only half of surveyed FDRs of women with breast or ovarian cancer felt that written permission should be required to disclose test results to a spouse or immediate family member. Attitudes toward testing varied by ethnicity, previous exposure to genetic information, age, optimism, and information style. Altruism is a factor motivating genetic testing in some people. Many professional groups have made recommendations regarding informed consent. There is some evidence that not all practitioners are aware of or follow these guidelines. Research shows that many genetic testing consent forms do not fulfill recommendations by professional groups about the 11 areas that should be addressed, and they omit highly relevant points of information. In a study of women with a history of breast or ovarian cancer, the interviews yielded that the women reported feeling inadequately prepared for the ethical dilemmas they encountered when imparting genetic information to family members. These data suggest that more preparation about disclosure to family members before testing reduces the emotional burden of disseminating genetic information to family members. Patients and health care providers would benefit from enhanced consideration of the ethical issues of warning family members about hereditary cancer risk. (Refer to the PDQ summaries Cancer Genetics Risk Assessment and Counseling and Cancer Genetics Overview for more information about the ethics of cancer genetics and genetic testing.)
Psychosocial Aspects of Cancer Risk Management for Hereditary Breast and Ovarian Cancer
Decision aids for persons considering risk management options for hereditary breast and ovarian cancer
There is a small but growing body of literature on the use of decision aids as an adjunct to standard genetic counseling to assist patients in making informed decisions about cancer risk management. One study showed that the use of a decision aid consisting of individualized value assessment and cancer risk management information after receiving positive test results was associated with fewer intrusive thoughts and lower levels of depression at the 6-month follow-up in unaffected women. Use of the decision aid did not alter cancer risk management intentions and behaviors. Slightly detrimental effects on well-being and several decision-related outcomes, however, were noted among affected women. Another study compared responses to a tailored decision aid (including a values-clarification exercise) versus a general information pamphlet intended for women making decisions about ovarian cancer risk management. In the short term, the women receiving the tailored decision aid showed a decrease in decisional conflict and increased knowledge compared with women receiving the pamphlet, but no differences in decisional outcomes were found between the two groups. In addition, the decision aid did not appear to alter the participant’s baseline cancer risk management decisions. A multisite randomized trial of 150 unaffected women with pathogenic variants assessed the effect of a decision aid on breast cancer risk management decisions and psychosocial outcomes. At 6-month and 12-month follow-up, women randomly assigned to the decision aid had lower levels of cancer-related distress ( = .01 at 6 months and = .05 at 12 months) than did the control group. Decisional conflict scores were relatively low at baseline and declined over time in both groups; the scores between the two groups were not statistically different.
Uptake of cancer risk management options
An increasing number of studies have examined uptake and adherence to cancer risk management options among individuals who have undergone genetic counseling and testing for and pathogenic variants. Findings from these studies are reported in Table 16 and Table 17. Outcomes vary across studies and include uptake or adherence to screening (mammography, magnetic resonance imaging [MRI], cancer antigen [CA] 125, transvaginal ultrasound [TVUS]) and selection of RRM and RRSO. Studies generally report outcomes by pathogenic variant carrier or testing status (e.g., positive for pathogenic variants, negative for pathogenic variants, or declined genetic testing). Follow-up time after notification of genetic risk status also varied across studies, ranging from 12 months up to several years.
Findings from these studies suggest that breast screening often improves after notification of pathogenic variant carrier status; nonetheless, screening remains suboptimal. Fewer studies have examined adoption of MRI as a screening modality, probably due to the recent availability of efficacy data. Screening for ovarian cancer varied widely across studies, and also varied based on type of screening test (i.e., CA-125 serum testing vs. TVUS screening). However, ovarian cancer screening does not appear to be widely adopted by carriers of pathogenic variants. Uptake of RRM varied widely across studies, and may be influenced by personal factors (such as younger age or having a family history of breast cancer), psychosocial factors (such as a desire for reduction of cancer-related distress), recommendations of the health care provider, and cultural or health care system factors. An individual’s choice to have a bilateral mastectomy also appears to be influenced by pretreatment genetic education and counseling regardless of the genetic test results. Similarly, uptake of RRSO also varied across studies, and may be influenced by similar factors, including older age, personal history of breast cancer, perceived risk of ovarian cancer, cultural factors (i.e., country), and the recommendations of the health care provider.
On the other hand, many women found to be pathogenic variant carriers express interest in RRM in hopes of minimizing their risk of breast cancer. In one study of a number of unaffected women with no previous risk-reducing surgery who received results of testing after genetic counseling, 17% of carriers (2 of 12) intended to have mastectomies and 33% (4 of 12) intended to have oophorectomies. In a later study of the same population, RRM was considered an important option by 35% of women who tested positive, whereas risk-reducing oophorectomy was considered an important option by 76%. A prospective study assessed the stability of risk management preferences over five time points (pre- testing to 9 months after results disclosure) among 80 Dutch women with a documented pathogenic variant. Forty-six participants indicated a preference for screening at baseline. Of 25 women who preferred RRM at baseline, 22 indicated the same preference 9 months after test results disclosure; however, it was not reported how many women actually had RRM.
Initial interest does not always translate into the decision for surgery. Two different studies found low rates of RRM among carriers of pathogenic variants in the year after result disclosure, one showing 3% (1 of 29) of carriers and the other 9% (3 of 34) of carriers having had this surgery. Among members from a large kindred, utilization of cancer screening and/or risk-reducing surgeries was assessed at baseline (before disclosure of results), and at 1 year and 2 years after disclosure of test results. Of the 269 men and women who participated, complete data were obtained on 37 female carriers and 92 female noncarriers, all aged 25 years or older. At 2 years after disclosure of test results, none of the women had undergone RRM, although 4 of the 37 carriers (10.8%) said they were considering the procedure. In contrast, of the 26 women who had not had an oophorectomy before baseline, 46% (12 of 26) had obtained an oophorectomy by 2 years after testing. Of those carriers aged 25 to 39 years, 29% (5 of 17) underwent oophorectomy, while 78% (7 of 9) of the carriers aged 40 years and older had this procedure. In a study assessing uptake of risk-reducing surgery 3 months after result disclosure, 7 of 62 women had undergone RRM and 13 of 62 women had undergone RRSO. Intent to undergo RRSO before testing correlated with procedure uptake. In contrast, intent to undergo RRM did not correlate with uptake. Overall, reasons given for indecision about risk-reducing surgery included complex testing factors such as the significance of family history in the absence of a pathogenic variant, concerns over the surgical procedure, and time and uncertainty regarding early menopause and the use of HRT. In a U.K. study, data were collected during observations of genetic consultations and in semistructured interviews with 41 women after they received genetic counseling. The option of risk-reducing surgery was raised in 29 consultations and discussed in 35 of the postclinic interviews. Fifteen women said they would consider having an oophorectomy in the future, and nine said they would consider having a mastectomy. The implications of undergoing oophorectomy and mastectomy were discussed in postclinic interviews. Risk-reducing surgery was described by the counselees as providing individuals with a means to (a) fulfill their obligations to other family members and (b) reduce risk and contain their fear of cancer. The costs of this form of risk management were described by the respondents as follows:
- Compromising social obligations.
- Upsetting the natural balance of the body.
- Not receiving protection from cancer.
- Operative and postoperative complications.
- The onset of menopause.
- The effects of body image, gender, and personal identity.
- Potential effects on sexual relationships.
A number of women choose to undergo RRM and RRSO without genetic testing because of the following:
- Testing is not readily accessible.
- They do not wish exposure to the psychosocial risks of genetic testing.
- They do not trust that a negative genetic test result means they are not at increased risk.
- They find any level of risk, even baseline population risk, unacceptable.
Among FDRs of breast cancer patients attending a surveillance clinic, women who expressed an interest in RRM and/or had undergone surgery were found to have significantly more breast cancer biopsies ( < .05) and higher subjective 10-year breast cancer risk estimates ( < .05) than women not interested in RRM. Cancer worry at the time of entry into the clinic was highest among women who subsequently underwent RRM compared with women who expressed interest but had not yet had surgery and women who did not intend to have surgery ( < .001).
Few studies have evaluated the impact of test results on risk-reducing surgery decisions among women affected with breast cancer. A study that evaluated predictors of contralateral RRM among 435 breast cancer survivors found that 16% had undergone contralateral RRM (in conjunction with mastectomy of the affected breast) before referral for genetic counseling and genetic testing. Predictors of contralateral RRM before genetic counseling and testing included younger age at breast cancer diagnosis, more time since diagnosis, having at least one affected FDR, and not being employed full-time. In the year after disclosure of test results, 18% of women who tested positive for a pathogenic variant and 2% of those whose test results were uninformative underwent contralateral RRM. Predictors of contralateral RRM after genetic testing included younger age at breast cancer diagnosis, higher cancer-specific distress before genetic counseling, and having a positive test result. In this study, contralateral RRM was not associated with distress at 1 year after disclosure of genetic test results. A retrospective chart review evaluated uptake of bilateral mastectomies in 110 women who underwent genetic testing before making surgical decisions about the treatment of newly diagnosed breast cancer. Carriers of pathogenic variants were more likely to undergo bilateral mastectomies than were women in whom no variant was detected (83% vs. 37%; = .046). The only predictor of contralateral RRM in women without a pathogenic variant was being married ( = .03). Age, race, parity, disease stage and biomarkers, increased mammographic breast density, and breast MRI did not influence contralateral RRM decisions at the time of primary surgical treatment.
Dutch women (N = 114) who had undergone unilateral or bilateral RRM with breast reconstruction between 1994 and 2002 were retrospectively surveyed to determine their satisfaction with the procedure. Sixty-eight percent were either unaffected carriers of pathogenic variants or at 50% risk of having a pathogenic variant in their family. Sixty percent of respondents indicated that they were satisfied with the procedure, 95% would opt for RRM again, and 80% would opt for the same reconstruction procedure. Less than half reported some perioperative or postoperative complications, ongoing physical complaints, or some physical limitations. Twenty-nine percent reported altered feelings of femininity after the procedure, 44% reported adverse changes in their sexual relationships, and 35% indicated that they believed their partners experienced adverse changes in their sexual relationship. Ten percent of women, however, reported positive changes in their sexual relationship after the procedure. Compared with patients who indicated satisfaction with this procedure, nonsatisfied patients were more likely to feel less informed about the procedure and its consequences, report more complications and physical complaints, feel that their breasts did not belong to their body, and indicate that they would not opt for reconstruction again. Those who reported a negative effect on their sexual relationship were more likely to:
- Feel less informed.
- Experience more physical complaints and limitations.
- Express that their breasts did not feel like their own.
- Be disinclined to opt for reconstruction again.
- State that the surgery had not met their expectations.
- Experience altered feelings of femininity and perceived adverse changes in their partner’s view of their femininity and their sexual relationship.
Ninety Swedish women who had undergone RRM between 1997 and 2005 were surveyed before surgery, 6 months after surgery, and 1 year after surgery to evaluate changes in health-related quality of life, depression, anxiety, sexuality, and body image. There were no significant changes in health-related quality of life or depression at the three time points; anxiety decreased over time ( = .0004). More than 80% of women reported having an intimate relationship at all three time points. Women who reported being sexually active were asked to respond to questions about sexual pleasure, discomfort, habit, and frequency of activity. There were no statistically significant differences related to frequency, habit, or discomfort. However, pleasure significantly decreased between baseline and 1 year after surgery ( = .005). At 1 year after surgery, 48% of women reported feeling less attractive, 48% reported feeling self-conscious, and 44% reported dissatisfaction with surgical scars.
Discussion of risk-reducing surgical options may not consistently occur during pretest genetic counseling. In one multi-institutional study, only one-half of genetics specialists discussed RRM and RRSO in consultations with women from high-risk breast cancer families, despite the fact that discussion of surgical options was significantly associated with meeting counselees’ expectations, and that such information was not associated with increased anxiety.
Given the increased risk of ovarian cancer faced by women with a or pathogenic variant, those who do receive information about RRSO show wide variations in surgery uptake (27%–72%). A study showed that clinical factors related to choosing RRSO versus surveillance alone are older age, parity of one or more, and a prior breast cancer diagnosis. In this study, the choice of RRSO was not related to family history of breast or ovarian cancer. Hysterectomy was presented as an option during genetic counseling and 80% of women who underwent RRSO also elected to have a hysterectomy.
Cancer screening and risk-reducing behaviors
Data are now emerging regarding uptake and adherence to cancer risk management recommendations such as screening and risk-reducing interventions. Cancer screening adherence and risk-reduction behaviors as defined by the National Comprehensive Cancer Network Guidelines were assessed in a cross-sectional study of 214 women with a personal history (n = 134) or family history (n = 80) of breast or ovarian cancer. Among unaffected women older than 40 years, 10% had not had a mammogram or clinical breast examination (CBE) in the previous year and 46% did not practice breast self-examination (BSE). Among women previously affected with breast or ovarian cancer, 21% had not had a mammogram, 32% had not had a CBE, and 39% did not practice BSE.
Three hundred and twelve women who were counseled and tested for pathogenic variants between 1997 and 2005 responded to a survey regarding their perception of genetic testing for hereditary breast and ovarian cancer. The survey included questions on risk reduction options, including screening and risk-reducing surgeries. Two hundred and seventeen (70%) of the women had been diagnosed with breast cancer, and 86 (28%) tested positive for a pathogenic variant in either the or gene. None of the -positive women agreed that mammograms are difficult procedures because of the discomfort, while 11 (5.4%) of the -negative women did agree with this statement. Both groups (-positive and -negative) agreed that risk-reducing surgeries provide the best means for lowering cancer risk and worry, and most patients in both groups expressed the belief that risk-reducing mastectomy is not too drastic, too scary, or too disfiguring.
A prospective study from the United Kingdom examined the psychological impact of mammographic screening in 1,286 women aged 35 to 49 years who have a family history of breast cancer and were participants in a multicenter screening program. Mammographic abnormalities that required additional evaluation were detected in 112 women. These women, however, did not show a statistically significant increase in cancer worry or negative psychological consequences as a result of these findings. The 1,174 women who had no mammographic abnormality detected experienced a decrease in cancer worry and a decrease in negative psychological consequences compared with baseline after receipt of their results. At 6 months, the entire cohort had experienced a decrease in measures of cancer worry and psychological consequences of breast screening.
A qualitative study explored health care professionals’ views regarding the provision of information about health protective behaviors (e.g., exercise and diet). Seven medical specialists and ten genetic counselors were interviewed during a focus group or individually. The study reported wide variation in the content and extent of information provided about health-protective behaviors and in general, participants did not consider it their role to promote such behaviors in the context of a genetic counseling session. There was agreement, however, about the need to form consensus about provision of such information both within and across risk assessment clinics.
Not all studies specify whether screening uptake rates fall within recommended guidelines for the targeted population or the specific clinical scenario, nor do they report on other variables that may influence cancer screening recommendations. For example, women who have a history of atypical ductal hyperplasia would be advised to follow screening recommendations that may differ from those of the general population.
Psychosocial Outcome Studies
A prospective study conducted in the Netherlands found that among 26 carriers of pathogenic variants, the 14 women who chose mastectomy had higher distress both before test result disclosure and 6 and 12 months later, compared with the 12 carriers who chose surveillance and compared with 53 women negative for a pathogenic variant. Overall, however, anxiety declined in women undergoing risk-reducing mastectomy (RRM); at 1 year, their anxiety scores were closer to those of women choosing surveillance and to the scores of women negative for a pathogenic variant. Interestingly, women opting for RRM had lower pretest satisfaction with their breasts and general body image than carriers who opted for surveillance or noncarriers of pathogenic variants. Of the women who had a RRM, all but one did not regret the decision at 1 year posttest disclosure, but many had difficulties with body image, sexual interest and functioning, and self-esteem. The perception that doctors had inadequately informed them about the consequences of RRM was associated with regret. At 5-year follow-up, women who had undergone RRM had less favorable body image and changes in sexual relationships, but also had a significant reduction in the fear of developing cancer. In a study of 78 women who underwent risk-reducing surgery (including carriers and women who were from high-risk families with no detectable pathogenic variant), cancer-specific and general distress were assessed 2 weeks before surgery and at 6 and 12 months postsurgery. The sample included women who had RRM and RRSO alone and women who had both surgeries. There was no observable increase in distress over the 1-year period.
Mixed psychosocial outcomes were reported in a follow-up study (mean 14 years) of 609 women who received RRM at the Mayo Clinic. Seventy percent were satisfied with RRM, 11% were neutral, and 19% were dissatisfied. Eighteen percent believed that if they had the choice to make again, they probably or definitely would not have a RRM. About three-quarters said their worry about cancer was diminished by surgery. One-half reported no change in their satisfaction with body image; 16% reported improved body image after surgery. Thirty-six percent said they were dissatisfied with their body image after RRM. About one-quarter of the women reported adverse impact of RRM on their sexual relationships and sense of femininity, and 18% had diminished self-esteem. Factors most strongly associated with satisfaction with RRM were postsurgical satisfaction with appearance, reduced stress, no reconstruction or lack of problems with implants, and no change or improvement in sexual relationships. Women who cited physician advice as the primary reason for choosing RRM tended to be dissatisfied after RRM.
A study of 60 healthy women who underwent RRM measured levels of satisfaction, body image, sexual functioning, intrusion and avoidance, and current psychological status at a mean of 4 years and 4 months postsurgery. Of this group, 76.7% had either a strong family history (21.7%) or carried a or pathogenic variant (55%). Overall, 97% of the women surveyed were either satisfied (17%) or extremely satisfied (80%) with their decision to have RRM, and all but one participant would recommend this procedure to other women. Most women (66.7%) reported that surgery had no impact on their sexual life, although 31.7% reported a worsening sexual life, and 76.6% reported either no change in body image or an improvement in body image, regardless of whether reconstruction was performed. Worsening self-image was reported by 23.3% of women after surgery. Women’s mean distress levels after surgery were only slightly above normal levels, although those women who continued to perceive their postsurgery breast cancer risk as high had higher mean levels of global and cancer-related distress than those who perceived their risk as low. Additionally, carriers of and pathogenic variants and women with a strong family history of breast and/or ovarian cancer had higher mean levels of cancer-related distress than women with a limited family history.
Very little is known about how the results of genetic testing affect treatment decisions at the time of cancer diagnosis. Two studies explored genetic counseling and genetic testing at the time of breast cancer diagnosis. One of these studies found that genetic testing at the time of diagnosis significantly altered surgical decision making, with more pathogenic variant carriers than noncarriers opting for bilateral mastectomy. Bilateral RRM was chosen by 48% of women with a known pathogenic variant and by 100% of women with a known pathogenic variant in a smaller series of women undergoing testing at the time of diagnosis. Of women in whom no pathogenic variant was found, 24% also opted for bilateral RRM. Four percent of the test decliners also underwent bilateral RRM. Among carriers of pathogenic variants, predictors of bilateral RRM included whether patients reported that their physicians had recommended testing and bilateral RRM before testing, and whether they received a positive test result. Data are lacking on quality-of-life outcomes for women who undergo RRM after genetic testing that is performed at the time of diagnosis.
A prospective study from the Netherlands evaluated long-term psychological outcomes of offering women with breast cancer genetic counseling and, if indicated, genetic testing at the onset of breast radiation for treatment of their primary breast cancer. Of those who were approached for counseling, some underwent genetic testing and chose to receive their result (n = 58), some were approached but did not fulfill referral criteria (n = 118), and some declined the option of counseling/testing (n = 44). Another subset of women undergoing radiation therapy was not approached for counseling (n = 182) but was followed using the same measures. Psychological distress was measured at baseline and at 4, 11, 27, and 43 weeks after initial consultation for radiation therapy. No differences were detected in general anxiety, depression or breast cancer–specific distress across all four groups.
A retrospective questionnaire study of 583 women with a personal and family history of breast cancer and who underwent contralateral RRM between 1960 and 1993 measured overall satisfaction after mastectomy and factors influencing satisfaction and dissatisfaction with this procedure. The mean time of follow-up was 10.3 years after risk-reducing surgery. Overall, 83% of all participants stated they were satisfied or very satisfied, 8% were neutral, and 9% were dissatisfied with contralateral RRM. Most women also reported favorable effects or no change in their self-esteem, level of stress, and emotional stability after surgery (88%, 83%, and 88%, respectively). Despite the high levels of overall satisfaction, 33% reported negative body image, 26% reported a reduced sense of femininity, and 23% reported a negative effect on sexual relationships. The type of surgical procedure also affected levels of satisfaction. The authors attributed this difference to the high rate of unanticipated reoperations in the group of women having subcutaneous mastectomy (43%) versus the group having simple mastectomy (15%) ( < .0001). Limitations to this study are mostly related to the time period during which participants had their surgery (i.e., availability of surgical reconstructive option). None of these women had genetic testing for pathogenic variants in the genes. Nevertheless, this study shows that while most women in this group were satisfied with contralateral RRM, all women reported at least one adverse outcome.
A retrospective survey of 137 carriers examined the psychosocial impact of preserving the nipple-areolar complex (NAC) in women with bilateral RRM. The study found that body image and sexual well-being differed significantly based on the type of RRM the women underwent. Women with NAC preservation were more satisfied with their breasts (72% vs. 61%), were more satisfied with the surgical outcome (85% vs. 74%), and had greater sexual well-being (68% vs. 52%) than women without NAC preservation. No differences in cancer-related distress, anxiety, depression, or risk perceptions were observed between the two groups. Oncologic outcomes of nipple-sparing mastectomy in carriers have not been inferior to RRM without NAC preservation. (Refer to the RRM section of this summary for more information.)
Another study compared long-term quality-of-life outcomes in 195 women after bilateral RRM performed between 1979 and 1999 versus 117 women at high risk of breast cancer opting for screening. No statistically significant differences were detected between the groups for psychosocial outcomes. Eighty-four percent of those opting for surgery reported satisfaction with their decision. Sixty-one percent of women from both the surgery and screening groups reported being very much or quite a bit contented with their quality of life.
In a study of psychosocial outcomes associated with RRM and immediate reconstruction, 61 high-risk women (27 carriers of pathogenic variants, others with high-risk family history), 31 of whom had a prior history of breast cancer, were evaluated on average 3 to 4 years after surgery. The study utilized questions designed to elicit yes versus no responses and found that the surgery was well-tolerated with 83% of participants reporting that the results of their reconstructive surgery were as they expected, 90% reporting that they had received adequate preoperative information, none reporting that they regretted the surgery, and all reporting that they would choose the same route if they had to do it again. Satisfaction with the results ranged from 74% satisfied with the shape of their breasts to 89% satisfied with the appearance of the scarring. Comparison of this group to normative samples on quality-of-life indicators (Short Form 36 Health Survey Questionnaire [SF-36]; Hospital Anxiety and Depression Scale questionnaire scores) indicated no reductions in quality of life in these women.
A qualitative study examining material on the FORCE website posted by 21 high-risk women ( positive) undergoing RRM showed that these women anticipated and received negative reactions from friends and family regarding the surgery, and that they managed disclosure in ways to maintain emotional support and self-protection for their decision. Many of the women expressed a relief from intrusive breast cancer thoughts and worry, and were satisfied with the cosmetic result of their surgery.
In contrast, another study examined long-term psychosocial outcomes in 684 women who had had bilateral or contralateral RRM on average 9 years before assessment. A majority of women (59%) also had reconstructive surgery. Interestingly, based on a Likert scale, 85% of women reported that they were satisfied or very satisfied with their decision to have an RRM. However, in qualitative interviews, a large number of women went on to describe dissatisfaction or negative psychosocial outcomes associated with surgery. The authors coded the responses as negative when women reported still being anxious about their breast cancer risk and/or reported negative feelings about their body image, pain, and sexuality. Seventy-nine percent of the women providing negative comments and 84% of those making mixed comments (mixture of satisfaction and dissatisfaction) responded that they were either satisfied or very satisfied with their decision. Twice as many women with bilateral mastectomy made negative and mixed comments than did women with contralateral mastectomy. The areas of most concern were body image, problems with breast implants, pain after surgery, and sexuality. The authors proposed that those who had undergone contralateral procedures had already been treated for cancer, while those who had undergone bilateral procedures had not been treated previously, and this may partially account for the differences in satisfaction between the two groups. These findings suggest that women's satisfaction with RRM may be tempered by their complex reactions over time.
In a qualitative study of 108 women who underwent or were considering RRM, more than half of those felt that presurgical consultation with a psychologist was advisable; nearly two-thirds thought that postsurgical consultation was also appropriate. All of the women believed that psychological consultation before surgery would facilitate decision-making.
A retrospective self-administered survey of 40 women aged 35 to 74 years at time of RRSO (57.5% were younger than 50 years), who had undergone the procedure through the Ontario Ministry of Health due to a family history of ovarian cancer, found that RRSO resulted in a significant reduction in perceived ovarian cancer risk. Fifty-seven percent identified a decrease in perceived risk as a benefit of RRSO (35% did not comment on RRSO benefits) and 49% reported that they would repeat RRSO to decrease cancer risk. The overall quality-of-life scores were consistent with those published for women who are menopausal or participating in hormone studies. Quality of life in 59 women who underwent RRSO was assessed at 24 months postprocedure. Overall quality of life was similar to the general population and breast cancer survivors, with approximately 20% reporting depression. The 30% of subjects reporting vaginal dryness and dyspareunia were more likely to report dissatisfaction with the procedure.
A Canadian prospective study examined the impact of RRSO on menopausal symptoms and sexual functioning before surgery and then 1 year later in a sample of 114 women with known pathogenic variants. Satisfaction with the decision to undergo RRSO was high regardless of symptoms reported. Those who were premenopausal at the time of surgery (n = 75) experienced a worsening of symptoms and a decline in sexual functioning. HRT addressed vaginal dryness and dyspareunia but not declines in sexual pleasure. HRT also resulted in fewer moderate to severe hot flashes.
Additional work reported by this group found that the majority of the 127 women who had undergone RRSO 1 year previously (75 with pathogenic variants; 52 with pathogenic variants) felt that RRSO reduced their risk of both breast and ovarian cancer. There was a wide range of risk perceptions for ovarian cancer noted in the group. Twenty percent of carriers of and pathogenic variants thought that their risk of ovarian cancer was completely eliminated; others had an inflated perception of their ovarian cancer risk both before and after surgery. A small group of these women were further surveyed at about 3 years postsurgery and their risk perceptions did not change significantly during this extended time period. These findings suggest that important misperceptions about ovarian cancer risk may persist after RRSO. Additional genetic education and counseling may be warranted.
A larger study assessed quality of life in women at high risk of ovarian cancer who opted for periodic gynecologic screening (GS) versus those who underwent RRSO. Eight hundred forty-six high-risk women, 44% of whom underwent RRSO and 56% of whom chose GS, completed questionnaires evaluating quality of life, cancer-specific distress, endocrine symptoms, and sexual functioning. Women in the RRSO group were a mean of 2.8 ±1.9 years from surgery and women in the GS group were a mean of 4.3 years from their first visit to a gynecologist for high-risk management. No statistical difference in overall quality of life was detected between the RRSO and GS groups. When compared with the GS group, women who underwent RRSO had poorer sexual functioning and more endocrine symptoms such as vaginal dryness, dyspareunia, and hot flashes. Women who underwent RRSO experienced lower levels of breast and ovarian cancer distress and had a more favorable perception of cancer risk.
Women (N = 182) at risk of hereditary breast and ovarian cancer referred for genetic counseling were surveyed concerning their satisfaction with their choice of either RRSO or periodic screening (PS) (biannual pelvic examination with TVUS and CA-125 determination) to manage their ovarian cancer risk. Overall satisfaction with both options was extremely high, but highest among those who chose RRSO over PS. There were no other demographic or clinical factors that distinguished satisfaction level. There was higher decisional ambivalence among those who chose PS.
A retrospective study assessed 98 carriers of pathogenic variants who underwent RRSO about their preoperative counseling regarding symptoms to expect after surgery. The mean age at RRSO was 45.5 years (range, ages 32–63 years). Eighty-five percent pursued RRSO after learning that they harbored a pathogenic variant, and 48.0% were premenopausal at the time of surgery. Participants reported ‘‘frequent’’ or ‘‘very frequent’’ postsurgical symptoms of vaginal dryness (52.1%), changes in interest in sex (50.0%), sleep disturbances (46.7%), changes in sex life (43.9%), and hot flashes (42.9%). Only vaginal dryness and hot flashes were commonly recalled to have been addressed preoperatively. While 96% would have the surgery again, participants reported that the discussion of the impact of surgery on their sex life (59.2%), risk of coronary heart disease (57.1%), and the availability of sex counseling (57.1%) would have been helpful.
A study of screening behaviors of 216 self-referred, high-risk (>10% risk of carrying a pathogenic variant) women who are members of hereditary breast cancer families found a range of screening practices. Even the presence of known pathogenic variants in their families was not associated with good adherence to recommended screening practices. Sixty-nine percent of women aged 50 to 64 years and 83% of women aged 40 to 49 years had had a screening mammogram in the previous year. Twenty percent of participants had ever had a CA-125 test and 31% had ever had a pelvic ultrasound or TVUS. Further analysis of this study population looking specifically at 107 women with informative test results found good use of breast cancer screening, though the uptake rate in younger carriers is lower. The reason for the lower uptake rate was not explored in this study. One survey of screening behaviors among women at increased risk of breast/ovarian cancer identified physician recommendations as a significant factor in adherence to screening.
While motivations cited for pursuing genetic testing often include the expectation that carriers of pathogenic variants will be more compliant with breast and/or ovarian screening recommendations, limited data exist about whether participants in genetic testing alter their screening behaviors over time and about other variables that may influence those behaviors, such as insurance coverage and physician recommendations or attitudes. The impact of cancer genetic counseling on screening behaviors was assessed in a U.K. study of 293 women followed for 12 months postcounseling at four cancer genetics clinics. BSE, CBE, and mammography were significantly increased after counseling; however, gaps in adherence to recommendations were noted: 38% of women aged 35 to 49 years had not had a mammogram by 12 months postcounseling. BSE was not done by most women at the recommended time and frequency.
This is a critical issue not only for women testing positive, but also for adherence to screening for those testing negative and those who have received indeterminate results or choose not to receive their results. It is possible that adherence actually diminishes with a decrease in the perceived risk that may result from a negative genetic test result.
In addition, while there is still some question regarding the link between cancer-related worry and breast cancer screening behavior, accumulating evidence appears to support a linear rather than a curvilinear relationship. That is, for some time, the data were not consistent; some data supported the hypothesis that mild-to-moderate worry may increase adherence, while excessive worry may actually decrease the utilization of recommended screening practices. Other reports support the notion that a linear relationship is more likely; that is, more worry increases adherence to screening recommendations. Few studies, however, have followed women to assess their health behaviors after genetic testing. Thus, a negative test result leading to decreased worry could theoretically result in decreased screening adherence. A large study found that patient compliance with screening practices was not related to general or screening-specific anxiety—with the exception of BSE, for which compliance is negatively associated with procedure-specific anxiety. Further research designed to clarify this potential concern would highlight the need for comprehensive genetic counseling to discuss the need for follow-up screening.
Further complicating this area of research are issues such as the baseline rate of mammography adherence among women older than 40 or 50 years before genetic testing. More specifically, the ability to note a significant difference in adherence on this measure may be affected by the high adherence rate to this screening behavior before genetic testing by women undergoing such testing. It may be easier to find significant changes in mammography use among women with a family history of breast cancer who test positive. Finally, adherence over time will likely be affected by how women undergoing genetic testing and their caregivers perceive the efficacy of many of the screening options in question, such as mammography for younger women, BSE, and ovarian cancer screening (periodic vaginal ultrasound and serum CA-125 measurements), along with the value of preventive interventions.
The issue of screening decision-making and adherence among women undergoing genetic testing for breast and ovarian cancer is the subject of several ongoing trials, and an area of much needed ongoing study.
Changes to This Summary (08/24/2017)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes
Added text about results from a meta-analysis of breast cancer risk in Lynch syndrome among 15 studies with molecular tumor testing results and evidence on breast cancer risk estimates among a total of 21 studies (cited Win et al. as reference 344).
This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of breast and gynecologic cancers. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
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The lead reviewers for Genetics of Breast and Gynecologic Cancers are:
- Doreen Agnese, MD (The Ohio State University)
- Kathleen A. Calzone, PhD, RN, AGN-BC, FAAN (National Cancer Institute)
- Ilana Cass, MD (Cedars-Sinai Medical Center)
- Lee-may Chen, MD (UCSF Helen Diller Family Comprehensive Cancer Center)
- Mary B. Daly, MD, PhD (Fox Chase Cancer Center)
- Jennifer K. Litton, MD (University of Texas, M.D. Anderson Cancer Center)
- Suzanne M. O'Neill, MS, PhD, CGC (Northwestern University)
- Tuya Pal, MD, FACMG, FCCMG (Vanderbilt-Ingram Cancer Center)
- Beth N. Peshkin, MS, CGC (Lombardi Comprehensive Cancer Center at Georgetown University Medical Center)
- Susan K. Peterson, PhD, MPH (University of Texas, M.D. Anderson Cancer Center)
- Mary Beth Terry, PhD (Columbia University Mailman School of Public Health)
- Susan T. Vadaparampil, PhD, MPH (H. Lee Moffitt Cancer Center & Research Institute)
- Catharine Wang, PhD, MSc (Boston University School of Public Health)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
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The preferred citation for this PDQ summary is:
PDQ® Cancer Genetics Editorial Board. PDQ Genetics of Breast and Gynecologic Cancers. Bethesda, MD: National Cancer Institute. Updated
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