|NCI/PDQ® Health professionals: Breast Cancer Prevention (PDQ®)|
|National Cancer Institute|
| Last Modified: October 5, 2012
Note: Separate PDQ® summaries on Breast Cancer Screening; Breast Cancer Treatment; Male Breast Cancer Treatment; Breast Cancer Treatment and Pregnancy; and Levels of Evidence for Cancer Screening and Prevention Studies are also available.
Based on solid evidence, combination hormone therapy (HT; estrogen-progestin) is associated with an increased risk of developing breast cancer. The evidence concerning the association between estrogen-only therapy and breast cancer incidence is mixed.
Magnitude of Effect for Combination Therapy: Approximately a 26% increase in incidence of invasive breast cancer; number needed to harm for every 237 patients participating in the Women's Health Initiative (WHI) trial and randomly assigned to the combination HT arm: 1 invasive breast cancer occurred beyond those that happened in the placebo arm of the trial.
Based on solid evidence, exposure of the breast to ionizing radiation is associated with an increased risk of developing breast cancer, starting 10 years after exposure and persisting lifelong. Risk depends on dose and age at exposure, with the highest risk occurring during puberty.
Based on solid evidence, obesity is associated with an increased breast cancer risk in postmenopausal women who have not used HT. It is uncertain whether reducing weight would decrease the risk of breast cancer.
Magnitude of Effect: The WHI observational study of 85,917 postmenopausal women found body weight to be associated with breast cancer. Comparing women weighing more than 82.2 kg with those weighing less than 58.7 kg, the relative risk (RR) was 2.85 (95% confidence interval [CI], 1.814.49).
Based on solid evidence, exposure to alcohol is associated with an increased breast cancer risk in a dose-dependent fashion. It is uncertain whether decreasing alcohol exposure would decrease the risk of breast cancer.
Magnitude of Effect: The RR for women consuming approximately four alcoholic drinks per day compared with nondrinkers is 1.32 (95% CI, 1.191.45). The RR increases by 7% (95% CI, 5.5%8.7%) for each drink per day.
Based on solid evidence, women who inherit gene mutations associated with breast cancer have an increased risk.
Based on solid evidence, exercising strenuously for more than 4 hours per week is associated with reduced breast cancer risk.
Based on solid evidence, women who have a full-term pregnancy before age 20 years have decreased breast cancer risk.
Based on solid evidence, women who breast-feed have a decreased risk of breast cancer.
Magnitude of Effect: The RR of breast cancer is decreased 4.3% for every 12 months of breast-feeding, in addition to 7% for each birth. 1
Based on solid evidence for tamoxifen and fair evidence for raloxifene, treatment reduces the incidence of breast cancer in postmenopausal women. Tamoxifen also reduced the risk of breast cancer in high-risk premenopausal women. The effects observed for tamoxifen show persistence several years after discontinuing active treatment.
Magnitude of Effect: Treatment with tamoxifen-reduced breast cancer by about 50%. Treatment with raloxifene has a similar effect on reduction of invasive breast cancer but appears to be less effective for prevention of noninvasive tumors.
Based on solid evidence, tamoxifen treatment increases the risk of endometrial cancer, thrombotic vascular events (pulmonary embolism, stroke, deep venous thrombosis), and cataracts. Many of these risks, notably pulmonary embolism and deep venous thrombosis, are reduced after discontinuing active treatment with tamoxifen. Based on fair evidence, raloxifene also increases venous pulmonary embolism and deep venous thrombosis but not endometrial cancer.
Based on solid evidence, aromatase inhibitors or inactivators (AIs) reduce the incidence of new breast cancers in postmenopausal women who have an increased risk of breast cancer.
Magnitude of Effect: After a median follow-up of 35 months, women aged 35 years and older who had at least one risk factor (e.g., women aged 60 years and older or those having a Gail 5-year risk >1.66% or ductal carcinoma in situ with mastectomy) and who took 25 mg of exemestane daily were less likely to be diagnosed with invasive breast cancer (hazard ratio [HR], 0.35; 95% CI, 0.180.70). The absolute risk reduction was 21 cancers avoided out of 2,280 participants over 35 months (number needed to treat [NNT], about 100). 2
Based on fair evidence because of a relatively short follow-up from a single RCT of 4,560 women over 35 months, exemestane is associated with slightly increased hot flashes (absolute increase, 8%) and fatigue (absolute increase, 2%), but not with fractures, osteoporosis, or cardiovascular (CV) events compared with placebo.
Magnitude of Effect: There was a small increase in adverse effects in the exemestane group compared with placebo, primarily in hot flashes (absolute increase, 8%) and fatigue (absolute increase, 2%). There was no difference in the occurrence of fractures or CV events.
Based on solid evidence, bilateral prophylactic mastectomy reduces the risk of breast cancer in women with a strong family history.
Based on fair evidence, physical and psychological effects include anxiety, depression, and impaired body image.
Magnitude of Effect: Of the women who chose to have a prophylactic mastectomy, usually for cosmesis, 6% were dissatisfied with their decision. Regrets about mastectomy were fewer in 185 women who opted not to have reconstruction than in 111 women who chose to have it. 3
Based on solid evidence, prophylactic oophorectomies in women with BRCA gene mutations document lower breast cancer incidence. Similarly, oophorectomy or ovarian ablation is associated with decreased breast cancer incidence in normal women or in those who received thoracic irradiation.
Based on solid evidence, castration may cause the abrupt onset of menopausal symptoms such as hot flashes, insomnia, anxiety, and depression. Long-term effects include decreased libido, vaginal dryness, and decreased bone mineral density.
With an estimated 226,870 cases expected, breast cancer will be the most frequently diagnosed nonskin malignancy in U.S. women in 2012. 1 In the same year, breast cancer will kill an estimated 39,510 women, second only to lung cancer as a cause of cancer mortality in women. Breast cancer also occurs in men, and it is estimated that 2,190 new cases will be diagnosed in 2012. 1 Despite a prior long-term trend of gradually increasing breast cancer incidence, data from the Surveillance, Epidemiology, and End Results Program show a decrease in breast cancer mortality of 1.9% per year from 1998 to 2007. 2
Screening for breast cancer decreases mortality by identifying and treating cases at an earlier stage. Screening also identifies more cases than would become symptomatic in a woman's lifetime, so breast cancer incidence is higher in screened populations.
Genetic, epidemiologic, and laboratory studies support a stochastic model of breast cancer development in which a series of genetic changes contribute to the dynamic process known as carcinogenesis. 3 An accumulation of genetic changes is thought to correspond to the phenotypic changes associated with the evolution of malignancy. The carcinogenesis sequence is viewed histologically as starting with tissue of normal appearance followed by changes that lead to hyperplasia and dysplasia, the most severe forms of which are difficult to distinguish from carcinoma in situ. 4
The concept that breast cancer may be preventable is supported by the wide international variation in breast cancer rates, which is an indicator that there are potentially modifiable environmental and lifestyle determinants of breast cancer. Migration studies reinforce this premise; for example, it has been observed that Japanese immigrants to the United States increase their breast cancer risk from Japanese to American levels within two generations. 5 6 7
Many of the risk factors for breast cancer, including age at menarche, first birth, and menopause, suggest hormonal influences for the development of the disease. Estrogen and progestin cause growth and proliferation of breast cells that may work through growth factors such as transforming growth factor (TGF)-alpha. 8 Women who develop breast cancer tend to have higher endogenous estrogen and androgen levels. 9
The role of ovarian hormones in the development of breast cancer is demonstrated by studies of artificial menopause. Following ovarian ablation, breast cancer risk may be reduced as much as 75% depending on age, weight, and parity, with the greatest reduction for young, thin, nulliparous women. 10 11 12 13 The removal of one ovary also reduces the risk of breast cancer, but to a lesser degree than the removal of both ovaries. 14
Other hormonal changes also influence breast cancer risk. Childbirth is followed by a transient increase in risk and then a long-term reduction in risk, which is greater for younger women. 13 15 16 In one study, women who experienced a first full-term pregnancy before age 20 years were half as likely to develop breast cancer as nulliparous women or women who underwent a first full-term pregnancy at age 35 years or older. 17 18 Age at menarche also affects breast cancer risk. Women who experienced menarche at age 11 years or younger have about a 20% greater chance of developing breast cancer than women who experienced menarche at age 14 years or older. 19 Women who experience late menopause also have increased risk. Reproductive risk factors may interact with more predisposing genotypes. In the Nurses' Health Study, 20 the associations between age at first birth, menarche, and menopause and the development of breast cancer were observed only among women without a family history of breast cancer in a mother or sister. Breast-feeding is associated with a decreased risk of breast cancer. 21 22
A number of studies suggest that endogenous estrogen and androgen levels are higher in women who develop breast cancer than in women who do not. 9 23 24 Methods shown to decrease endogenous estrogen include maintenance of ideal body weight (refer to the Obesity section of this summary for more information), adoption of a low-fat diet in postmenopausal women, 25 and moderate exercise in adolescent girls. 26 Whether such interventions will decrease breast cancer risk is worthy of study.
The inherited genetic profile of an individual influences susceptibility to mutagens and growth factors, which initiate or promote the carcinogenic process. Known genetic syndromes related to specific aberrant alleles account for approximately 5% of breast cancers. Identifying high-risk genes provides insight into breast cancer etiology and allows the development of preventive interventions for affected populations. (Refer to the PDQ® summary on Genetics of Breast and Ovarian Cancer for more information.)
Women who inherit a deleterious mutation in BRCA1 27 28 or BRCA2 29 have an increased lifetime risk of breast cancer (which occurs at a younger age), ovarian cancer, and possibly colon cancer. Deleterious BRCA2 mutations are less common than BRCA1 30 mutations; BRCA2 mutations are also associated with male breast cancer, prostate cancer, pancreatic cancer, and lymphomas. 31
Exogenous hormone therapy (HT) after menopause is associated with increased breast cancer risk. 32
The Heart and Estrogen/Progestin Replacement Study 33 included an open-label follow-up of a randomized controlled trial (RCT) of estrogen and progestin therapy in 2,763 women (mean age 67 years) who had coronary heart disease. After a mean follow-up of 6.8 years, the relative risk [RR] for breast cancer was 1.27 (95% confidence interval [CI], 0.841.94). Though not statistically significant, the RR estimate is consistent with the much larger Women's Health Initiative (WHI) study.
The WHI-combined HT trial was terminated early (in July 2002) because the overall health risks exceeded benefits. 34
The randomized trial component of the WHI investigated the effect of hormones and dietary interventions on breast cancer risk. 34 Women aged 50 to 79 years who had intact uteri were randomly assigned to receive combined conjugated estrogen with continuous progestin (n = 8,506) or placebo (n = 8,102). Breast cancer risk was increased with combined HT, with a hazard ratio (HR) of 1.24 (95% CI, 1.021.50), consistent with prior reports from observational studies. The trial was terminated early because overall health risks, including cardiovascular disease and thrombotic events, exceeded benefit. 34 HT was also associated with a higher percentage of abnormal mammograms. 35 The excess risk was observed in all subgroups of women for invasive breast cancer but not for in situ breast cancer. The combined HT-related cancers had similar grade, histology, and expression of estrogen receptor (ER), progesterone receptor, and HER2/neu compared with those related to placebo, with a trend toward larger size and higher incidence of lymph node metastases. 36 Extended follow-up (mean follow-up of 11 years) of these women showed higher breast cancer-specific mortality for the HT group compared with those randomly assigned to receive placebo (25 vs. 12 deaths, 0.03% vs. 0.01% per year, HR = 1.95; 95% CI, 1.04.04; P = .049).
The WHI Estrogen-Alone Trial was a double-masked, placebo-controlled randomized clinical trial conducted among women who have had a hysterectomy. Women were randomly assigned to receive conjugated equine estrogens (CEE) or placebo. Estrogen-only preparations should only be considered among women who have had a hysterectomy since unopposed estrogen increases the risk of uterine cancer. Like the WHI combined-HT trial, this trial was stopped early because of an increased risk of stroke and no evidence of benefit as measured by a global index of risks and benefits. 37 38 After an average of 6.8 years of follow-up, the incidence of breast cancer was lower in the group receiving CEE compared with placebo but the difference was not statistically significant (HR = 0.77; 95% CI, 0.591.01; 26 vs. 33 cases of invasive breast cancer per 10,000 person-years [annualized rate of 0.26% vs. 0.33%], respectively). For the global index of risks and benefits (based on outcomes of stroke, pulmonary embolus, breast cancer, colorectal cancer, hip fractures, and death), there was a nonstatistically significant excess of two events per 10,000 person-years. 37 An extended follow-up for a median of 11.8 years was conducted with 78% of the trial participants consenting to take part. 38 39 Characteristics among those in the extended follow-up who were randomly assigned to receive active intervention with CEE or placebo were similar, except for slight imbalances in history of prior breast biopsy (19.8% among the CEE group and 22.3% among the placebo group) and prior hormone use (48.9% among the CEE group and 50.4% among the placebo group). At the end of the follow-up period, 151 cases of breast cancer occurred among the CEE group (0.27% per year) compared with 199 cases of breast cancer among the placebo group (0.35% per year) (HR = 0.77; 95% CI, 0.620.95). 38 39 Breast cancer mortality was statistically significantly lower in the CEE group (6 deaths, 0.009% per year) than in the placebo group (16 deaths, 0.024% per year) (HR = 0.37; 95% CI, 0.130.91). All-cause mortality was also lower in the CEE group (0.046% per year) than in the placebo group (0.076% per year) (HR = 0.62; 95% CI 0.390.97). Following discontinuation of CEE, the risk of stroke decreased in the postintervention period. Over the entire follow-up period, there was no increased or decreased risk of coronary heart disease, deep vein thrombosis, stroke, hip fracture, or colorectal cancer. 38 Among the subset of women in the WHI trial who initiated estrogen-only therapy within the first 5 years of onset of menopause, neither an excess nor decreased risk of developing breast cancer was observed (HR = 1.06; 95% CI, 0.741.51).
The evidence from this clinical trial should be put into context with the evidence from observational studies that suggest that there is an increased risk of developing breast cancer associated with estrogen-only postmenopausal HT. The Million Women Study 40 observed no increased risk of breast cancer among women whose first use of estrogen-only therapy was 5 or more years after menopause, but the risk was statistically significantly higher among women initiating therapy within 5 years of menopause (RR = 1.43; 95% CI, 1.361.49). Among that group, the risk increased with duration of hormone use. Overall, risks associated with estrogen-only HT were lower than those observed for combined estrogen-progestin HT. 40 Estrogen-only therapy, even for more than 25 years duration, was not associated with invasive breast cancer in a case-control study of women aged 65 years and older. 41 The Collaborative Group on Hormonal Factors in Breast Cancer, a reanalysis of data from 52 observational studies of HT and breast cancer, had information on specific hormonal preparations for 39% of eligible women and most of these women reported use of estrogen-alone preparations. 32 The combined analysis showed no marked variation between estrogen-only preparations and combined HT. 32 However, the collaborative analysis, overall, provided limited information on estrogen-only versus combination estrogen-progestin therapy. Factors that may explain the disparate findings of the association between estrogen-only use and the risk of developing breast cancer, which were observed in the clinical trial and observational studies, include an imbalance in the prevalence of routine screening between users and nonusers of hormones, and gap time between the onset of menopause and the first use of postmenopausal hormone therapy. 42 43
Following publication of the WHI results, HT use dropped dramatically in the United States and elsewhere. Follow-up of participants on the combined HT arm demonstrated a rapid decrease in the elevated breast cancer risk of therapy within 2 years, despite similar rates of mammography screening. 44 Analysis of changes in breast cancer rates in the United States observed a sharp decline in breast cancer incidence rates from 2002 to 2003, following the release of the WHI trial data among women aged 50 years and older. 45 46 The decreased incidence is primarily the result of changes in the incidence of ERpositive breast cancer 45, which provides additional support for the causal association between combined HT and the risk of breast cancer. Similarly, in multiple countries where the prevalence of HT use was high, breast cancer rates decreased in a similar time frame, coincident with changes in prescribing patterns and/or reported prevalence of use. 47 48 49 A study among women receiving regular mammography screening supports that the observed sharp decline from 2002 to 2003 in breast cancer incidence was primarily caused by withdrawal of HT rather than declines in mammography rates. 50 Since the decline in breast cancer incidence noted from 2002 to 2003, rates in the United States have stabilized. 50 51 These observations support the causal effect of combined HT on breast cancer incidence and modification of breast cancer risk through either withdrawal of HT or never having used HT.
A well-established relationship exists between exposure to ionizing radiation and the risk of developing breast cancer. 52 Excess breast cancer risk is consistently observed in association with a variety of exposures such as fluoroscopy for tuberculosis and radiation treatments for acne, tinea, thymic enlargement, postpartum mastitis, or Hodgkin lymphoma. Although risk is inversely associated with age at radiation exposure, the manifestation of breast cancer risk occurs according to the usual age-related pattern. 53 An estimate of the risk of breast cancer associated with medical radiology puts the figure at less than 1% of the total. 54 However, it has been theorized that certain populations, such as AT heterozygotes, are at an increased risk of breast cancer from radiation exposure. 55 A large cohort study of women who carry mutations of BRCA1 or BRCA2 concluded that chest x-rays increase the risk of breast cancer still further (RR = 1.54; 95% CI, 1.12.1), especially for women who were x-rayed before age 20 years. 56
Women treated for Hodgkin lymphoma by age 16 years may have a subsequent risk, which is as high as 35%, of developing breast cancer by age 40 years. 57 58 One study suggests that higher doses of radiation (median dose, 40 Gy in breast cancer cases) and treatment received between the ages of 10 and 16 years corresponds with higher risk. 57 Unlike the risk for secondary leukemia, the risk of treatment-related breast cancer did not abate with duration of follow-up; that is, increased risk persisted more than 25 years after treatment. 57 59 60 In these studies, most patients (85%100%) who developed breast cancer did so either within the field of radiation or at the margin. 57 58 59 A Dutch study examined 48 women who developed breast cancer at least 5 years after treatment for Hodgkin disease and compared them with 175 matched female Hodgkin disease patients who did not develop breast cancer. Patients treated with chemotherapy and mantle radiation were less likely to develop breast cancer than those treated with mantle radiation alone, possibly because of chemotherapy-induced ovarian suppression (RR = 0.06; 95% CI, 0.010.45). 61 Another study of 105 radiation-associated breast cancer patients and 266 age-matched and radiation-matched controls showed a similar protective effect for ovarian radiation. 60 These studies suggest that ovarian hormones promote the proliferation of breast tissue with radiation-induced mutations. 60
The question arises whether breast cancer patients treated with lumpectomy and radiation therapy (L-RT) are at increased risk for second breast malignancies or other malignancies compared with those treated by mastectomy. Outcomes of 1,029 L-RT patients were compared with 1,387 patients who underwent mastectomies. After a median follow-up of 15 years, there was no difference in the risk of second malignancies. 62 Further evidence from three RCTs is also reassuring. One report of 1,851 women randomly assigned to undergo total mastectomy, lumpectomy alone, or L-RT showed rates of contralateral breast cancer to be 8.5%, 8.8%, and 9.4%, respectively. 63 Another study of 701 women randomly assigned to undergo radical mastectomy or breast-conserving surgery followed by radiation therapy demonstrated the rate of contralateral breast carcinomas per 100 woman-years to be 10.2 versus 8.7, respectively. 64 The third study compared 25-year outcomes of 1,665 women randomly assigned to undergo radical mastectomy, total mastectomy, or total mastectomy with radiation. There was no significant difference in the rate of contralateral breast cancer according to the treatment group, and the overall rate was 6%. 65
Obesity is associated with increased breast cancer risk, especially among postmenopausal women who do not use HT. The WHI observational study observed 85,917 women aged 50 to 79 years and collected information on weight history as well as known risk factors for breast cancer. 66 Height, weight, and waist and hip circumferences were measured. With a median follow-up of 34.8 months, 1,030 of the women developed invasive breast cancer. Among the women who never used HT, increased breast cancer risk was associated with weight at entry, body mass index (BMI) at entry, BMI at age 50 years, maximum BMI, adult and postmenopausal weight change, and waist and hip circumferences. Weight was the strongest predictor, with a RR of 2.85 (95% CI, 1.814.49) for women weighing more than 82.2 kg, compared with those weighing less than 58.7 kg.
Many epidemiologic studies have shown an increased risk of breast cancer associated with alcohol consumption. Individual data from 53 case-control and cohort studies were included in a British meta-analysis. 67 Compared with women who reported no alcohol consumption, the RR of breast cancer was 1.32 (95% CI, 1.191.45; P < .001) for women consuming 35 g to 44 g of alcohol per day and 1.46 (95% CI, 1.331.61; P < .001) for those consuming at least 45 g of alcohol per day. The RR of breast cancer increases by about 7% (95% CI, 5.5%8.7%; P < .001) for each 10 g of alcohol (i.e., one drink) consumed per day. The same result was obtained, even after additional stratification for race, education, family history, age at menarche, height, weight, BMI, breast-feeding, oral contraceptive use, menopausal hormone use and type, and age at menopause.
Active exercise may reduce breast cancer risk, particularly in young parous women. 68Numerous observational studies have examined the relationship between physical activity and breast cancer risk. 69 Most of these studies have shown an inverse relationship between level of physical activity and breast cancer incidence. The average RR reduction is reportedly 30% to 40%. However, it is not known to what degree, if at all, the observed association is to the result of confounding variables, such as diet or a genetic predisposition to breast cancer. A prospective study of more than 25,000 women in Norway suggests that doing heavy manual labor or exercising 4 or more hours per week is associated with a decrease in breast cancer risk. This decrease is more pronounced in premenopausal women and in women of normal or lower-than-normal body weight. 70 In a case-control study of African American women, strenuous recreational physical activity (>7 hours per week) was associated with decreased breast cancer incidence. 71
Data from adjuvant breast cancer trials using tamoxifen have shown that tamoxifen not only suppresses the recurrence of breast cancer but also prevents new primary contralateral breast cancers. 72 Tamoxifen also maintains bone density among postmenopausal women with breast cancer. 73 74 75 76 77 Adverse effects include hot flashes, venous thromboembolic events, and endometrial cancer. 78 79 80
These adjuvant trial results were the basis for the Breast Cancer Prevention Trial (BCPT) that randomly assigned 13,388 patients at elevated risk of breast cancer to receive tamoxifen or placebo. 81 82 The independent Endpoint Review, Safety Monitoring, and Advisory Committee closed the study early because of a 49% reduction in the incidence of breast cancer for tamoxifen-treated versus placebo-treated participants. After about 4 years of follow-up, placebo-treated women had 154 cases of invasive breast cancer compared with 85 cases in women who received tamoxifen. Noninvasive breast cancers were also reduced, with 59 cases in the placebo group versus 31 in the tamoxifen-treated group. Another benefit of tamoxifen use was a reduction in fractures, with 47 occurring in the tamoxifen-treated women compared with 71 in the placebo group. These benefits were accompanied by an increased incidence of endometrial cancer and thrombotic events in women aged 50 years and older. There were 33 endometrial cancers and 99 vascular events (including 17 cases of pulmonary embolism and 30 cases of deep vein thrombosis) in women who received tamoxifen compared with 14 endometrial cancers and 70 vascular events (including 6 cases of pulmonary embolism and 19 cases of deep vein thrombosis) in women who received a placebo. 82
An update of the BCPT results after 7 years of follow-up demonstrates results similar to those in the initial report. 83 Follow-up was more complete for the tamoxifen group than for the placebo group because of a greater drop-out rate among women in the placebo group after early termination of the study. In addition, women who received a placebo were given the option of taking tamoxifen or participating in the Study of Tamoxifen and Raloxifene (STAR), and 32% did so. Breast cancer rates decreased among women in the placebo group from year 6 to year 7 of follow-up. A statistically significant RR of 43% for invasive breast cancer persisted at follow-up despite the addition of women to the placebo arm. The rate of invasive breast cancer among women in the placebo group was 6.29 per 1,000 women versus 3.59 per 1,000 women for women in the tamoxifen group, for a risk reduction of 0.27%. Benefits and risks of tamoxifen were not significantly different from those in the original report, with persistent benefit of reductions in fracture and persistent risks of endometrial cancer, thrombosis, and cataract surgery. No overall mortality benefit was observed after 7 years of follow-up (RR = 1.10; 95% CI, 0.851.43).
Other trials of tamoxifen for primary prevention of breast cancer have been completed. 84 85 86 Initial analyses from two smaller trials, one in the United Kingdom (U.K.) 84 and one primarily in Italy, 85 showed no protective effect, perhaps because of differences between target populations and study designs and those in the U.S. study. The U.K. study focused on 2,471 women at increased breast cancer risk because of their family history of breast and/or ovarian cancer; about 36% of participants were from families that had a greater than 80% chance of carrying a breast cancer susceptibility gene. After a median follow-up of nearly 6 years, no protective effect of tamoxifen was detected (RR = 1.06). Subsequent follow-up shows that at a median of 13 years, there was a statistically nonsignificant reduction in breast cancer risk in the tamoxifen arm compared with the placebo arm (HR = 0.78; 95% CI, 0.581.04). However, risk of ERpositive breast cancer was significantly reduced in the treatment arm (HR = 0.61; 95% CI, 0.430.86), an effect noted predominantly in the posttreatment period. 87 The Italian study focused on 5,408 women who had undergone hysterectomy and who were described as low-to-normal risk women. At the initial report, after a median follow-up of nearly 4 years, no protective effect of tamoxifen was observed. Longer follow-up and subgroup analysis in the Italian trial found a protective effect of tamoxifen among women at high risk for hormone receptorpositive breast cancer (RR = 0.24; 95% CI, 0.100.59) and among women who were taking HT during the trial (RR = 0.43; 95% CI, 0.200.95). 88 89
The last trial of tamoxifen for primary prevention of breast cancer was the International Breast Cancer Intervention Study (IBIS-I). This trial randomly assigned 7,152 women aged 35 to 70 years who were at increased risk of breast cancer to receive tamoxifen (20 mg/day for 5 years) or placebo. 86 After a median follow-up of 50 months, 32% fewer women (95% CI, 8%50%) in the tamoxifen group than in the placebo group had developed breast cancer (invasive plus carcinoma in situ with an absolute reduction from 6.75 to 4.6 breast cancers per 1,000 woman-years). The RR reduction in ERpositive invasive breast cancer was 31%; there was no reduction in ERnegative cancers. In this trial, but in none of the other tamoxifen trials, there was an excess of all-cause mortality in the tamoxifen group (25 vs. 11; P = .028), which the authors attributed to chance. The prophylactic effect of tamoxifen on breast cancer persisted after active treatment, with 27% fewer women in the tamoxifen arm developing breast cancer than did women in the placebo arm (142 vs. 195 cases, respectively; RR = 0.73, 95% CI, 0.580.91) over the full study period after a further 46 months of median follow-up. 90 In this report, most of the additional follow-up time accrued after the discontinuation of active treatment in the treatment arm.
A meta-analysis of the early report of these primary prevention trials was performed, and its findings showed a 38% reduction in the incidence of breast cancer without statistically significant heterogeneity. 80 ERpositive tumors were reduced by 48%. Rates of endometrial cancer were increased (consensus RR = 2.4; 95% CI, 1.54.0), as were venous thromboembolic events (RR = 1.9; 95% CI, 1.42.6). None of these primary prevention trials was designed to detect differences in breast cancer mortality.
Treatment decisions are complex and need to be individualized, weighing estimates of a woman's chance of reducing breast cancer and fracture risks against the chance of developing detrimental side effects, some of which may be life threatening. The risks and benefits of taking tamoxifen have been estimated for women according to age, race, and risk group based on the results of the BCPT, additional risk/benefit analyses, and review of the literature. 91 Because adverse effects of tamoxifen increase with age, tamoxifen is most beneficial for women younger than 50 years who have an increased risk of developing breast cancer. Overall, the net benefit or risk depends on age, whether a woman has a uterus, and her baseline risk of breast cancer.
Women with a history of ductal carcinoma in situ (DCIS) are at increased risk (3.4%) for contralateral breast cancer but were not eligible for the BCPT because of competing treatment trials. In a trial of DCIS treatment, however, 13.4% of women treated with lumpectomy and radiation had breast cancer events within approximately 6 years, compared with 8.2% of those who also received tamoxifen. 92 The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 RCT evaluated the added benefit of tamoxifen to lumpectomy and radiation therapy for women with DCIS. 92 The risk of all breast cancer events, invasive and noninvasive, was reduced with tamoxifen (rate ratio = 0.63; 95% CI, 0.470.83); the risk of contralateral breast cancer (invasive and noninvasive) associated with tamoxifen was 0.49 (95% CI, 0.260.87). Given the results of the NSABP B-24 trial and the BCPT, it is reasonable to consider the use of tamoxifen for breast cancer risk reduction among women with DCIS.
In addition to tamoxifen, other hormonal manipulations have been proposed to modulate the production of breast cell growth factors by suppressing ovarian function 93 or changing the endogenous hormonal environment. 94 The list of chemoprevention agents that may be used in breast cancer prevention is long.
Raloxifene hydrochloride is a SERM that has antiestrogenic effects on breast and endometrial tissue and estrogenic effects on bone, lipid metabolism, and blood clotting. 95 The Multiple Outcomes of Raloxifene Evaluation (MORE), a randomized, double-blind trial, evaluated 7,705 postmenopausal women with osteoporosis from 1994 to 1998 at 180 clinical centers in the United States. The effect on breast cancer incidence was a secondary endpoint and therefore should be judged with caution. After a median follow-up of 47 months, the risk of invasive breast cancer decreased by 72%. 96 Breast cancer was reported in 79 women and confirmed in 77 women. Invasive breast cancer occurred in 39 women treated with placebo and in 22 women who were randomly assigned to either of the two raloxifene arms (raloxifene 120 mg daily or raloxifene 60 mg; RR = 0.25; 95% CI, 0.170.45; 4.71.3 invasive breast cancers per 1,000 woman-years in the placebo and combined-treatment groups, respectively). DCIS occurred in five women treated with a placebo and in 11 women treated with raloxifene. After combining noninvasive and invasive cancer occurrences, the RR of breast cancer among women in the raloxifene group was 0.38 (95% CI, 0.240.58; 5.31.9 breast cancers per 1,000 woman-years in the placebo and combined-treatment groups, respectively). As with tamoxifen, raloxifene reduced the risk of ERpositive breast cancer but not ERnegative breast cancer. Similar to tamoxifen, raloxifene is associated with an excess risk of hot flashes and thromboembolic events. The risk of venous thromboembolic disease (deep venous thrombosis or pulmonary embolism) was 2.4 times higher in women assigned to the raloxifene groups compared with the placebo group. One woman (in the 60-mg raloxifene group) died from pulmonary embolism. There was little difference in the rate of venous thromboembolic disease between the 60-mg and 120-mg groups (3.323.63 events per 1,000 woman-years, respectively). No excess risk of endometrial cancer was observed after 47 months of follow-up; five cases occurred among women on placebo (0.77 cases per 1,000 woman-years), five cases among women treated with 60 mg of raloxifene (0.77 cases per 1,000 woman-years), and four cases among women treated with 120 mg of raloxifene (0.60 cases per 1,000 woman-years). Raloxifene did not increase the risk of endometrial hyperplasia. 97 Of 1,781 women who underwent transvaginal ultrasonography at baseline and had at least one follow-up test, endometrial thickness increased by an average of 0.01 mm in the raloxifene groups and decreased by 0.27 mm in the placebo group after 3 years of follow-up (P < .01 for the difference between the two groups). Sixty participants (10.1%) in the placebo group and 168 women (14.2%) in the raloxifene groups (P = .02) had endometrial thickness that was greater than 5 mm on at least one follow-up ultrasound. Among the 196 women who still had a uterus (48 in the placebo group and 148 in the raloxifene group), there were three cases of hyperplasia and two cases of endometrial cancer in the placebo group and three cases of hyperplasia and two cases of endometrial cancer in the combined raloxifene group. Subgroup analyses after 4 years of follow-up suggest that, among women who have osteoporosis, raloxifene reduces breast cancer incidence for both women at higher and lower risk of developing breast cancer.
An extension of the MORE study, the Continuing Outcomes Relevant to Evista (CORE) study, continued studying about 80% of MORE participants in their randomized groups for 4 years beyond the original 4 years of MORE. Although there was a median 10-month gap between the two studies and only about 55% of women were adherent to their assigned medications, the raloxifene group continued to experience a lower incidence of invasive breast cancer. As in MORE, this effect resulted from a reduction in ERpositive but not ERnegative invasive breast cancer. There was no reduction in noninvasive breast cancer. The overall reduction in invasive breast cancer during the 8 years of MORE and CORE was 66% (HR = 0.34; 95% CI, 0.220.50); the reduction for ERpositive invasive breast cancer was 76% (HR = 0.24; 95% CI, 0.150.40). 98
The Raloxifene Use for the Heart trial was a randomized, placebo-controlled trial to evaluate the effects of raloxifene on incidence of coronary events and invasive breast cancer. Similar to the MORE and CORE studies, raloxifene reduced the risk of invasive breast cancer (HR = 0.56; 95% CI, 0.380.83). The annualized rate of invasive breast cancer in the raloxifene group was 0.20% compared with 0.29% in the placebo group. Raloxifene did not reduce the risk of ERnegative breast cancer or noninvasive breast cancer. The annualized rate of noninvasive breast cancer in the raloxifene group was 0.04% compared with 0.02% in the placebo group. 99
STAR (NSABP P-2) compared tamoxifen and raloxifene in 19,747 high-risk women during a mean of 3.9 years of follow-up. The primary outcome measure was breast cancer incidence, which was approximately the same for invasive cancer, but favored tamoxifen for noninvasive cancer. Adverse events of uterine cancer, venous thrombolic events, and cataracts were more common in tamoxifen-treated women, and there was no difference in ischemic heart disease events, strokes, or fractures. 100 Treatment-associated symptoms of dyspareunia, musculoskeletal problems, and weight gain favored tamoxifen, whereas vasomotor flushing, bladder control symptoms, gynecologic symptoms, and leg cramps favored raloxifene. 101
Another class of agents, commercially available for the treatment of hormone-sensitive breast cancer, may also prevent breast cancer. These three drugs interfere with the adrenal enzyme aromatase, which is responsible for estrogen production in postmenopausal women. Anastrozole (Arimidex) and letrozole (Femara) inhibit aromatase activity, whereas exemestane (Aromasin) inactivates the enzyme. All three drugs have similar side effects, infrequently causing fatigue, arthralgia, and myalgia. Bone mineral density may be decreased, and fracture rate is increased, possibly because of the decreased bone density.
All three drugs decrease the incidence of new breast cancers in women with a history of breast cancer. The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial compared anastrozole, tamoxifen, and the combination when used as an adjuvant HT after treatment of the primary breast cancer. 102 Anastrozole-treated patients had a 7.1% rate of locoregional and distant recurrence versus 8.5% for those treated with tamoxifen and 9.1% for the combination. A more impressive result was the decreased rate of primary contralateral breast cancers (0.4% vs. 1.1% vs. 0.9%). Another trial analyzed the use of letrozole versus placebo in 5,187 women with breast cancer, following 5 years of treatment with adjuvant tamoxifen. 103 After only 2.5 years of median follow-up, the study was terminated, because previously defined efficacy endpoints had been reached. Not only did letrozole-treated patients have a lower incidence of locoregional and distant cancer recurrence, they also had a lower rate of contralateral breast cancer (14 vs. 26). A third trial randomly assigned 4,742 women who had already received 2 years of adjuvant tamoxifen. Women either continued the tamoxifen or switched to exemestane. 104 After 2.4 years' median follow-up, the women assigned to receive exemestane had a decreased risk of local or metastatic recurrence and a decreased risk of new primary contralateral breast cancer (9 vs. 20).
An RCT has reported the effect of aromatase inhibitors in preventing invasive breast cancer among women who have no history of breast cancer. In this study, 4,560 women aged 35 years and older who had at least one risk factor (e.g., women aged 60 years and older or those having a Gail 5-year risk >1.66% or a history of DCIS with mastectomy) were randomly assigned to receive exemestane 25 mg daily or a placebo. After 35 months median follow-up, 32 women of the 2,275 in the placebo group had been diagnosed with invasive breast cancer, compared with 11 women in the exemestane group (HR, 0.35; 95% CI, 0.180.70; NNT, about 100 for 35 months). There was a small increase in adverse effects in the exemestane group compared with the placebo group, primarily in hot flashes (increase, 8%) and fatigue (increase, 2%). There was no difference in the occurrence of fractures or cardiovascular events. 105 A second trial (IBIS-2) is under way.
A retrospective cohort study was conducted to evaluate the impact of bilateral prophylactic mastectomy on the subsequent occurrence of brea