National Cancer Institute
Post Date: Nov 30, 2017
Expert-reviewed information summary in which cancer risk perception, risk communication, and risk counseling are discussed. The summary also contains information about recording and analyzing a family history of cancer and factors to consider when offering genetic testing.
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about cancer genetics risk assessment and counseling. 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).
Risk Assessment & Genetic Counseling
Cancer Genetics Risk Assessment and Counseling
This executive summary reviews the topics covered in this PDQ summary on cancer genetics risk assessment and genetic counseling, with hyperlinks to detailed sections below that describe the evidence on each topic.
- Identification of Individuals for Cancer Genetics Risk Assessment and Counseling
Individuals are considered to be candidates for cancer risk assessment if they have a personal and/or family history (on the maternal or paternal side) or clinical characteristics with features suggestive of hereditary cancer. These features vary by type of cancer and specific hereditary syndrome. Criteria have been published to help identify individuals who may benefit from genetic counseling. It is important that individuals who are candidates for genetic testing undergo genetic education and counseling before testing to facilitate informed decision-making and adaptation to the risk or condition. Genetic education and counseling allows individuals to consider the various medical uncertainties, diagnosis, or medical management options based on varied test results; and the risks, benefits, and limitations of genetic testing.
- Components of Cancer Genetics Risk Assessment and Counseling
Comprehensive cancer risk assessment and counseling is a consultative service that includes clinical assessment, genetic testing when appropriate, and risk management recommendations delivered in the context of one or more genetic counseling sessions. Pretest genetic counseling is an important part of the risk assessment process and helps patients understand their genetic testing options and potential outcomes. Posttest genetic counseling helps patients understand their test results, including the medical implications for themselves and their relatives.
The recommended provision of cancer risk assessment services optimally involves care providers from multiple disciplines, including a genetic counselor; a genetics advanced practice nurse; a medical geneticist or a physician, such as an oncologist, surgeon, or internist; and potential referrals to other specialists, such as mental health professionals, endocrinologists, and reproductive specialists.
Traditionally, genetic counseling services have been delivered using individualized, in-person appointments. However, other methodologies are being explored, including group sessions, telephone counseling, and telemedicine by videoconferencing.
- Genetic Testing Considerations
There are many factors that can influence an individual’s decision to undergo genetic testing and which type of test to use, including the presence of a known pathogenic variant in the family, patterns of cancer in the family, insurance coverage, family planning considerations, and the psychological impact of a test result. Previously, most germline genetic testing was offered for a single gene at a time; however, recent technological advances have resulted in the widespread availability of multigene (panel) testing, which can simultaneously test for pathogenic variants in many genes at once, often at costs comparable to single-gene testing. Research examining the use of multigene testing is under way. Some genetic tests are also offered directly to the consumer (DTC). While these tests may promote patient autonomy and increased awareness of the importance of family history, DTC genetic testing may not include genetic counseling or interpretation of the results by a genetics professional.
- Ethical, Legal, and Social Implications
Having an understanding of the ethical, legal, and social implications regarding cancer genetic testing may influence the clinician’s response to the complex questions and issues that may arise during the process of risk assessment and counseling. The tenets of beneficence, nonmaleficence, autonomy, and justice are part of a framework needed to balance the complex and potentially conflicting factors surrounding a clinician’s role in respecting privacy, confidentiality, and fair use of genetic information obtained from cancer genetic testing.
Employment and insurance discrimination are common concerns for individuals considering genetic testing. The Genetic Information Nondiscrimination Act, a Federal law passed in 2008, protects the provision of health insurance and employment discrimination on the basis of genetics information; however, it does not apply to members of the military or to long-term care insurance.
This summary describes current approaches to assessing and counseling people about their chance of having an inherited susceptibility to cancer. Genetic counseling is defined by the National Society of Genetic Counselors as the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease. Several reviews present overviews of the cancer risk assessment, counseling, and genetic testing process.
Individuals are considered to be candidates for cancer risk assessment if they have a personal and/or family history (maternal or paternal lineage) with features suggestive of hereditary cancer. These features vary by type of cancer and specific hereditary syndrome. Criteria have been published to help identify individuals who may benefit from genetic counseling. The PDQ cancer genetics information summaries on breast, ovarian, endometrial, colorectal, prostate, kidney, and skin cancers and endocrine and neuroendocrine neoplasias describe the clinical features of hereditary syndromes associated with these conditions.
The following are features that suggest hereditary cancer:
- Unusually early age of cancer onset (e.g., premenopausal breast cancer).
- Multiple primary cancers in a single individual (e.g., colorectal and endometrial cancer).
- Bilateral cancer in paired organs or multifocal disease (e.g., bilateral breast cancer or multifocal renal cancer).
- Clustering of the same type of cancer in close relatives (e.g., mother, daughter, and sisters with breast cancer).
- Cancers occurring in multiple generations of a family (i.e., autosomal dominant inheritance).
- Occurrence of rare tumors (e.g., retinoblastoma, adrenocortical carcinoma, granulosa cell tumor of the ovary, ocular melanoma, or duodenal cancer).
- Unusual presentation of cancer (e.g., male breast cancer).
- Uncommon tumor histology (e.g., medullary thyroid carcinoma).
- Rare cancers associated with birth defects (e.g., Wilms tumor and genitourinary abnormalities).
- Geographic or ethnic populations known to be at high risk of hereditary cancers. Genetic testing candidates may be identified based solely on ethnicity when a strong founder effect is present in a given population (e.g., Ashkenazi heritage and pathogenic variants).
As part of the process of genetic education and counseling, genetic testing may be considered when the following factors are present:
- An individual's personal history (including ethnicity) and/or family history are suspicious for a genetic predisposition to cancer.
- The genetic test has sufficient sensitivity and specificity to be interpreted.
- The test will impact the individual's diagnosis, cancer management or cancer risk management, and/or help clarify risk in family members.
It is important that individuals who are candidates for genetic testing undergo genetic education and counseling before testing to facilitate informed decision making and adaptation to the risk or condition. Genetic education and counseling allows individuals to consider the various medical uncertainties, diagnosis, or medical management based on varied test results, and the risks, benefits, and limitations of genetic testing.
Identification of Candidates for Referral to Genetic Counseling
After an individual’s personal and family cancer histories have been collected, several factors could warrant referral to a genetics professional for evaluation of hereditary cancer susceptibility syndromes. The American College of Medical Genetics and Genomics and the National Society of Genetic Counselors have published a comprehensive set of personal and family history criteria to guide the identification of at-risk individuals and appropriate referral for cancer genetic risk consultation. These practice guidelines take into account tumor types or other features and related criteria that would indicate a need for a genetics referral. The authors state that the guidelines are intended to maximize appropriate referral of at-risk individuals for cancer genetic consultation but are not meant to provide genetic testing or treatment recommendations.
Tools to Identify Candidates for Genetic Counseling and Genetic Testing
Identification of patients at moderate to high risk of hereditary cancer for genetic services is recommended by all major societies. Primary care physicians have a number of tools available to triage patients. In addition to the published categorical guidelines available through professional organizations, there are also red flag cards, paper-based checklists, and patient-directed online referral tools. Table 1 provides a list of several publically available resources that can be used to identify patients for referral to genetic services. Although most tools are brief and simple enough for patients to complete on their own, either previsit, online, or in the waiting room, clinical review is warranted. Many include the commonly known features suggestive of hereditary cancers, but exclusions are noted in the table below.
Cancer Risk Assessment and Counseling
Comprehensive cancer risk assessment is a consultative service that includes clinical assessment, genetic testing when appropriate, and risk management recommendations delivered in the context of one or more genetic counseling sessions. Pretest genetic counseling is an important part of the risk assessment process and helps patients understand their genetic testing options and potential outcomes. Posttest genetic counseling helps patients understand their test results, including the medical implications for themselves and their relatives.
Several professional organizations emphasize the importance of genetic counseling in the cancer risk assessment and genetic testing process. Examples of these organizations include the following:
- American College of Medical Genetics and Genomics.
- American Society of Clinical Oncology.
- American Society of Human Genetics.
- International Society of Nurses in Genetics.
- National Society of Genetic Counselors.
- National Comprehensive Cancer Network.
- Oncology Nursing Society.
- Society of Gynecologic Oncologists.
- U.S. Preventive Services Task Force.
A list of organizations that have published clinical practices guidelines related to genetic counseling, risk assessment, genetic testing, and/or management for hereditary breast and ovarian cancers is available in the PDQ summary on Genetics of Breast and Gynecologic Cancers.
Genetic counseling informs the consultand about potential cancer risks and the benefits and limitations of genetic testing and offers an opportunity to consider the potential medical, psychological, familial, and social implications of genetic information. Descriptions of genetic counseling and the specialized practice of cancer risk assessment counseling are detailed below.
Genetic counseling has been defined by the American Society of Human Genetics as “a communication process that deals with the human problems associated with the occurrence, or risk of occurrence, of a genetic disorder in a family." The process involves an attempt by one or more appropriately trained persons to help the individual or family do the following:
In 2006, the National Society of Genetic Counselors further refined the definition of genetic counseling to include the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease, including integration of the following:
- Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence.
- Education about inheritance, testing, management, prevention, resources, and research.
- Counseling to promote informed choices and adaptation to the risk or condition.
Central to the philosophy and practice of genetic counseling are the principles of voluntary utilization of services, informed decision making, attention to psychosocial and affective dimensions of coping with genetic risk, and protection of patient confidentiality and privacy. This is facilitated through a combination of rapport building and information gathering; establishing or verifying diagnoses; risk assessment and calculation of quantitative occurrence/recurrence risks; education and informed consent processes; psychosocial assessment, support, and counseling appropriate to a family’s culture and ethnicity; and other relevant background characteristics. The psychosocial assessment is especially important in the genetic counseling process because individuals most vulnerable to adverse effects of genetic information may include those who have had difficulty dealing with stressful life events in the past. Variables that may influence psychosocial adjustment to genetic information include individual and familial factors; cultural factors; and health system factors such as the type of test, disease status, and risk information. Findings from a psychosocial assessment can be used to help guide the direction of the counseling session. An important objective of genetic counseling is to provide an opportunity for shared decision making when the medical benefits of one course of action are not demonstrated to be superior to another. The relationship between the availability of effective medical treatment for carriers of pathogenic variants and the clinical validity of a given test affects the degree to which personal choice or physician recommendation is supported in counseling at-risk individuals. Uptake of genetic counseling services among those referred varies based on the cancer syndrome and the clinical setting. Efforts to decrease barriers to service utilization are ongoing (e.g., a patient navigator telephone call may increase utilization of these services). Readers interested in the nature and history of genetic counseling are referred to a number of comprehensive reviews.
Pretest Genetic Education and Counseling Outcomes
Cancer risk assessment counseling has emerged as a specialized practice that requires knowledge of genetics, oncology, and individual and family counseling skills that may be provided by health care providers with this interdisciplinary training. Some centers providing cancer risk assessment services involve a multidisciplinary team, which may include a genetic counselor; a genetics advanced practice nurse; a medical geneticist or a physician, such as an oncologist, surgeon, or internist; and a mental health professional. The Cancer Genetics Services Directory provides a partial list of individuals involved in cancer risk assessment, genetic counseling, testing, and other related services and is available on the National Cancer Institute's website.
The need for advanced professional training in cancer genetics for genetics counselors, physicians, nurses, laboratory technicians, and others has been widely reported. Despite these identified needs, the evidence indicates that competency in genetics and genomics remains limited across all health care disciplines, with the exception of genetic specialists. Deficits in the following have been identified: (1) knowledge about hereditary cancer syndromes and risk-appropriate management strategies; (2) provision of genetic counseling services; (3) documentation and use of personal and family cancer history to identify and refer patients at increased risk of hereditary cancer syndromes; and (4) knowledge about genetic nondiscrimination laws. (Refer to the table on Health Professional Practice and Genetic Education Information in the PDQ Cancer Genetics Overview summary for more information.)
The National Coalition for Health Professional Education in Genetics (whose work was transitioned to The Jackson Laboratory in 2013) has published core competencies for all health professionals. Building on this work, individual health professions, such as physicians, nurses, physician assistants, pharmacists, and genetic counselors, have developed and published core competencies specific to their profession. A number of other organizations have also published professional guidelines, scopes, and standards of practice.
Modalities of genetic counseling
Traditionally, genetic counseling services have been delivered using individualized in-person appointments. However, other methodologies have been implemented, including group sessions, telephone counseling, and online genetic counseling using remote videoconferencing, which is often referred to as . Of these alternative approaches, only telephone counseling has been examined for noninferiority against in-person genetic counseling in a randomized controlled trial.
Telephone genetic counseling
Two large randomized trials have compared in-person versus telephone genetic counseling on short-term (1–2 weeks) and intermediate-term (3–6 months) patient outcomes in women at increased risk for hereditary breast and ovarian cancer. Both studies assessed psychosocial and behavioral outcomes after counseling, including the uptake of / genetic testing. (The studies were conducted prior to the adoption of multigene panel testing.)
A multisite randomized controlled study in the eastern United States recruited women at high risk of carrying a / pathogenic variant from genetics clinics and assigned them to usual care (i.e., in-person genetic counseling; n = 334) or telephone counseling (n = 335). Telephone counseling resulted in similar outcomes to usual care with respect to patient knowledge, satisfaction, decisional conflict, distress, and quality of life at 2 weeks and 3 months following pretest genetic counseling.
A second multisite cluster randomized trial assigned women residing in rural and urban areas in Utah to receive in-person (n = 510) or telephone (n = 502) genetic counseling. High-risk women were identified from population-based resources including the Utah Population Database and the Utah Cancer Registry. Similarly, findings showed no differences on patient knowledge, decisional conflict, decisional regret, cancer-specific distress, anxiety, quality of life, or patient-centered communication at 1 week, 6 months, or 12 months after counseling.
Both studies also examined the uptake of genetic testing in each of the counseling groups and, despite dramatically different rates of uptake, found a 6% to 10% higher uptake of testing in the in-person cohort compared with the telephone counseling cohort. In the study conducted in the eastern United States, the uptake rates in the in-person and telephone counseling cohorts were 90.1% and 84.2%, respectively (absolute difference, 5.9; 90% confidence interval [CI], -10.3% to -0.01%). However, patients in the usual care group could undergo testing immediately following the pretest genetic counseling while those in the telephone counseling group had to come in for a subsequent blood draw. Longer-term reports of uptake were not presented in this study. In the Utah study, uptake data were reported at 6 months and 12 months following counseling. At 6 months, the uptake rates for the in-person and the telephone counseling cohorts were 31.8% and 21.8%, respectively (absolute difference, 10.2%; 95% CI, 3.9%–16.3%) and at 12 months, the rates were 37.3% versus 27.9%, respectively (absolute difference, 9.4%; 95% CI, 2.3%–16.8%). The authors speculate that the lower rates of testing as compared with other studies may be due to the population-based recruitment strategies.
Video-assisted genetic counseling
Studies have also examined the use of online genetic counseling using remote videoconferencing (telegenetics) as an alternative to in-person genetic counseling and demonstrated increases in patient knowledge, high levels of satisfaction, and minimal negative psychosocial outcomes.
Components of the Risk Assessment Process
This section provides an overview of critical elements in the cancer risk assessment process.
A number of professional guidelines on the elements of cancer genetics risk assessment and counseling are available. Except where noted, the discussion below is based on these guidelines.
The cancer risk assessment and counseling process, which may vary among providers, requires one or more consultative sessions and generally includes the following:
- A detailed, multifaceted assessment including family history.
- A determination of the risk of cancer and/or indication for genetic testing based on evidence of an inherited cancer syndrome.
- Education and counseling.
- Review of genetic testing options.
- Establishment of a cancer risk management plan.
At the outset of the initial counseling session, eliciting and addressing the consultand's perceptions and concerns about cancer and his or her expectations of the risk assessment process helps to engage the consultand in the session. This also helps inform the provider about practical or psychosocial issues and guides the focus of counseling and strategies for risk assessment.
The counseling process that takes place as part of a cancer risk assessment can identify factors that contribute to the consultand's perception of cancer risk and motivations to seek cancer risk assessment and genetic testing. It can also identify potential psychological issues that may need to be addressed during or beyond the session. Information collected before and/or during the session may include the following:
- Motivations for seeking cancer risk assessment.
- Beliefs about the causes of cancer.
- Experiences with cancer and feelings, perceptions, concerns, or fears related to those experiences.
- The influence of cancer experiences and perceptions on health behaviors and cancer screening practices.
- Cultural, religious, and socioeconomic background.
- General psychological issues, such as depression or anxiety.
- Coping mechanisms.
- Support systems.
Either alone or in consultation with a mental health provider, health care providers offering cancer risk counseling attempt to assess whether the individual's expectations of counseling are realistic and whether there are factors suggesting risk of adverse psychological outcomes after disclosure of risk and/or genetic status.
Concepts of personal cancer risk, genetics, and the relationship between the two can be complex and can be difficult for patients to understand. A number of factors influence a person’s concept of his or her risk, which may not be congruent with evidence-based quantitative calculations. These factors include:
- Experiential and empathetic knowledge.
- People's beliefs regarding the basis for the occurrence of cancer in themselves and/or their relatives.
- Sources of information and inaccuracies and/or misperceptions.
- Literacy level, including health and numeracy.
- Personal theories of inheritance.
- Patterns of decision making (deliberate vs. experiential).
A thorough understanding of these issues can greatly inform genetic education and counseling. These factors influence the processing of risk information and subsequent health behaviors.
The communication of risk involves the delivery of quantitative information regarding what the data indicate about the likelihood of developing illness given various preventive actions. More broadly, however, risk communication is an interactive process regarding the individual’s knowledge, beliefs, emotions, and behaviors associated with risk and the risk message conveyed. Accordingly, the goal of risk communication may be to impact the individual’s knowledge of risk factors, risk likelihoods, potential consequences of risk, and the benefits and drawbacks of preventive actions.
Even before the provision of risk information, the provider may anticipate that the individual already has some sense of his or her own risk of cancer. The individual may have derived this information from multiple sources, including physicians, family members, and the media. This information may be more salient or emotional if a family member has recently died from cancer or if there is a new family diagnosis. Additionally, individuals may have beliefs about how genetic susceptibility works in their family. For example, in a family where only females have been affected with an autosomal dominant cancer susceptibility syndrome thus far, it may be difficult to convince the consultand that her sons have a 50% risk of inheriting the disease-related pathogenic variant. The social-ecological context through which risk beliefs develop and are maintained are important as potential moderators of individuals’ receptivity to the cancer risk communication process and also represent the context in which individuals will return to continue ongoing decision making about how to manage their risk. As such, individuals’ beliefs, and the social context of risk, are important to discuss in education and genetic risk counseling.
Perceived risk can play an important role in an individual’s decision to participate in counseling, despite the fact that perceived risk often varies substantially from statistical risk estimates.
Personal health history
Consideration of the consultand's personal health history is essential in cancer risk assessment, regardless of whether the individual has a personal history of cancer. Important information to obtain about the consultand's health history includes the following:
- Current age.
- Race and ethnicity.
- History of benign or malignant tumors, surgeries, biopsies, major illnesses, medications, and reproductive history (for women, this includes age at menarche, parity, age at first live birth, age at menopause, and history of exogenous hormone use).
- Environmental exposures.
- Diet and exercise practices.
- Complementary and alternative medicine practices.
- Past and current alcohol intake and tobacco use.
- Screening practices and date of last screening exams, including imaging and/or physical examinations.
For consultands with a history of cancer, additional information collected includes the following:
- Site of primary tumor.
- Age at diagnosis.
- Tumor pathology.
- Treatment (e.g., surgery, chemotherapy, and radiation therapy).
- Bilaterality of disease, if applicable.
- Current surveillance plan.
In some cases, a physical exam is conducted by a qualified medical professional to determine whether the individual has physical findings suggestive of a hereditary cancer predisposition syndrome or to rule out evidence of an existing malignancy. For example, a medical professional may look for the sebaceous adenomas seen in Muir-Torre syndrome, measure the head circumference or perform a skin exam to rule out benign cutaneous features associated with Cowden syndrome, or perform a clinical breast and axillary lymph node exam on a woman undergoing a breast cancer risk assessment.
Documenting the family history
The family history is an essential tool for cancer risk assessment. The family history can be obtained via interview or written self-report; both were found to result in equivalent information in a study that utilized a sample (N = 104) that varied widely in educational attainment. A nine-question family history screening tool has been shown to identify individuals at increased risk of common health conditions, including cancer, who warrant a more detailed family history (receiver operating characteristic, 84.6% [range, 81.2%–88.1%]; sensitivity, 95% [range, 92%–98%]; specificity, 54% [range, 48%–60%]). Studies suggest that paper-based family history questionnaires completed before the appointment provide accurate family history information and that the use of these questionnaires is an acceptable and understandable family history collection method. However, questionnaire-based assessments may lead to some underreporting of family history; therefore, a follow-up interview to confirm the reported information and to capture all relevant family history information may be required. Routine chart reviews (e.g., via electronic medical records) may be worthwhile to maximize the identification of appropriate candidates for genetic counseling referral. In a single nonacademic institution, systematic chart review by a genetic counselor increased the number of referrals for genetics consultation. The most significant improvement was in ovarian cancer referrals. In conjunction with other efforts to collect and review family history, the performance of routine chart reviews may help identify gaps in existing referral patterns. Additionally, collecting family history from multiple relatives in a single family has been shown to increase the number of reported family members with cancer, compared with family history information provided by a single family member.
Details of the family health history are best summarized in the form of a family tree, or pedigree. The pedigree, a standardized graphic representation of family relationships, facilitates identification of patterns of disease transmission, recognition of the clinical characteristics associated with specific hereditary cancer syndromes, and determination of the best strategies and tools for risk assessment. Factors suggesting inherited cancer risk in a family are described below.
Both multimedia-based (e.g., Internet) and print-based (e.g., family history questionnaires) tools are currently available to gather information about family history. In the United States, many are written at reading grade levels above 8th grade, which may reduce their effectiveness in gathering accurate family history information. On average, print-based tools have been found to be written at lower reading grade levels than multimedia-based tools.
Standards of pedigree nomenclature have been established. Refer to Figure 1 for common pedigree symbols.
Figure 1. Standard pedigree nomenclature. Common symbols are used to draw a pedigree (family tree). A pedigree shows relationships between family members and patterns of inheritance for certain traits and diseases.
Documentation of a family cancer history typically includes the following:
- A minimum of first- and second-degree relatives on both the maternal and paternal sides of the family. Information on multiple generations helps to demonstrate inheritance patterns. Hereditary cancer can be inherited from either the maternal or paternal side of the family and is often an adult-onset disease.
- Race, ancestry, and ethnicity of all grandparents. This may influence decisions about genetic testing because specific pathogenic variants in some genes are known to occur with increased frequency in some populations (founder effect).
- Information about seemingly unrelated conditions, such as birth defects, atypical skin bumps, or other nonmalignant conditions of children and adults that may aid in the diagnosis of a cancer susceptibility syndrome.
- Notation of adoption, nonpaternity (the biologic father should be included in the pedigree), consanguinity, and use of assisted reproductive technology (e.g., donor egg or sperm), when available.
A three-generation family history includes the following:
- First-degree relatives (e.g., children, brothers and sisters, and parents).
- Second-degree relatives (e.g., grandparents, aunts and uncles, nieces and nephews, grandchildren, and half-siblings).
- Third-degree relatives (e.g., first cousins, great aunts, and great uncles).
- Additional distant relatives are included if information is available, especially when there are known cancer histories among them.
For any relative with cancer, collect the following information:
- Primary site of each cancer, with supportive documentation of key cancers (if available) to confirm primary site and histology (e.g., pathology reports, clinical documents, and death certificates).
- Age at diagnosis for each primary cancer.
- Where the relative was diagnosed and/or treated.
- History of surgery or treatments that may have reduced the risk of cancer. For example, bilateral salpingo-oophorectomy in a premenopausal woman significantly reduces the risk of ovarian and breast cancers. This may mask underlying hereditary predisposition to these cancers.
- Current age (if living).
- Age at death and cause of death (if deceased).
- Carcinogenic exposures (e.g., tobacco use and radiation exposure).
- Other significant health problems.
For relatives not affected with cancer, collect the following information:
- Current age or age at death.
- Cause of death (if deceased).
- History of any surgeries or treatments that may have reduced the risk of cancer.
- Cancer screening practices.
- Any nonmalignant features associated with the syndrome in question.
- Carcinogenic exposures.
- Other significant health problems.
Accuracy of the family history
The accuracy of the family history has a direct bearing on determining the differential diagnoses, selecting appropriate testing, interpreting results of the genetic tests, refining individual cancer risk estimates, and outlining screening and risk reduction recommendations. In a telephone survey of 1,019 individuals, only 6% did not know whether a first-degree relative had cancer; this increased to 8.5% for second-degree relatives. However, people often have incomplete or inaccurate information about the cancer history in their family. Patient education has been shown to improve the completeness of family history collection and may lead to more-accurate risk stratification, referrals for genetic counseling, and changes to management recommendations. Confirming the primary site of cancers in the family that will affect the calculation of hereditary predisposition probabilities and/or estimation of empiric cancer risks may be important, especially if decisions about treatments such as risk-reducing surgery will be based on this family history.
A population-based survey of 2,605 first- and second-degree relatives confirmed proband reports of cancer diagnoses and found that the accuracy of reported cancer diagnoses in relatives was low to moderate, while reports of no history of cancer were accurate. Accuracy varies by cancer site and degree of relatedness. Reporting of cancer family histories may be most accurate for breast cancer and less accurate for gynecologic malignancies and colon cancer. Self-reported family histories may contain errors and, in rare instances, could be fictitious. The most reliable documentation of cancer histology is the pathology report. Verification of cancers can also be made through other medical records, tumor registries, or death certificates. A U.K. study illustrates the importance of verification of the cancer family history in individuals with a family history of breast cancer (n = 2,278) and colon cancer (n = 1,184). Changes in genetic risk assignment (reassignment) from baseline to final time points (e.g., low risk to high risk) warranting management changes were reported in nearly 30% of families with colorectal cancer and 20% of families with breast cancer. Verification of reported cancer diagnoses in this cohort revealed a lower overall degree of consistency between reported and confirmed diagnoses than in other studies.
It is also important to consider limited, missing, or questionable information when reviewing a pedigree for cancer risk assessment. It is more difficult to identify features of hereditary disease in families with a truncated family structure due to loss of contact with relatives, small family size, or deaths at an early age from unrelated conditions. When there are few family members of the at-risk gender when considering a particular syndrome with primarily male or female specific disease manifestations, the family history may be difficult to assess (e.g., few female members in a family at risk of hereditary breast and ovarian cancer syndrome). In addition, information collected on risk-reducing surgical procedures, such as oophorectomy, could significantly change prior probability estimation and the constellation of cancers observed in a family. Other factors to clarify and document whenever possible are adoptions, use of donor egg or sperm, consanguinity, and uncertain paternity.
Additionally, family histories are dynamic. The occurrence of additional cancers may alter the likelihood of a hereditary predisposition to cancer, and consideration of differential diagnoses or empiric cancer risk estimates may change if additional cancers arise in the family. Furthermore, changes in the cancer family history over time may alter recommendations for earlier or more intense cancer screening. A descriptive study that examined baseline and follow-up family history data from a U.S. population-based cancer registry reported that family history of breast cancer or colorectal cancer becomes increasingly relevant in early adulthood and changes significantly from age 30 years to age 50 years. Therefore, it is important to advise the consultand to take note of, confirm, and report cancer diagnoses or other pertinent family health history that occurs after completion of the initial risk assessment process. This is especially important if genetic testing was not performed or was uninformative.
Finally, the process of taking the family history has a psychosocial dimension. Discussing and documenting discrete aspects of family relationships and health brings the family into the session symbolically, even when a single person is being counseled. Problems that may be encountered in eliciting a family history and constructing a pedigree include difficulty contacting relatives with whom one has little or no relationship, differing views between family members about the value of genetic information, resistance to discussion of cancer and cancer-related illness, unanticipated discovery of previously unknown medical or family information, and coercion of one relative by another regarding testing decisions. In addition, unexpected emotional distress may be experienced by the consultand in the process of gathering family history information.
Determining Cancer Risk
Analysis of the family history
Because a family history of cancer is one of the important predictors of cancer risk, analysis of the pedigree constitutes an important aspect of risk assessment. This analysis might be thought of as a series of the following questions:
- What is the evidence that a cancer susceptibility syndrome is present in this family?
- If a syndrome is present, what is the most probable diagnosis?
- What could make this family history difficult to interpret?
- What is the most likely mode of inheritance, regardless of whether a specific syndrome diagnosis can be established?
- What is the chance of a member of this family developing cancer, if an inherited susceptibility exists?
- If no recognizable syndrome is present, is there a risk of cancer based on other epidemiological risk factors?
The following sections relate to the way that each of these questions might be addressed:
Methods of quantifying cancer risk
The overarching goal of cancer risk assessment is to individualize cancer risk management recommendations based on personalized risk. Methods to calculate risk utilize health history information and risk factor and family history data often in combination with emerging biologic and genetic/genomic evidence to establish predictions. Multiple methodologies are used to calculate risk, including statistical models, prevalence data from specific populations, penetrance data when a documented pathogenic variant has been identified in a family, Mendelian inheritance, and Bayesian analysis. All models have distinct capabilities, weaknesses, and limitations based on the methodology, sample size, and/or population used to create the model. Methods to individually quantify risk encompass two primary areas: the probability of harboring a pathogenic variant in a cancer susceptibility gene and the risk of developing a specific form of cancer.
Risk of harboring a pathogenic variant in a cancer susceptibility gene
The decision to offer genetic testing for cancer susceptibility is complex and can be aided in part by objectively assessing an individual's and/or family's probability of harboring a pathogenic variant. Predicting the probability of harboring a pathogenic variant in a cancer susceptibility gene can be done using several strategies, including empiric data, statistical models, population prevalence data, Mendel’s laws, Bayesian analysis, and specific health information, such as tumor-specific features. All of these methods are gene specific or cancer-syndrome specific and are employed only after a thorough assessment has been completed and genetic differential diagnoses have been established.
If a gene or hereditary cancer syndrome is suspected, models specific to that disorder can be used to determine whether genetic testing may be informative. (Refer to the PDQ summaries on the Genetics of Breast and Gynecologic Cancers; Genetics of Colorectal Cancer; or the Genetics of Skin Cancer for more information about cancer syndrome-specific probability models.) The key to using specific models or prevalence data is to apply the model or statistics only in the population best suited for its use. For instance, a model or prevalence data derived from a population study of individuals older than 35 years may not accurately be applied in a population aged 35 years and younger. Care must be taken when interpreting the data obtained from various risk models because they differ with regard to what is actually being estimated. Some models estimate the risk of a pathogenic variant being present in the family; others estimate the risk of a pathogenic variant being present in the individual being counseled. Some models estimate the risk of specific cancers developing in an individual, while others estimate more than one of the data above. (Refer to NCI's Risk Prediction Models website or the disease-specific PDQ cancer genetics summaries for more information about specific cancer risk prediction and pathogenic variant probability models.) Other important considerations include critical family constructs, which can significantly impact model reliability, such as small family size or male-dominated families when the cancer risks are predominately female in origin, adoption, and early deaths from other causes. In addition, most models provide gene and/or syndrome-specific probabilities but do not account for the possibility that the personal and/or family history of cancer may be conferred by an as-yet-unidentified cancer susceptibility gene. In the absence of a documented pathogenic variant in the family, critical assessment of the personal and family history is essential in determining the usefulness and limitations of probability estimates used to aid in the decisions regarding indications for genetic testing.
When a pathogenic variant has been identified in a family and a test report documents that finding, prior probabilities can be ascertained with a greater degree of reliability. In this setting, probabilities can be calculated based on the pattern of inheritance associated with the gene in which the pathogenic variant has been identified. In addition, critical to the application of Mendelian inheritance is the consideration of integrating Bayes Theorem, which incorporates other variables, such as current age, into the calculation for a more accurate posterior probability. This is especially useful in individuals who have lived to be older than the age at which cancer is likely to develop based on the pathogenic variant identified in their family and therefore have a lower likelihood of harboring the family pathogenic variant when compared with the probability based on their relationship to the carrier in the family.
Even in the case of a documented pathogenic variant on one side of the family, careful assessment and evaluation of the individual’s personal and family history of cancer is essential to rule out cancer risk or suspicion of a cancer susceptibility gene pathogenic variant on the other side of the family (maternal or paternal, as applicable). Segregation of more than one pathogenic variant in a family is possible (e.g., in circumstances in which a cancer syndrome has founder pathogenic variants associated with families of particular ancestral origin).
Risk of developing cancer
Unlike pathogenic variant probability models that predict the likelihood that a given personal and/or family history of cancer could be associated with a pathogenic variant in a specific gene(s), other methods and models can be used to estimate the risk of developing cancer over time. Similar to pathogenic variant probability assessments, cancer risk calculations are also complex and necessitate a detailed health history and family history. In the presence of a documented pathogenic variant, cancer risk estimates can be derived from peer-reviewed penetrance data. Penetrance data are constantly being refined and many genetic variants have variable penetrance because other variables may impact the absolute risk of cancer in any given patient. Modifiers of cancer risk in carriers of pathogenic variants include the variant's effect on the function of the gene/protein (e.g., variant type and position), the contributions of modifier genes, and personal and environmental factors (e.g., the impact of bilateral salpingo-oophorectomy performed for other indications in a woman who harbors a pathogenic variant). When there is evidence of an inherited susceptibility to cancer but genetic testing has not been performed, analysis of the pedigree can be used to estimate cancer risk. This type of calculation uses the probability the individual harbors a genetic variant and variant-specific penetrance data to calculate cancer risk.
In the absence of evidence of a hereditary cancer syndrome, several methods can be utilized to estimate cancer risk. Relative risk data from studies of specific risk factors provide ratios of observed versus expected cancers associated with a given risk factor. However, utilizing relative risk data for individualized risk assessment can have significant limitations: relative risk calculations will differ based on the type of control group and other study-associated biases, and comparability across studies can vary widely. In addition, relative risks are lifetime ratios and do not provide age-specific calculations, nor can the relative risk be multiplied by population risk to provide an individual's risk estimate.
In spite of these limitations, disease-specific cumulative risk estimates are most often employed in clinical settings. These estimates usually provide risk for a given time interval and can be anchored to cumulative risks of other health conditions in a given population (e.g., the 5-year risk by the Gail model). Cumulative risk models have limitations that may underestimate or overestimate risk. For example, the Gail model excludes paternal family histories of breast cancer. Furthermore, many of these models were constructed from data derived from predominately Caucasian populations and may have limited validity when used to estimate risk in other ethnicities.
Cumulative risk estimates are best used when evidence of other underlying significant risk factors have been ruled out. Careful evaluation of an individual's personal health and family history can identify other confounding risk factors that may outweigh a risk estimate derived from a cumulative risk model. For example, a woman with a prior biopsy showing lobular carcinoma in situ (LCIS) whose mother was diagnosed with breast cancer at age 65 years has a greater lifetime risk from her history of LCIS than her cumulative lifetime risk of breast cancer based on one first-degree relative. In this circumstance, recommendations for cancer risk management would be based on the risk associated with her LCIS. Unfortunately, there is no reliable method for combining all of an individual's relevant risk factors for an accurate absolute cancer risk estimate, nor are individual risk factors additive.
In summary, careful ascertainment and review of personal health and cancer family history are essential adjuncts to the use of prior probability models and cancer risk assessment models to assure that critical elements influencing risk calculations are considered. Influencing factors include the following:
- Differential diagnosis that is consistent with the personal and cancer family history.
- Consideration of factors that influence how informative the family history may be.
- Population that is best suited for the use of the model.
- Tumor-specific features that may be suspicious for an inherited predisposition or modify individual cancer risk predictions.
- Model-specific limitations that can overestimate or underestimate calculations.
A number of investigators are developing health care provider decision support tools such as the Genetic Risk Assessment on the Internet with Decision Support (GRAIDS), but at this time, clinical judgment remains a key component of any prior probability or absolute cancer risk estimation.
Education and Counseling About Risk/Risk Communication
Specific clinical programs for risk management may be offered to persons with an increased genetic risk of cancer. These programs may differ from those offered to persons of average risk in several ways: screening may be initiated at an earlier age or involve shorter screening intervals; screening strategies not in routine use, such as screening for ovarian cancer, may be offered; and interventions to reduce cancer risk, such as risk-reducing surgery, may be offered. Current recommendations are summarized in the PDQ summaries addressing the genetics of specific cancers.
The goal of genetic education and counseling is to help individuals understand their personal risk status, their options for cancer risk management, and to explore feelings regarding their personal risk status. Counseling focuses on obtaining and giving information, promoting autonomous decision making, and facilitating informed consent if genetic testing is pursued.
Optimally, education and counseling about cancer risk includes providing the following information:
- Purpose, strengths, and limitations of cancer risk assessment.
- Basic genetics and patterns of inheritance.
- Genetic basis of cancer.
- Clinical features of relevant hereditary cancer syndromes.
- Evidence of a hereditary cancer syndrome from the consultand's personal and family history.
- Options for clarifying cancer risk, including genetic testing, if indicated.
- Options available for risk management, including data (or lack of data) on the efficacy of different measures for early detection and risk reduction.
- Signs and symptoms of cancer.
When a clinically valid genetic test is available, education and counseling for genetic testing typically includes the following:
- Risk of having a pathogenic variant and patterns of transmission.
- Alternatives to genetic testing.
- Risks, benefits and limitations of genetic testing, including psychological and discriminatory risks.
- Possible test outcomes, including likelihood of uninformative results and identifying variants of uncertain significance.
- Sensitivity of the genetic test, including the techniques utilized to perform the test and their associated limitations.
- Health care management options based on possible test results.
- Implications for children and other family members based on pattern of transmission.
- Dissemination of risk and genetic information to family members.
- Cost associated with testing, counseling, medical management, and options for insurance coverage.
- How genetic information and genetic test results will be recorded in the medical record.
- Specimen storage and reuse, if applicable.
If a second session is held to disclose and interpret genetic test results, education and counseling focuses on the following:
- Interpretation of test results.
- Discussion of further testing that may clarify risk (e.g., large rearrangement testing and testing the other genes based on the patient's differential cancer syndrome list).
- Assessment of the emotional and behavioral responses to genetic test results.
- Recommendations for coping and communication strategies to address issues related to cancer risk.
- Cancer risk management recommendations.
- Risk analysis and dissemination of risk results to family members.
The process of counseling may require more than one visit to address medical, genetic testing, and psychosocial support issues. Additional case-related preparation time is spent before and after the consultation sessions to obtain and review medical records, complete case documentation, seek information about differential diagnoses, identify appropriate laboratories for genetic tests, find patient support groups, research resources, and communicate with or refer to other specialists.
Information about inherited risk of cancer is growing rapidly. Many of the issues discussed in a counseling session may need to be revisited as new information emerges. At the end of the counseling process, individuals are typically reminded of the possibility that future research may provide new options and/or new information on risk. Individuals may be advised to check in with the health care provider periodically to determine whether new information is sufficient to merit an additional counseling session. The obligation of health care providers to recontact individuals when new genetic testing or treatment options are available is controversial, and standards have not been established.
Methods of Risk Presentation
The usage of numerical probabilities to communicate risk may overestimate the level of risk certainty, especially when wide confidence intervals exist to the estimates or when the individual may differ in important ways from the sample on which the risk estimate was derived. Also, numbers are often inadequate for expressing gut-level or emotional aspects of risk. Finally, there are wide variations in individuals’ level of understanding of mathematical concepts (i.e., numeracy). For all the above reasons, conveying risk in multiple ways, both numerically and verbally, with discussion of important caveats, may be a useful strategy to increase risk comprehension. The numerical format that facilitates the best understanding is natural frequencies because frequencies include information concerning the denominator, the reference group to which the individual may refer. In general, logarithmic scales are to be avoided. Additionally, important “contextual” risks may be included with the frequency in order to increase risk comprehension; these may include how the person’s risk compares with those who do not have the risk factor in question and the risks associated with common hazards, such as being in a car accident. Additional suggestions include being consistent in risk formats (do not mix odds and percentages), using the same denominator across risk estimates, avoiding decimal points, including base rate information, and providing more explanation if the risk is less than 1%.
The communication of risk may be numerical, verbal, or visual. Use of multiple strategies may increase comprehension and retention of cancer genetic risk information. Recently, use of visual risk communication strategies has increased (e.g., histograms, pie charts, and Venn diagrams). Visual depictions of risk may be very useful in avoiding problems with comprehension of numbers, but research that confirms this is lacking. A study published in 2008 examined the use of two different visual aids to communicate breast cancer risk. Women at an increased risk of breast cancer were randomized to receive feedback via a bar graph alone or a bar graph plus a frequency diagram (i.e., highlighted human figures). Results indicate that overall, there were no differences in improved accuracy of risk perception between the two groups, but among those women who inaccurately perceived very high risk at baseline, the group receiving both visual aids showed greater improvement in accuracy.
The purpose of risk counseling is to provide individuals with accurate information about their risk, help them understand and interpret their risk, assist them as they use this information to make important health care decisions, and help them make the best possible adjustment to their situation. A systematic review of 28 studies that evaluated communication interventions showed that risk communication benefits users cognitively by increasing their knowledge and understanding of risk perception and does not negatively influence affect (anxiety, cancer-related worry, and depression). Risk communication does not appear to result in a change in use of screening practices and tests. Users received the most benefit from an approach utilizing risk communication along with genetic counseling. Perceptions of risk are affected by the manner in which risk information is presented, difficulty understanding probability and heredity, and other psychological processes on the part of individuals and providers. Risk may be communicated in many ways (e.g., with numbers, words, or graphics; alone or in relation to other risks; as the probability of having an adverse event; in relative or absolute terms; and through combinations of these methods). The way in which risk information is communicated may affect the individual’s perception of the magnitude of that risk. In general, relative risk estimates (e.g., "You have a threefold increased risk of colorectal cancer") are perceived as less informative than absolute risk (e.g., "You have a 25% risk of colorectal cancer") or risk information presented as a ratio (e.g., 1 in 4). A strong preference for having pathogenic variant risk estimates expressed numerically is reported by women considering testing. Individuals associate widely differing quantitative risks with qualitative descriptors of risk such as “rare” or “common.” More research is needed on the best methods of communicating risk in order to help individuals develop an accurate understanding of their cancer risks.
Recent descriptive examination of the process of cancer genetic counseling has found that counseling sessions are predominantly focused on the biomedical teaching required to inform clients of their choices and to put genetic findings in perspective but that attention to psychosocial issues does not detract from teaching goals and may enhance satisfaction in clients undergoing counseling. For instance, one study of communication patterns in 167 pretest counseling sessions for found the sessions to have a predominantly biomedical and educational focus; however, this approach was client focused, with the counselor and client contributing equally to the dialogue. These authors note that there was a marked diversity in counselor styles, both between counselors and within different sessions, for each counselor. The finding of a didactic style was corroborated by other researchers who examined observer-rated content checklists and videotape of 51 counseling sessions for breast cancer susceptibility. Of note, genetic counselors seemed to rely on demographic information and breast cancer history to tailor genetic counseling sessions rather than client’s self-reported expectations or psychosocial factors. Concurrent provision of psychosocial and scientific information may be important in reducing worry in the context of counseling about cancer genetics topics. An increasing appreciation of language choices may contribute to enhanced understanding and reduced anxiety levels in the session; for example, it was noted that patients may appreciate synonymic choices for the word “mutation,” such as “altered gene”. Some authors have published recommendations for cultural tailoring of educational materials for the African-American population, such as a large flip chart, including the use of simple language and pictures, culturally identifiable images (e.g., spiritual symbols and tribal patterns), bright colors, and humor.
Studies have examined novel channels to communicate genetic cancer risk information, deliver psychosocial support, and standardize the genetic counseling process for individuals at increased risk of cancer. Much of this literature has attempted to make the genetic counseling session more efficient or to limit the need for the counselor to address basic genetic principles in the session to free up time for the client’s personal and emotional concerns about his or her risk. For example, the receipt of genetic feedback for and mismatch repair gene testing by letter, rather than a face-to-face genetic counseling feedback session, has been investigated. Other modalities include the development of patient assessments or checklists, CD-ROM programs, and interactive computer programs.
Patient assessments or checklists have been developed to facilitate coverage of important areas in the counseling session. One study assessed patients’ psychosocial needs before a hereditary cancer counseling session to determine the assessment’s effect on the session. A total of 246 participants from two familial cancer clinics were randomly assigned to either an intervention arm in which the counselor received assessment results or a usual care control arm. Study results demonstrated that psychosocial concerns were discussed more frequently among intervention participants than among controls, without affecting session length. Moreover, cancer worry and psychological distress were significantly lower for intervention versus control participants 4 weeks after the counseling session.
A second study compared a feedback checklist completed by 197 women attending a high-risk breast clinic prior to the counseling session to convey prior genetic knowledge and misconceptions to aid the counselor in tailoring the session for that client. The use of the feedback checklist led to gains in knowledge from the counseling session but did not reduce genetic counseling time, perhaps because the genetic counselor chose to spend time discussing topics such as psychosocial issues. Use of the checklist did decrease the time spent with the medical oncologist, however. The feedback checklist was compared to a CD-ROM that outlined basic genetic concepts and the benefits and limitations of testing and found that those viewing the CD-ROM spent less time with counselors and were less likely to choose to undergo genetic testing. The CD-ROM did not lead to increased knowledge of genetic concepts, as did use of the checklist.
A prospective study evaluated the effects of a CD-ROM decisional support aid for microsatellite instability (MSI) tumor testing in 239 colorectal cancer patients who met the revised Bethesda criteria but who did not meet the Amsterdam criteria. The study also tested a theoretical model of factors influencing decisional conflict surrounding decisions to pursue MSI tumor testing. Within the study, half of the sample was randomly assigned to receive a brief description of MSI testing within the clinical encounter, and the other half was provided the CD-ROM decisional support aid in addition to the brief description. The CD-ROM and brief description intervention increased knowledge about MSI testing more than the brief description alone did. As a result, decisional conflict decreased because participants felt more prepared to make a decision about the test and had increased perceived benefits of MSI testing.
Other innovative strategies include educational materials and interactive computer technology. In one study, a 13-page color communication aid using a diverse format for conveying risk, including graphic representations and verbal descriptions, was developed. The authors evaluated the influence of the communication aid in 27 women at high risk of a pathogenic variant and compared those who had read the aid to a comparison sample of 107 women who received standard genetic counseling. Improvements in genetic knowledge and accuracy of risk perception were documented in those who had read the aid, with no differences in anxiety or depression between groups. Personalized, interactive electronic materials have also been developed to aid in genetic education and counseling. In one study, an interactive computer education program available prior to the genetic counseling session was compared with genetic counseling alone in women undergoing counseling for testing. Use of the computer program prior to genetic counseling reduced face-time with the genetic counselor, particularly for those at lower risk of a pathogenic variant. Many of the counselors reported that their client’s use of the computer program allowed them to be more efficient and to reallocate time spent in the sessions to clients’ unique concerns.
Videoconferencing is an innovative strategy to facilitate genetic counseling sessions with clients who cannot travel to specialized clinic settings. In 37 individuals in the United Kingdom, real-time video conferencing was compared with face-to-face counseling sessions; both methods were found to improve knowledge and reduce anxiety levels. Similarly, teleconferencing sessions, in which the client and genetic specialists were able to talk with each other in real time, were used in rural Maine communities in the pediatric context to convey genetic information and findings for developmental delays and were found to be comparable to in-person consultations in terms of decision-making confidence and satisfaction with the consultations. An Australian study compared the experiences of 106 women who received hereditary breast and ovarian cancer genetic counseling via videoconferencing with the experiences of 89 women who received counseling face to face. Pre- and 1-month postcounseling assessments revealed no significant differences in knowledge gains, satisfaction, cancer-specific anxiety, generalized anxiety, depression, and perceived empathy of the genetic counselor.
The Option of Genetic Testing
Factors to Take into Consideration in Offering Testing
Indications for testing
Experts recommend offering genetic testing when a risk assessment suggests the presence of an inherited cancer syndrome for which specific genes have been identified. The American Society of Clinical Oncology (ASCO) Policy Statement on Genetic Testing for Cancer Susceptibility proposes that genetic testing be offered when the following conditions apply:
- An individual has a personal or family history suggestive of a genetic cancer susceptibility syndrome.
- The results of the test can be interpreted.
- Testing will influence medical management.
Characteristics used in making this determination are discussed in the PDQ summaries on the genetics of specific cancers. Even when individual and family history characteristics indicate a possible inherited cancer syndrome, individuals may elect not to proceed with testing after discussion of potential risks, benefits, and limitations, as discussed below. Conversely, individuals whose pedigrees are incomplete or uninformative due to very small family size, early deaths, or incomplete data on key family members may elect to pursue genetic testing in an attempt to better define their risk status. In these situations, it is particularly important that the pretest counseling fully explore the limitations of the testing process.
In 2010, ASCO updated its policy statement to address testing for low- to moderate-penetrance genes, multigene (panel) testing, and direct-to-consumer (DTC) testing. This ASCO framework (Table 2) recommends that the provider consider the evidence for clinical utility of the test in addition to whether the test was obtained through a health care provider or directly by the consumer.
ASCO’s position is that when a test, regardless of clinical utility, is ordered by a health care professional, the provider is responsible for organizing follow-up care based on the findings. For tests that were ordered by the consumer without health care professional involvement, management decisions are based on the evidence for clinical utility. For tests with accepted clinical utility, follow-up care can be guided by the evidence for cancer risk associated with the genetic test finding. However, in tests ordered by the consumer that have uncertain clinical utility, ASCO recommends that follow-up care consist of education regarding the lack of evidence regarding the test's clinical utility and that cancer risk management decisions be guided by established cancer risk factors.
Genetic education and counseling, including the interpretation of genetic test results, will vary depending on whether a previous attempt at genetic testing has been made (refer to Figure 2). In general, there are two primary circumstances in which genetic testing is performed:
- Families with evidence of an inherited susceptibility that have not had any genetic testing or in which genetic testing has not identified a pathogenic variant.
- Families with a documented pathogenic variant.
Figure 2. This genetic testing algorithm depicts the multistep process of testing for cancer susceptibility.
Value of testing an affected family member first
Genetic susceptibility testing generally yields the most useful information when a living family member affected with the cancer of concern is tested first to determine whether a genetic basis for the cancer diagnosis can be established. If testing is deferred while follow-up with an affected relative is pending, consider providing interim cancer risk management guidelines to the unaffected proband. Three possible outcomes of testing include the following (refer to Figure 2):
- Pathogenic variant detected.
- No variant detected.
- Variant of uncertain significance (VUS) detected.
If a documented pathogenic variant (associated with cancer risk) is identified, risks are based on penetrance data for pathogenic variants of that specific gene. In addition, other family members may be tested for the presence or absence of this specific pathogenic variant. If no variant is found in an affected family member, testing is considered uninformative and thus there is no basis for testing unaffected relatives. Failure of the laboratory to detect a pathogenic variant in an affected family member does not rule out an inherited basis for the cancer in that family. Reasons why testing could be uninformative include the following:
- The cancer in the family may be associated with a cancer susceptibility gene other than the gene that was tested.
- The cancer in the family may be associated with a pathogenic variant, but the cancer in the specific family member who underwent testing is not associated with that variant. This can occur especially with cancers that are common in the general population, such as breast cancer or prostate cancer. The family member who is affected with the disease but is not a carrier of the pathogenic variant associated with the inherited predisposition to cancer in the family is considered a phenocopy.
- Identifying a genetic variant may not be possible given the limited sensitivity of the laboratory techniques used to detect genetic variants. There may be additional testing available to detect certain types of variants that would have been missed by the initial genetic test.
- The function of the gene could be altered by a pathogenic variant in a different gene.
Lastly, testing may reveal a VUS. This result means that a genetic variant has been found; however, the extent that this variant increases cancer risk, or whether it is associated with the history of cancer in the family, is uncertain. In this circumstance, some clues as to the significance of the variant can be derived from the following:
- The location of the variant in relation to regions and function of a gene.
- The specific change; since many variants are missense variants, not all amino acid substitutions are as significant.
- Whether the variant has been documented in the presence of a documented pathogenic variant.
- Whether the variant is associated with the branch in the family with the cancer and/or whether the variant tracks with the cancers in the family.
Unfortunately, even with this information, there is often insufficient evidence to document the significance of a specific variant, and further clarifying research is required.
If there is no close, living, affected relative to undergo testing, or the living affected relative declines testing, other options may be discussed with the patient and the testing laboratory. In rare instances, if proper authorization is secured from the family, testing the stored tissue of a deceased relative may be considered. However, genetic tests done on stored tissue are technically difficult and may not yield a definitive result. Therefore, testing an unaffected person without prior testing of an affected family member may be performed. In these instances, counseling includes discussing that a negative test result does not rule out the presence of a cancer susceptibility gene in the family or in the patient and may be uninformative.
Testing in families with a documented pathogenic variant
Genetic susceptibility testing for a documented pathogenic variant in the family can be very informative and will yield one of the following two results (refer to Figure 2):
- Positive for the familial pathogenic variant.
- Negative for the familial pathogenic variant.
If the familial pathogenic variant is detected in a family member, their cancer risks are based on penetrance data for pathogenic variants in that specific gene. If the documented pathogenic variant is not found in a family member, the risk of cancer in that individual is equivalent to cancer risk in the general population. However, other risk factors and family history from the side of the family not associated with the documented pathogenic variant may increase the cancer risk above the general population levels.
In summary, genetic education and counseling includes identifying the most informative person in the family to test, which may be an affected family member rather than the individual seeking genetic services. In addition, counseling includes a discussion of the limitations of the test, all possible test outcomes, and the consequences of identifying a VUS.
Insurance coverage varies for cancer susceptibility testing, including multigene (panel) testing. In general, most individuals who meet specific criteria (e.g., National Comprehensive Cancer Network [NCCN] guidelines for or Lynch syndrome testing) are able to obtain insurance coverage for multigene testing. Of note, some insurance companies have contracts with specific laboratories through which testing must be ordered.
The Affordable Care Act (ACA) requires that private insurers cover—with no out-of-pocket costs to the insured—genetic counseling and testing for unaffected women meeting United States Preventive Services Task Force guidelines. Importantly, under ACA guidelines, women with a prior cancer diagnosis are not covered. The ACA does not stipulate that follow-up care based on genetic test results be covered (e.g., risk-reducing surgeries). However, some insurance companies require that pretest genetic counseling be performed by a credentialed genetics provider before testing is authorized. Before testing is ordered, it is important to verify costs and insurance coverage, including for Medicaid and Medicare patients. Medicare does not cover genetic testing if the patient has not had a cancer diagnosis associated with the pathogenic variants for which testing is ordered. In addition, unaffected individuals with Medicare are not covered for testing, even if they are tested for only a known familial pathogenic variant. Further, Medicare does not cover genetic counseling as a separately billable service. For individuals without insurance coverage and the underinsured, some laboratories offer low-cost options or have financial assistance programs.
Genetic testing and assisted reproductive technology
There is a risk of carriers passing on cancer pathogenic variants to offspring. Assisted reproductive technology can be used for preimplantation genetic diagnosis (PGD) and for prenatal cancer predisposition genetic testing using chorionic villus sampling and amniocentesis. For individuals with autosomal dominant hereditary cancer syndromes (e.g., those associated with , , , or pathogenic variants), reproductive options exist for prenatal testing and PGD to detect offspring with one copy of the pathogenic variant (heterozygotes). However, with the advent of multigene (panel) testing, more individuals are being identified with single pathogenic variants in a broad array of genes that had been previously identified primarily in individuals with two copies of the pathogenic variant (homozygotes).
Thus, when an individual tests positive for one pathogenic variant in genes such as these, counseling about reproductive implications addresses not only the risks associated with autosomal dominant inheritance but also the potential risks of having a child with two pathogenic variants in the same gene (biallelic) that could result in a severe condition. Therefore, assessing the tested individual’s partner (i.e., his or her personal and family history and ethnicity) is important. In the unlikely event that both parents are heterozygous for specific pathogenic variants, there is a 25% risk that a child will be homozygous and could have a severe phenotype. In light of this information, couples may consider PGD or prenatal testing.
A proposed analytic framework for counseling carriers about reproduction options includes consideration of the following issues:
In a study of 320 patients with different hereditary cancer syndromes, most were unaware of PGD; however, the majority expressed interest in learning more about the availability of PGD. Patients also preferred having a discussion about PGD with their genetic counselor or primary physician. Disease-specific factors (e.g., severity of the hereditary condition, quality of life, and medical interventions) and individual factors (e.g., gender, childbearing status, and religious beliefs) affected patient attitudes about PGD.
Determining the Test to Be Used
Genetic testing is highly specialized. A given test is usually performed in only a small number of laboratories. There are also multiple molecular testing methods available, each with its own indications, costs, strengths, and weaknesses. Depending on the method employed and the extent of the analysis, different tests for the same gene will have varying levels of sensitivity and specificity. Even assuming high analytic validity, genetic heterogeneity makes test selection challenging. A number of different genetic syndromes may underlie the development of a particular cancer type. For example, hereditary colon cancer may be due to familial adenomatous polyposis (FAP), Lynch syndrome, Peutz-Jeghers syndrome, juvenile polyposis syndrome, or other syndromes. Each of these has a different genetic basis. In addition, different genes may be responsible for the same condition (e.g., Lynch syndrome can be caused by pathogenic variants in one of several mismatch repair [MMR] genes).
In some genes, 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 back to a small group of founders isolated by geographic, cultural, or other factors. For example, two specific pathogenic variants (185delAG and 5382insC) and one pathogenic variant (6174delT) have been reported to be common in Ashkenazi Jews. Other genes also have reported founder pathogenic variants. The presence of 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. For example, approximately 15% of and pathogenic variants that occur among Ashkenazim are nonfounder pathogenic variants. Also, for genes in which large genome rearrangements are common in the founder population, ordering additional testing using different techniques may be needed.
Allelic heterogeneity (i.e., different variants within the same gene) can confer different risks or be associated with a different phenotype. For example, though the general rule is that () pathogenic variants are associated with hundreds or thousands of colonic polyps and colon cancer of the classical FAP syndrome, some pathogenic variants cause a milder clinical picture, with fewer polyps and lower colorectal cancer risk. In addition, other disorders may be part of the FAP spectrum. Pathogenic variants in a certain portion of the gene also predispose to retinal changes, for example, when pathogenic variants in a different region of predispose to desmoid tumors. Thus, selection of the appropriate genetic test for a given individual requires considerable knowledge of genetic diagnostic methods, correlation between clinical and molecular findings, and access to information about rapidly changing testing options. These issues are addressed in detail in PDQ summaries on the genetics of specific cancers. (Refer to the PDQ summaries on Genetics of Breast and Gynecologic Cancers; Genetics of Colorectal Cancer; and Genetics of Endocrine and Neuroendocrine Neoplasias for more information.)
Multigene (panel) testing
Next-generation sequencing (NGS) and the removal of most patent barriers to diagnostic DNA sequencing have resulted in the availability of multigene testing, which can simultaneously test more than 50 genes for pathogenic variants, often at costs comparable to single-gene testing. These multigene panels can include genes with pathogenic variants that are associated with high risks of cancer and genes that confer moderate and uncertain risks. The multigene panels can be limited to specific cancer types (e.g., breast, ovarian, colon) or can include many cancer types. This type of testing has both advantages and disadvantages, and much of the information presented in this section is not based on empirical data but rather on commentaries.
Genetic education and counseling for multigene testing
ASCO has stressed the importance of genetic counseling to ensure patients are adequately informed about the implications of this type of testing and recommends that tests be ordered by cancer genetic professionals. Yet, the use of multigene testing requires modification of traditional approaches to genetic counseling. Optimal evidence-based counseling strategies have not yet been established. Unlike in-person, single-gene pretest genetic counseling models, these approaches have not been examined for outcomes of counseling such as comprehension, satisfaction, psychosocial outcomes, and testing uptake. Table 3 summarizes recommendations from ASCO on elements of pretest genetic counseling and informed consent for germline cancer genetic testing.
Research examining multigene testing
The range of results from NGS multigene panels is emerging in both data from clinical and laboratory series. Several of the studies are collaborations between the two. There are several important caveats about the research that has been conducted so far with regard to multigene testing:
- The studies differ in their aims, approaches, ascertainment of subjects, and panels used.
- Laboratory- and clinic-based studies likely differ with regard to their sampling frames (the population a study draws from and its characteristics). For example, some studies may include testing by a wide variety of health care professionals, some of whom may not be as experienced in triaging, testing, and advising high-risk patients.
- Testing methodologies also differ among laboratories regarding exon/intron coverage, read depth, Sanger sequencing confirmation, and variant interpretation.
- The genes to be tested as part of a multigene panel are constantly changing. In some studies, the composition of multigene panels changed during the course of the study, usually to include more genes.
- Some patient populations included a mix of patients already tested by traditional single-gene methods and those undergoing testing for the first time, making it difficult to establish true diagnostic yield.
In the studies that essentially replicated previous testing, the analytic validity of the NGS multigene panel tests is equivalent to the former single-gene tests, with almost 100% concordance in patients who had both single-gene testing and multigene testing. However, it seems clear that there are some patients in whom pathogenic variants are found that either were or would have been missed by single-gene testing. The additional yield of multigene testing ranges according to the test used and the disease, but currently seems to be approximately 4%. The most common non- pathogenic variants found are in , , and . In some cases, the identification of pathogenic variants from panel testing resulted in additional recommendations for screening and risk reduction beyond what would have been indicated based on family history alone. Similarly, the rates of VUS vary across studies. Table 4 presents data from a selection of the emerging reports on rates of both pathogenic variants and VUS found using the multigene tests. The table comprises studies that included more than 1,000 participants. The multigene panels are constantly changing, with genes being added or removed; therefore, comparisons of the rates between studies should be made with caution. VUS rates increase with the number of genes included on the panel. Some patients had more than one VUS, but this is not noted in the table. It is important to note that these data are preliminary and may change as academic clinics and commercial laboratories partner to pool the data needed to refine and standardize variant interpretation.
Outcomes of multigene testing
Results from multigene tests have several possible outcomes, including the following:
- No variant detected.
- VUS detected.
- Pathogenic variant in a high-penetrance gene concordant with the existing personal/family history (e.g., a germline pathogenic variant in an individual who meets Amsterdam criteria for Lynch syndrome).
- Pathogenic variant in a high-penetrance gene discordant with the existing personal/family history (e.g., a germline pathogenic variant in an individual with no personal/family history of gastric cancer).
- Pathogenic variant in a moderate-penetrance gene (e.g., , ).
- Pathogenic variant in a gene with uncertain cancer risks and/or cancer associations (e.g., ).
Results can also reveal more than one finding given that multiple genes are being tested simultaneously and the elevated rate of VUS. There has been no assessment of outcomes of multigene tests such as comprehension, psychosocial outcomes, and uptake of cancer risk management options.
Considerations when using multigene testing
Utilizing multigene panels can be complex but may offer advantages over sequential testing strategies. First, in some types of cancer, several genes can be associated with specific phenotypes; therefore, testing for all genes associated with a given phenotype can save both time and money. Additionally, multigene testing may help identify the genetic basis for cancer in families in whom the differential diagnosis includes multiple syndromes or when the family history does not meet standard criteria for a single cancer syndrome. (Refer to the Analysis of the family history section of this summary for a list of factors that may make a family history difficult to interpret.)
However, there can be challenges to employing this testing approach. Clinical laboratories now offer a varying array of clinical cancer susceptibility gene panels. Multigene panels continue to evolve, and the genes included on the panels can change. Other challenges of interpreting multigene test results include higher rates of VUS than with single-gene testing (the rate of VUS increases with the number of genes tested), higher rates of VUS in some minority populations, and the detection of variants in genes associated with uncertain cancer risks.
In addition to these primary challenges, providers deciding the optimal testing strategy may also consider the following: the overall expense and out-of-pocket expense to the patient; insurance reimbursement; time frame to complete the test; ease of laboratory use for the clinician ordering testing; the probability of identifying a VUS and management of those findings, such as the reclassification process and provision of supplemental data regarding the variant; technical differences, such as the presence of a deletion/duplication assay; patient preference; and clinical history.
Overall, there is insufficient evidence to determine superiority of multigene testing over phenotype-guided testing or sequential gene testing. As a consequence, practice guidelines for optimal clinical use of multigene tests continue to evolve. The NCCN and ASCO guidelines suggest that efficiencies may be gained by using multigene testing when there is more than one cancer syndrome or gene on the differential diagnosis list. Additionally, NCCN states that there may be a role for multigene testing when a patient has a personal or family history that is consistent with an inherited susceptibility but single-gene testing has not identified a pathogenic variant.
Another important consideration is that multigene tests may include genes in which pathogenic variants are associated with moderate or uncertain penetrance. Management of individuals with pathogenic variants in such genes can present additional challenges, particularly when expert consensus or evidence-based recommendations are not available. (Refer to Figure 1 in the Cancer Genetics Overview PDQ summary for information about moderate and low penetrance.) Moreover, there may be limited or no evidence to support changes to medical management based on the level of risk or uncertain risk; however, management may still be affected by family history. A framework for clinical management incorporates emerging data on age-specific, lifetime, and absolute cancer risks conferred by pathogenic variants in several moderate-risk genes. (Refer to the Penetrance of Inherited Susceptibility to Hereditary Breast and/or Gynecologic Cancers section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about this framework.)
Regulation of genetic tests
Government regulation of genetic tests to date remains extremely limited in terms of both analytic and clinical validity with little interagency coordination. The Centers for Medicare & Medicaid Services, using the Clinical Laboratory Improvement Act (CLIA), regulates all clinical human laboratory testing performed in the United States for the purposes of generating diagnostic or other health information. CLIA regulations address personnel qualifications, laboratory quality assurance standards, and documentation and validation of tests and procedures. For laboratory tests themselves, CLIA categorizes tests based on the level of complexity into waived tests, moderate complexity, or high complexity. Genetic tests are considered high complexity, which indicates that a high degree of knowledge and skill is required to perform or interpret the test. Laboratories conducting high complexity tests must undergo proficiency testing at specified intervals, which consists of an external review of the laboratory's ability to accurately perform and interpret the test. However, a specialty area specific for molecular and biologic genetic tests has yet to be established; therefore, specific proficiency testing of genetic testing laboratories is not required by CLIA.
In regard to analytic validity, genetic tests fall into two primary categories; test kits and laboratory-developed tests (previously called home brews). Test kits are manufactured for use in laboratories performing the test and include all the reagents necessary to complete the analysis, instructions, performance outcomes, and details about which genetic variants can be detected. The U.S. Food and Drug Administration (FDA) regulates test kits as medical devices; however, despite more than 1,000 available genetic tests, there are fewer than ten FDA-approved test kits. Laboratory-developed tests are performed in a laboratory that assembles its own testing materials in-house; this category represents the most common form of genetic testing. Laboratory-developed tests are subject to the least amount of oversight, as neither CLIA nor the FDA evaluate the laboratories' proficiency in performing the test or clinical validity relative to the accuracy of the test to predict a clinical outcome. The FDA does regulate manufactured analyte-specific reagents (ASRs) as medical devices. These small molecules are used to conduct laboratory-developed tests but can also be made by the laboratory. ASRs made in the laboratory are not subject to FDA oversight. For laboratory-developed tests utilizing manufactured commercially available ASRs, the FDA requires that the test be ordered by a health professional or other individual authorized to order the test by state law. However, this regulation does not distinguish between health providers caring for the patient or health providers who work for the laboratory offering the test.
In addition to classical clinical genetic tests is the regulatory oversight of research genetic testing. Laboratories performing genetic testing on a research basis are exempt from CLIA oversight if the laboratory does not report patient-specific results for the diagnosis, prevention, or treatment of any disease or impairment or the assessment of the health of individual patients. However, there are anecdotal reports of research laboratories providing test results for clinical purposes with the caveat that the laboratory recommends that testing be repeated in a clinical CLIA-approved laboratory. In addition, there is no established mechanism that determines when a test has sufficient analytic and clinical validity to be offered clinically. Currently, the decision to offer a genetic test clinically is at the discretion of the laboratory director.
Evidence regarding the implications of this narrow regulatory oversight of genetic tests is limited and consists predominately of laboratory director responses to quality assurance surveys. A survey of 133 laboratory directors performing genetic tests found that 88% of laboratories employed one or more American Board of Medical Genetics (ABMG)-certified or ABMG-eligible professional geneticists, and 23% had an affiliation with at least one doctoral-prepared geneticist. Eight percent of laboratories did not employ and were not affiliated with doctoral-level genetics professionals. Laboratory-developed tests were performed in 70% of laboratories. Sixty-three percent of laboratories provided an interpretation of the test result as part of the test report. Another survey of 190 laboratory directors found that 97% were CLIA-certified for high complexity testing. Sixteen percent of laboratories reported no specialty area certification; those without specialty certification represented laboratories with the most volume of tests performed and offered the most extensive test selection. Of laboratories with specialty certification, not all had certification relevant to genetic tests, with 48% reporting pathology certification, 46% chemistry certification, and 41% clinical cytogenetics certification. Sixteen percent of directors reported participation in no formal external proficiency testing program, although 77% performed some informal proficiency testing when a formal external proficiency testing program was not available.
The most frequent reason cited for lack of proficiency testing participation was lack of available proficiency testing programs. Laboratory directors estimated that in the past 2 years 37% issued three or fewer incorrect reports, and 35% issued at least four incorrect reports. Analytic errors such as faulty reagent, equipment failure, or human error, increased 40% with each decrease in level of proficiency training completed. An international genetic testing laboratory director survey involving 18 countries found that 64% of the 827 laboratories that responded accepted samples from outside their country. Similar to the U.S. study, 74% reported participation in some form of proficiency testing. Fifty-three percent of the laboratories required a copy of the consent to perform the test, and 72% of laboratories retained specimens indefinitely that were submitted for testing.
The U.S. Department of Health and Human Services Secretary’s Advisory Committee on Genetics, Health, and Society has published a detailed report regarding the adequacy and transparency of the current oversight system for genetic testing in the United States. The Committee identified gaps in the following areas:
- Regulations governing clinical laboratory quality.
- Oversight of the clinical validity of genetic tests.
- The number and identification of laboratories performing genetic tests and the specific genetic tests being performed.
- Level of current knowledge about the clinical usefulness of genetic tests.
- Educational preparation in genetics of health providers, the public health community, patients, and consumers.
Direct-to-Consumer (DTC) Genetic Tests
Most genetic testing for cancer and other health risks is offered by health care providers on the basis of a patient’s personal history, family history, or ethnicity. Increasingly, however, individuals can order genetic testing through DTC companies without the input of health care providers. DTC tests may provide information about ancestry, paternity, propensity toward certain physical traits, risk of adverse drug reactions, and disease risks. With respect to disease risk, DTC companies have traditionally relied primarily on testing for single nucleotide polymorphisms (SNPs) to generate risk estimates for common diseases, including many cancers. However, DTC offerings are evolving to include whole-genome sequencing (WGS) and whole-exome sequencing (WES). Some DTC companies offer consumers the option of speaking with a genetics professional, but this is not required for test ordering or interpretation. This section focuses on major points related to DTC testing for cancer risks using data from SNPs, WES, or WGS.
Testing for SNPs
In the past, several DTC companies offered only SNP-based testing to generate information about health risks, including risks of cancer. Selection of SNPs may be based on data from genome-wide association studies (GWAS); however, there is no validated algorithm outlining how to generate cancer risk estimates from different SNPs, which individually are generally associated with modestly increased disease risks (usually conferring odds ratios <2.0) or modestly decreased disease risks. (Refer to the GWAS section in the Cancer Genetics Overview PDQ summary for more information.) As a result, predicted disease risks from different DTC companies may yield different results. For example, a sample comparison of SNP-based risk prediction from two different companies for four different cancers yielded relative risks of 0.64 to 1.42 (excluding the three Ashkenazi founder pathogenic variants). In addition, because commercial companies use different panels of SNPs, there is seldom concordance about the predicted risks for common diseases, and such risk estimates have not been prospectively validated.
Another area of investigation is whether predicted disease risks from SNP testing are consistent with family history–based assessments. Studies using data from one commercial personal genomic testing company revealed that there was generally poor concordance between the SNP and family history risk assessment for common cancers such as breast, prostate, and colon. Importantly, one of these studies highlighted that the majority of individuals with family histories suggestive of hereditary breast/ovarian cancer or Lynch syndrome received SNP results yielding lifetime cancer risks that were average or below average.
Studies have begun to examine whether SNP testing could be used together with other established risk factors to assess the likelihood of developing cancer. For example, adding SNP data to validated breast cancer prediction tools such as those included in the National Cancer Institute's Breast Cancer Risk Assessment Tool (based on the Gail model) may improve the accuracy of risk assessment. However, this approach is not currently FDA-approved.
These findings underscore that SNP testing has not been validated as an accurate risk assessment tool and does not replace the collection, integration, and interpretation of personal and family history risk factor information by qualified health care professionals.
DTC whole-exome/genome sequencing and interpretation
Increasingly, DTC testing companies offer WGS or WES, including SNP data. (Refer to the Clinical Sequencing section in the Cancer Genetics Overview PDQ summary for a description of WGS and WES.) In addition, consumers who submit their DNA to a DTC lab for a specific indication (e.g., ancestry testing) may be given access to their raw sequence data and may consult with other companies, websites, and open-access databases for interpretation.
Some factors to consider when determining the utility of full-sequence data for cancer (or other disease) risk assessment include the sequencing depth of the genes of interest, whether large rearrangements or gene deletions would be detected, and whether or how positive results are confirmed (e.g., through Sanger sequencing). For example, if sequencing depth is low or rare variants cannot be detected, then there is a concern about false-negative results. There is also a risk that sequence changes will be erroneously labeled as pathogenic when confirmatory testing or different interpretative approaches would determine that the variant identified is benign (false positive). When WES or WGS is performed, VUS are also likely to be identified, and DTC companies have varying protocols for classification, which may or may not be consistent with national guidelines (e.g., refer to ). In addition, as evidence evolves and variants are reclassified, consumers need to be aware of the process the DTC lab has, if any, for updating information and re-contacting consumers with revised interpretations.
There may be potential benefits associated with DTC testing. DTC marketing and provision of genetic tests may promote patient autonomy. Individuals may develop an increased awareness of the importance of family history, the relationship between risk and family history, the role of genetics in disease, and a better understanding of the value of genetic counseling. Although results of SNP-based DTC testing appear to motivate some individuals to seek the advice of their doctor, make lifestyle changes, and pursue screening tests, short-term modest effects on risk perception after notification of an elevated risk (e.g., for cancer) may not significantly alter lifestyle or cancer screening behaviors. Further, psychological distress has not been widely reported among consumers who have undergone DTC testing for a variety of conditions. However, little is known about how individuals respond after learning that they carry pathogenic variants in high-risk genes such as when testing is performed within a DTC context and without traditional forms of pre- and posttest genetic education and counseling.
Given the complexity of genomic testing, several professional organizations have released position statements about DTC genetic testing. For example, in 2010, ASCO published a position statement outlining several considerations related to DTC cancer genomic tests, including those mentioned above. They endorsed pre- and posttest genetic counseling and informed consent by qualified health care professionals. ASCO’s 2015 position statement on genetic and genomic testing for cancer susceptibility reinforces the importance of provider education given the complexity of genomic testing and interpretation and discusses their recommendations for regulatory review of genomic tests, including those offered by DTC companies.
In 2016, a statement by the American College of Medical Genetics and Genomics about DTC genetic testing similarly endorsed the involvement of qualified genetics professionals in the processes of test ordering and interpretation. The statement also emphasized the need to incorporate established methods of risk assessment into disease risk prediction (such as personal and family medical history information) and stressed that consumers need to be informed about the potential limitations and risks associated with DTC testing.
Informed consent can enhance preparedness for testing, including careful weighing of benefits and limitations of testing, minimization of adverse psychosocial outcomes, appropriate use of medical options, and a strengthened provider-patient relationship based on honesty, support, and trust.
Consensus exists among experts that a process of informed consent should be an integral part of the pretest counseling process. This view is driven by several ethical dilemmas that can arise in genetic susceptibility testing. The most commonly cited concern is the possibility of insurance or employment discrimination if a test result, or even the fact that an individual has sought or is seeking testing, is disclosed. In 2008, Congress passed the Genetic Information Nondiscrimination Act (GINA). This federal law provides protections related to health insurance and employment discrimination based on genetic information. However, GINA does not cover life, disability, or long-term-care insurance discrimination. A related issue involves stigmatization that may occur when an individual who may never develop the condition in question, or may not do so for decades, receives genetic information and is labeled or labels himself or herself as ill. Finally, in the case of genetic testing, medical information given to one individual has immediate implications for biologic relatives. These implications include not only the medical risks but also disruptions in familial relationships. The possibility for coercion exists when one family member wants to be tested but, to do so optimally, must first obtain genetic material or information from other family members.
Inclusion of an informed consent process in counseling can facilitate patient autonomy. It may also reduce the potential for misunderstanding between patient and provider. Many clinical programs provide opportunities for individuals to review their informed consent during the genetic testing and counseling process. Initial informed consent provides a verbal and/or written overview of the process.
Some programs use a second informed consent process prior to disclosure to the individual of his or her genetic test results. This process allows for the possibility that a person may change his or her mind about receiving test results. After the test result has been disclosed, a third informed consent discussion often occurs. This discussion concerns issues regarding sharing the genetic test result with health providers and/or interested family members, currently or in the future. Obtaining written permission to provide the test result to others in the family who are at risk can avoid vexing problems in the future should the individual not be available to release his or her results.
Core elements of informed consent
Major elements of an informed consent discussion are highlighted in the preceding discussion. The critical elements, as described in the literature, include the following:
- Elicitation and discussion of a person’s expectations, beliefs, goals, and motivations.
- Explanation of how inheritance of genetic factors may affect cancer susceptibility.
- Clarification of a person’s increased risk status.
- Discussion of potential benefits, risks, and limitations of testing.
- Discussion of costs and logistics of testing and follow-up.
- Discussion of possible outcomes of testing (e.g., true positive, true negative, VUS, inconclusive, false positive).
- Discussion of medical management options based on risk assessment and/or test results available for those who choose to test, for those who choose not to test, and for those who have positive, negative, or inconclusive results.
- Data on efficacy of methods of cancer prevention and early detection.
- Discussion of possible psychological, social, economic, and family dynamic ramifications of testing or not testing.
- Discussion of alternatives to genetic testing (e.g., tissue banking, risk assessment without genetic testing).
- Attainment of verbal and written informed consent or clarification of the decision to decline testing.
All individuals considering genetic testing should be informed that they have several options even after the genetic testing has been completed. They may decide to receive the results at the posttest meeting, delay result notification, or less commonly, not receive the results of testing. They should be informed that their interest in receiving results will be addressed at the beginning of the posttest meeting (see below) and that time will be available to review their concerns and thoughts on notification. It is important that individuals receive this information during the pretest counseling to ensure added comfort with the decision to decline or defer result notification even when test results become available.
Testing in children
Genetic testing for pathogenic variants in cancer susceptibility genes in children is particularly complex. While both parents and providers may request or recommend testing for minor children, many experts recommend that unless there is evidence that the test result will influence the medical management of the child or adolescent, genetic testing should be deferred until legal adulthood (age 18 years or older) because of concerns about autonomy, potential discrimination, and possible psychosocial effects. A number of cancer syndromes include childhood disease risk, such as retinoblastoma, multiple endocrine neoplasia (MEN) types 1 and 2 (MEN1 and MEN2), neurofibromatosis types 1 and 2 (NF1 and NF2), Beckwith–Wiedemann syndrome, Fanconi anemia, FAP, and Von Hippel-Lindau disease (VHL). As a consequence, decisions about genetic testing in children are made in the context of a specific gene in which a pathogenic variant is suspected. The ASCO statement on genetic testing for cancer susceptibility maintains that the decision to consider offering childhood genetic testing should take into account not only the risk of childhood malignancy but also the evidence associated with risk reduction interventions for that disorder. Specifically, ASCO recommends that:
- When screening or preventive strategies during childhood are available (e.g., MEN and FAP), testing should be encouraged on clinical grounds.
- When no risk reduction strategies are available in childhood and the probability of developing a malignancy during childhood is very low (e.g., hereditary breast/ovarian cancer syndrome), testing should not be offered.
- Some patients may be at risk of developing a malignancy during childhood without the availability of validated risk-reduction strategies (e.g., pathogenic variants). The decision to test in such circumstances is particularly controversial.
Special considerations are required when genetic counseling and testing for pathogenic variants in cancer susceptibility genes are considered in children. The first issue is the age of the child. Young children, especially those younger than 10 years, may not be involved or may have limited involvement in the decision to be tested, and some may not participate in the genetic counseling process. In these cases, the child’s parents or other legal surrogate will be involved in the genetic counseling and will ultimately be responsible for making the decision to proceed with testing. Counseling under these circumstances incorporates a discussion of how test results will be shared with the child when he or she is older. Children aged 10 to 17 years may have more involvement in the decision-making process. In a qualitative study of parents and children aged 10 to 17 years assessing decision making for genetic research participation, older, more mature children and families with open communication styles were more likely to have joint decision making. The majority of children in this study felt that they should have the right to make the final decision for genetic research participation, although many would seek input from their parents. While this study is specific to genetic research participation, the findings allude to the importance children aged 10 to 17 years place on personal decision making regarding factors that impact them. Unfortunately cognitive and psychosocial development may not consistently correlate with the age of the child. Therefore, careful assessment of the child’s developmental stage may help in the genetic counseling and testing process to facilitate parent and child adaptation to the test results. Another complicating factor includes potential risks for discrimination. (Refer to the Employment and Insurance Discrimination section in the Ethical, Legal, and Social Implications section of this summary for more information.)
The consequences of genetic testing in children have been reviewed. In contrast to observations in adults, young children in particular are vulnerable to changes in parent and child bonding based on test results. Genetic testing could interfere with the development of self-concept and self-esteem. Children may also be at risk of developing feelings of survivor guilt or heightened anxiety. All children are especially susceptible to not understanding the testing, results, or implications for their health. As children mature, they begin to have decreased dependency on their parents while developing their personal identity. This can be altered in the setting of a serious health condition or an inherited disorder. Older children are beginning to mature physically and develop intimate relationships while also changing their idealized view of their parents. All of this can be influenced by the results of a genetic test. In its recommendations for genetic testing in asymptomatic minors, the European Society of Human Genetics emphasizes that parents have a responsibility to inform their children about their genetic risk and to communicate this information in a way that is tailored to the child’s age and developmental level.
In summary, the decision to proceed with testing in children is based on the use of the test for medical decision making for the child, the ability to interpret the test, and evidence that changes in medical decision making in childhood can positively impact health outcomes. Deferral of genetic testing is suggested when the risk of childhood malignancy is low or absent and/or there is no evidence that interventions can reduce risk. When offering genetic testing in childhood, consideration of the child’s developmental stage is used to help determine his or her involvement in the testing decision and who has legal authority to provide consent. In addition, careful attention to intrafamilial issues and potential psychosocial consequences of testing in children can enable the provider to deliver support that facilitates adaptation to the test result. (Refer to the PDQ summaries on Genetics of Breast and Gynecologic Cancers; Genetics of Colorectal Cancer; and Genetics of Endocrine and Neuroendocrine Neoplasias for more information about psychosocial research in children being tested for specific cancer susceptibility gene pathogenic variants.)
Testing in vulnerable populations
Genetic counseling and testing requires special considerations when used in vulnerable populations. In 1995, the American Society of Human Genetics published a position statement on the ethical, legal, and psychosocial implications of genetic testing in children and adolescents as a vulnerable population. However, vulnerable populations encompass more than just children. Federal policy applicable to research involving human subjects, 45 CFR Code of Federal Regulations part 46 Protection Of Human Subjects, considers the following groups as potentially vulnerable populations: prisoners, traumatized and comatose patients, terminally ill patients, elderly/aged persons who are cognitively impaired and/or institutionalized, minorities, students, employees, and individuals from outside the United States. Specific to genetic testing, the International Society of Nurses in Genetics further expanded the definition of vulnerable populations to also include individuals with hearing and language deficits or conditions limiting communication (for example, language differences and concerns with reliable translation), cognitive impairment, psychiatric disturbances, clients undergoing stress due to a family situation, those without financial resources, clients with acute or chronic illness and in end-of-life, and those in whom medication may impair reasoning.
Genetic counseling and testing in vulnerable populations raises special considerations. The aim of genetic counseling is to help people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease, which in part involves the meaningful exchange of factual information. In a vulnerable population, health care providers need to be sensitive to factors that can impact the ability of the individual to comprehend the information. In particular, in circumstances of cognitive impairment or intellectual disability, special attention is paid to whether the individual’s legally authorized representative should be involved in the counseling, informed consent, and testing process.
Providers need to assess all patients for their ability to make an uncoerced, autonomous, informed decision prior to proceeding with genetic testing. Populations that do not seem vulnerable (e.g., legally adult college students) may actually be deemed vulnerable because of undue coercion for testing by their parents or the threat of withholding financial support by their parents based on a testing decision inconsistent with the parent’s wishes. Alteration of the genetic counseling and testing process may be necessary depending on the situation, such as counseling and testing in terminally ill individuals who opt for testing for the benefit of their children, but given their impending death, results may have no impact on their own health care or may not be available before their death. In summary, genetic counseling and testing requires that the health care provider assess all individuals for any evidence of vulnerability, and if present, be sensitive to those issues, modify genetic counseling based on the specific circumstances, and avoid causing additional harm.
Importance of Pretest Counseling
The complexity of genetic testing for cancer susceptibility has led experts to suggest that careful, in-depth counseling should precede any decision about the use of testing, in keeping with the accepted principles for the use of genetic testing.
Qualitative and quantitative research studies indicate that families hold a variety of beliefs about the inheritance of characteristics within families; some of these beliefs are congruent with current scientific understanding, whereas others are not. These beliefs may be influenced by education, personal and family experiences, and cultural background. Because behavior is likely to be influenced by these beliefs, the usefulness of genetic information may depend on recognizing and addressing the individual’s preexisting cognitions. This process begins with initial discussion and continues throughout the genetic counseling process.
Psychological Impact of Genetic Information/Test Results on the Individual
An accurate assessment of psychosocial functioning and emotional factors related to testing motivation and potential impact and utilization is an important part of pretest counseling. Generally, a provider inquires about a person’s emotional response to the family history of cancer and also about a person’s response to his or her own risk of developing cancer. People have various coping strategies for dealing with stressful circumstances such as genetic risk. Identifying these strategies and ascertaining how well or poorly they work will have implications for the support necessary during posttest counseling and will help personalize the discussion of anticipated risks and benefits of testing. Taking a brief history of past and current psychiatric symptoms (e.g., depression, extreme anxiety, or suicidality) will allow for an assessment of whether this individual is at particular risk of adverse effects after disclosure of results. In such cases, further psychological assessment may be indicated.
In addition, cognitive deficits in the person being counseled may significantly limit understanding of the genetic information provided and hinder the ability to give informed consent and may also require further psychological assessment. Emotional responses to cancer risk may also affect overall mood and functioning in other areas of life such as home, work, and personal health management, including cancer screening practices. Education and genetic counseling sessions provide an ongoing opportunity for informal assessment of affective and cognitive aspects of the communication process. Since behavioral factors influence adherence to screening and surveillance recommendations, consideration of emotional barriers is important in helping a person choose prevention strategies and in discussing the potential utility of genetic testing.
The discussion of issues such as history of depression, anxiety, and suicidal thoughts or tendencies requires sensitivity to the individual. The individual must be assured that the counseling process is a collaborative effort to minimize intrusiveness while maximizing benefits. Determining whether the individual is currently receiving treatment for major psychiatric illness is an important part of the counseling process. Consultation with a mental health professional familiar with psychological assessments may be useful to help the provider develop the strategies for these discussions. It also may be beneficial for the individual to be given standard psychological self-report instruments that assess levels of depression, anxiety, and other psychiatric difficulties that he or she may be experiencing. This step provides objective comparisons with already established normative data.
In addition to the clinical assessment of psychological functioning, several instruments for cancer patients and people at increased risk of cancer have been utilized to assess psychological status. These include the Center for Epidemiological Studies-Depression scale, the Profile of Mood States, the Hospital Anxiety and Depression Scale, and the Brief Symptom Inventory. Research programs have included one or more of these instruments as a way of helping refine the selection of people at increased risk of adverse psychosocial consequences of genetic testing. Psychological assessments are an ongoing part of genetic counseling. Some individuals with symptoms of increased distress, extreme avoidance of affect, or other marked psychiatric symptoms may benefit from a discussion with, or evaluation by, a mental health professional. It may be suggested to some people (generally, a very small percentage of any population) that testing be postponed until greater emotional stability has been established.
Psychological Impact of Genetic Information/Test Results on the Family
In addition to making an assessment of the family history of cancer, the family as a social system may also be assessed as part of the process of cancer genetic counseling. Hereditary susceptibility to cancer may affect social interactions and attitudes toward the family.
In assessing families, characteristics that may be relevant are the organization of the family (including recognition of individuals who propose to speak for or motivate other family members), patterns of communication within the family, cohesion or closeness of family members (or lack thereof), and the family beliefs and values that affect health behaviors. Ethnocultural factors may also play an important role in guiding behavior in some families.
Assessment also evaluates the impact of the family’s prior experience with illness on their attitudes and behaviors related to genetic counseling and testing. Prior experience with cancer diagnosis and treatment, loss due to cancer, and the family members’ interaction with the medical community may heavily influence attitudes toward receiving genetic information and may play a major role in the emotional state of individuals presenting for genetic services.
The practitioner may use the above framework to guide inquiries about the relationship of the individual to (1) the affected members of the family or (2) others who are considering or deciding against the consideration of genetic counseling or testing. Inquiries about how the family shares (or does not share) information about health, illness, and genetic susceptibility may establish whether the individual feels under pressure from other family members or anticipates difficulty in sharing genetic information obtained from counseling or testing. Inquiries about the present health (new diagnoses or deaths from cancer) or relationship status (divorce, marriage, grieving) of family members may inform the provider about the timing of the individual’s participation in counseling or testing and may also reveal possible contraindications for testing at present.
In addition to using a pedigree to evaluate family health history, tools such as the genogram and ecomap can provide specific information regarding the nature of interpersonal relationships within the family and the connections with social networks outside of the family.
Evidence from a study of 297 persons from 38 Lynch syndrome–affected families suggested that the timing of genetic counseling and testing services may influence psychological test-related distress responses. Specifically, family members in the same generation as the index case were more likely to experience greater test-related distress with increasingly longer lengths of time between the index case's receipt of MMR pathogenic variant results and the provision of genetic counseling and testing services to family members. However, it was unclear whether time lapses were due to a delay in the index case communicating test results or the family member choosing to delay genetic testing, despite being aware of the index case’s results.
More specific information about family functioning in coping with hereditary cancers can be found in the psychosocial or counseling sections of PDQ summaries on the genetics of specific types of cancer. (Refer to the PDQ summaries on Genetics of Breast and Gynecologic Cancers and Genetics of Colorectal Cancer for more information.)
Exploration of potential risks, benefits, burdens, and limitations of genetic susceptibility testing
There is substantial evidence that many people do not understand the potential limitations of genetic testing and may give too much weight to the potential benefits. Counseling provides the opportunity to present a balanced view of the potential risks and benefits of testing and to correct misconceptions. It may be helpful to ask individuals to identify their perceptions about the pros and cons of testing as part of this discussion.
Posttest education and result notification
The primary component of the posttest session is result notification. An individual may change his or her mind about receiving results, however, until the moment of results disclosure. Therefore, one typically begins the disclosure session by confirming that test results are still desired. Some people may decline or delay receipt of test results. The percentage of people who will make this decision is unknown. Such people need ongoing follow-up and the opportunity to receive test results in the future.
Once confirmed, people appreciate direct, immediate reporting of the results; they often describe the wait for results as one of the most stressful aspects of undergoing testing. Often, people need a few minutes of privacy to gather their composure after hearing their test results. Sometimes this precludes all but the briefest discussion at the initial posttest visit. Usually, individuals who have been properly prepared through the pretest counseling process do not exhibit disabling distress. Although it is rare that an acute psychological reaction will occur at disclosure, it is useful for providers of genetic test results to establish a relationship with a mental health provider who can be consulted should extreme reactions occur or who can be available by referral for people seeking further exploration of emotional issues.
Either at the time of disclosure or shortly thereafter, a session for the provider and the individual to consider the genetic, medical, psychological, and social ramifications of the test result is advisable. Despite having extensive pretest education, people may still be confused about the implications and meaning of the test results. Examples of frequently documented misconceptions include the belief that a positive result means that cancer is present or certain to develop; the belief that a negative result means that cancer will never occur; and failure to understand the uncertainty inherent in certain test results, as when only a limited gene panel was examined. Regarding medical implications, it is important to inform the person of risk implications and management options for all of the cancer types associated with an inherited syndrome and to revisit options for risk management.
Posttest counseling may include consideration of the implications of the test results for other family members. It has been suggested that some individuals affected by an inherited disorder agree to have genetic testing performed in order to acquire information that could be shared with family members. There is evidence that implementation of a follow-up counseling program with the index patient, after test results are revealed, will significantly increase the proportion of relatives informed of their genetic risk. Follow-up counseling may include telephone conversations with the index patient verifying which family members have been contacted and an offer to assist with conveying information to family members. Some experts have suggested that if a test result is positive, plans should be made at this time for the notification, education, and counseling of other relatives based on the test result of the individual. Written materials, brochures, or personal letters may aid people in informing the appropriate relatives about genetic risk.
When a test result is negative, the posttest session may be briefer. It is important, however, to discuss genetic, medical, and psychological implications of a negative result in a family with a known pathogenic variant. For example, it is essential that the person understand that the general population risks for relevant cancer types still apply and that the person’s individual risk of cancer may still be influenced by other risk factors and family history from the other side of the family. Furthermore, people may be surprised to feel distress even when a test is negative. This outcome has been documented in the context of pathogenic variant testing and may also be anticipated in other cancer susceptibility testing. Posttest results discussion of such distress may lead to referral for additional counseling in some cases.
Many individuals benefit from follow-up counseling and consultation with medical specialists after disclosure of test results. This provides an opportunity for further discussion of feelings about their risk status, options for risk management including screening and detection procedures, and implications of the test results for other family members.
Ethical, Legal, and Social Implications
Having an understanding of the ethical, legal, and social implications (ELSI) regarding cancer genetic testing may influence the clinician’s response to the complex questions and issues that may arise during the process of risk assessment and counseling. This section discusses biomedical ethics codes, legal and social issues relevant to privacy, and fair use in the interpretation of genetic information. In order to integrate the different perspectives of bioethics, law, and psychosocial influences, case scenarios are offered to illustrate dilemmas encountered in the clinical setting. (Refer to the Determining the Test to Be Used section of this summary for more information about the regulation of genetic tests.)
Bioethical Issues in Cancer Genetic Testing
Bioethical tenets can guide health care providers in dealing with the complex issues surrounding predictive testing for hereditary cancer. The tenets of beneficence, nonmaleficence, autonomy, and justice are part of a framework needed to balance the complex and potentially conflicting factors surrounding a clinician’s role in respecting privacy, confidentiality and fair use of genetic information obtained from cancer genetic testing.
The concept of beneficence dictates that the primary goal of medical care is to provide benefit through appropriate health care. In the field of oncology, this translates into using early detection and effective treatment protocols to improve outcomes. Providing beneficent care may go beyond medical outcomes of treatment to encompass the patient’s life circumstances, expectations, and values. Consideration of the patient’s psychological and emotional ability to handle the testing and results disclosure process can help avoid doing harm. (Refer to the Psychological Impact of Genetic Testing/Test Results on the Individual section of this summary for more information.)
Nonmaleficence is the bioethical code that directs health care providers to do no harm, inclusive of physical and emotional harm, and acknowledges that medical care involves risks and benefits. Particular to the field of oncology, adherence to this construct includes taking measures to minimize the adverse effects of cancer prevention, treatment, and control. This may encompass taking precautionary measures to prevent inadvertent disclosure of sensitive information.
Autonomous decision making respects individual preferences by incorporating informed consent and education. Individuals have the right to be informed about the risks and benefits of genetic testing and to freely choose or decline testing for themselves. Additionally, it is beneficial to consider the sociocultural context and family dynamics to ensure medical decision making takes places without coercion or interference.
Justice refers to the equitable distribution of the benefits and risks of health care. A goal in oncology is ensuring access to cancer genetic services. The availability of predictive genetic testing should not be dependent on ethnic background, geographical location, or ability to pay. Genetic discrimination should not be a result of predictive testing. Equitable distribution balances individual rights with responsibilities of community membership.
Privacy and Confidentiality: Disclosure of Patient’s Genetic Information
A strong provider-patient relationship is founded on respect for the patient’s privacy and confidentiality; therefore, protecting the patient’s personal information from third parties is key to building trust. Predictive testing for cancer susceptibility presents a challenge because of the hereditary nature of the diseases being tested and the implications of genetic risk for family members. Physicians are faced with a duty to warn or to act to prevent foreseeable harm. One practical suggestion for facilitating family-based communication is providing patients with education and information materials to facilitate disease susceptibility discussions with family members. The next section discusses the legal, legislative, and ethical basis for balancing patient confidentiality with duty to warn.
Disclosure in research
Privacy and confidentiality also applies to research, such as population screening for genetic diseases. The U.S. Department of Health and Human Services authorizes the use of Certificates of Confidentiality to researchers. This certificate, issued by the National Institutes of Health, protects the researcher from having to reveal the identity of any research subject “in any Federal, State, or local civil, criminal, administrative, legislative, or other proceedings.” The protections offered by the certificate of confidentiality are limited to personally identifiable information collected beginning on the date of issuance and ending on the expiration date, which matches the date of study completion. The NIH Office of Extramural Research policy and guidance on Certificates of Confidentiality notes that any personally identifiable information collected during that time interval is protected in perpetuity. In regard to family-based recruitment strategies, the Cancer Genetics Network Bioethics Committee assembled a group of experts to develop recommendations for researchers to use in approaching family members. Due to the wide spectrum of research strategies, there are different levels of concern. Essential to family-based recruitment strategies is informing potential research participants how their personal information was obtained by the researcher, why the researcher is approaching them, what the researcher knows about them, and for what purpose the information will be used, whether or not they decide to participate.
“Duty to warn”: Legal proceedings, federal/state legislation, and recommendations of professional organizations
“Duty to warn” requires balancing the bioethical constructs of beneficence and autonomy with other factors such as case proceedings, legislation, and professional societies’ recommendations. As of September 2008, the National Council of State Legislatures lists the states that have legislation requiring consent to disclose genetic information. The definition of "genetic information" can vary depending on the legal case and the language used in state and federal legislation, and generally includes genetic testing and family history information; however, the definition generally does not apply to current diagnoses. Genetic diagnosis can be done through direct genetic tests for disorders linked to a specific gene and indirect genetic tests for disorders in which the specific genes are not known or there are multiple different genes involved (genetic heterogeneity). There are four state case laws that apply to duty to warn. Two cases deal directly with testing for hereditary cancer predisposition syndromes; one case deals with a psychotherapist's duty to warn a relative of imminent threat, and another with genetic testing as a tool for reproductive decisions. Table 5 summarizes the cases.
At the federal level, there are strict nondisclosure policies governing private health information. The Standards for Privacy of Individually Identifiable Health Information (Privacy Rule), which summarizes the Health Insurance Portability and Accountability Act (HIPAA) of 1996, finds it permissible to disclose health information without consent when the public interest is at risk; therefore, under certain conditions, there are exceptions to the nondisclosure policy include the following:
Professional societies and government advisory agencies have published their different positions and recommendations on communication between a physician and a patient's relatives in regard to disclosure of genetic disease.
The Council on Ethical and Judicial Affairs of the American Medical Association (AMA) and the American Society of Clinical Oncology (ASCO) encourage discussing the importance of patients sharing genetic information with family members. Specifically, the Council on Ethical and Judicial Affairs of the American Medical Association states that “Physicians …should identify circumstances under which they would expect patients to notify biological relatives of the availability of information related to risk of disease…(and) physicians should make themselves available to assist patients in communicating with relatives to discuss opportunities for counseling and testing, as appropriate.” ASCO’s position is that providers “should remind patients of the importance of communicating test results to family members… ASCO believes that the cancer care provider’s obligations (if any) to at-risk relatives are best fulfilled by communication of familial risk to the person undergoing testing, emphasizing the importance of sharing this information with family members so that they may also benefit.” These organizations recommend that family members disclose genetic information.
The National Society of Genetic Counselors and the International Society of Nurses in Genetics support the release of any genetic information upon request to third parties including relatives but only with the patient's consent. One of the tenets of genetic counseling is to maintain information received from clients as confidential, unless released by the client or consent for disclosure is provided as required by law.
Similar to the Privacy Rule, the U.S. Bioethics Commission, American Society of Human Genetics, and National Human Genome Research Institute (NHGRI) recommend the following guidelines to identify exceptional circumstances under which it is ethically acceptable to breach confidentiality.
At an international level, the World Health Organization and World Medical Association have similar guidelines. Additionally, Australia, Canada, Germany, Japan, the Netherlands, and the United Kingdom have guidelines supporting the disclosure of genetic information to relatives under similar exceptional circumstances.
Employment and Insurance Discrimination
Genetic information obtained from genetic susceptibility tests may have medical, economic, and psychosocial implications for the individual tested and his or her family members. The potential for employment and insurance discrimination is a common concern for individuals considering genetic testing. However, there is limited documentation of the occurrence of employment and insurance discrimination on the basis of hereditary cancer genetic testing results.
Public awareness of the federal Genetic Information Nondiscrimination Act (GINA) and its protections is limited. In a multistate survey conducted in 2010, more than 80% of respondents indicated that they were unaware of the law. In a 2014 survey of 1,479 U.S. adults, 79% indicated that they were unaware of the law. Of those who were aware of GINA, 44% knew that it protected against health insurance and 33% knew it protected against employment discrimination; 23% incorrectly believed the law protected against life, disability, and long-term insurance discrimination. After reading a description of GINA, 30% of respondents indicated that they were actually more concerned about discrimination [note: The denominator for the latter finding is uncertain]. Although genetic testing has increased since the passage of the law, relatively few cases of discrimination in which GINA’s authority can be tested have been reported.
(Refer to the Informed Consent and Exploration of potential risks, benefits, burdens, and limitations of genetic susceptibility testing subsections of this summary for more information about discrimination issues related to cancer genetics services.)
Legal proceedings, federal/state legislation, and recommendations of professional organizations
A legal case example at the federal district court level involves the Burlington Northern Santa Fe Railroad. The U.S. Equal Employment and Opportunities Commission requested that Burlington Northern Santa Fe Railroad not be allowed to use medical information obtained from genetic tests for employment decisions.
In the last 15 years, state and federal legislation statutes have been developed to prevent the use of genetic information for employment practices, such as hiring, promotion, and salary decisions; and insurance policies, including life and health coverage, by employers, schools, government agencies, and insurers. According to Executive Order 13145, federal departments and agencies are prohibited from discriminating against employees on the basis of genetic test results or information about a request for genetic testing services. Employers and insurers are prohibited from intentionally lowering policy rates by using practices such as screening for individuals who are at risk of becoming ill or dying due to genetic disease susceptibility, such as cancer. Federal laws, including GINA, do not cover employer-provided life and disability; however, some states do have legislation addressing the use of genetic information for life and disability policies. The National Conference of State Legislatures (NCSL) summarized current health legislation of the U.S. Congress. Examples of relevant legislation regarding genetic information include, GINA, HIPAA, Americans with Disabilities Act (ADA), and Employee Retirement Income Security Act (ERISA).
Genetic Information Nondiscrimination Act 2008
GINA 2008 protects the provision of health insurance and employment against discrimination based on genetic information as follows:
- Prohibits access to individuals’ personal genetic information by insurance companies and by employers.
- Prohibits insurance companies from requesting that applicants for group or individual health coverage plans be subjected to genetic testing or screening and prohibits them from discriminating against health plan applicants based on individual genetic information.
- Prohibits employers from using genetic information to refuse employment, and prohibits them from collecting employees’ personal genetic information without their explicit consent.
- Prohibits employment agencies from failing or refusing to refer a candidate on the basis of genetic information.
- Prohibits labor organizations from refusing membership based on a member's genetic make-up.
- Does not mandate coverage for medical tests or treatments.
- Does not prohibit medical underwriting based on current health status.
- Does not limit a treating health provider, including those employed by or affiliated with health plans, from requesting or notifying individuals about genetic tests.
- Does not prohibit occupational testing for toxic monitoring programs, employer-sponsored wellness programs, administration of federal and state family and medical leave laws, and certain cases of inadvertent acquisition of genetic information.
GINA amends and/or extends coverage of HIPAA, ADA, and ERISA by including genetic information under medical privacy and confidentiality legislation and employment and insurance determinations. Additionally, with the passage of GINA, researchers and clinicians can encourage participation in clinical trials and appropriate genetic testing knowing that there are federal protections against discrimination based on the results of genetic testing. GINA established the minimum protection level that must be met in all states. However, for states with more robust legislation in place, GINA does not weaken existing protections provided by state law.
However, GINA has several limitations.
A study conducted between 2009 and 2010 via a survey posted on the Facing Our Risk of Cancer Empowered (FORCE) website provides insight into consumers' perspectives regarding insurance discrimination based on genetic test results after the passage of GINA. Of the 1,669 participants (69% of whom previously received genetic testing), 53% indicated that they had heard about insurance discrimination based on genetic test results. More than half the sample (54%) reported that they had not heard about GINA before the survey. After being provided with a brief description of GINA as part of the survey process, 60% (n = 886) reported a change in their feelings about genetic testing, with the majority (573 of 886 participants) indicating less concern about health insurance discrimination. Finally, when asked whom they would contact regarding questions about GINA, 38% indicated their health care provider.
Exception to protections against employment and insurance discrimination: Active duty military personnel
GINA and other state and federal protections do not extend to genetic testing of active duty military personnel or genetic information obtained from active duty military personnel. In the military, genetic testing provides medical information that is to be used to protect military personnel from harmful duty or other exposures that could stimulate or aggravate a health problem. For example, use of certain antimalaria medication in individuals with glucose 6-phosphate dehydrogenase deficiency can result in red blood cell rupture. Therefore, some genetic information is critical for maintaining the health and safety of military personnel, given the possible stressful occupational environments they face. In addition, all military personnel provide a DNA sample to be maintained in a repository that can be used for identification purposes.
Results of genetic tests for disease predisposition could influence military eligibility for new enlistments, and for current military personnel, genetic test results could influence worldwide eligibility, assignments, and promotions. For example, a young woman found to carry a pathogenic variant may not be considered eligible for deployment for 12-15 months because access to recommended health care may not be easily accessible, such as breast MRI, a recommended screening modality for carriers of pathogenic variants. Active duty military personnel with less than eight years of active duty service are especially vulnerable in the event they become disabled and must go before the medical board to establish benefit eligibility.
In 2006, Department of Defense Instruction Number 1332.38 (DODINST 1332.38) redefined as a result of two cases brought by service members who each had a hereditary condition that presented later in their military careers. The disability instructions state that any injury or disease discovered after a service member enters active duty—with the exception of congenital and hereditary conditions—is presumed to have been incurred in the line of duty. Any hereditary and/or genetic disease shall be presumed to have been incurred prior to entry into active duty. However, DODINST 1332.38 further states that any aggravation of that disease, incurred in the line of duty, beyond that determined to be due to natural progression, shall be deemed service aggravated. As a result of these two cases, the 8-year active duty service limit was established. This means that after 8 or more years of military service, the natural progression of a genetic condition would be deemed aggravated by military service. Therefore, until late 2008, the presence of a congenital or hereditary condition would not be considered a preexisting condition in disability decision making for those with 8 or more years of service.
In October 2008, in response to the National Defense Authorization Act of 2008 (NDAA) Title XVI: “Wounded Warrior Matters,” a policy memorandum was issued providing supplemental and clarifying guidance on implementing disability-related provisions, including new language related to hereditary or genetic diseases. The policy memorandum states, “Any hereditary or genetic disease shall be evaluated to determine whether clear and unmistakable evidence demonstrates that the disability existed before the Service member’s entrance on active duty and was not aggravated by military service. However, even if the conclusion is that the disability was incurred prior to entry on active duty, any aggravation of that disease, incurred while the member is entitled to basic pay, beyond that determined to be due to natural progression shall be determined to be service aggravated.” The interpretation of this policy is uncertain at this time.
Case scenarios involving ELSI issues in cancer genetic testing
There are multiple psychosocial, ethical, and legal issues to consider in cancer genetic testing. Genetic tests for germline pathogenic variants have social and family implications. In addition to prevention and surveillance options, genetic testing should be offered in conjunction with genetic education and counseling. A comprehensive strategy for dealing with ethical dilemmas can incorporate a shared approach to decision making, including open discussion, planning, and involvement of the family. To integrate the different perspectives of bioethics, law, and psychosocial influences, the following scenarios can help health care providers become familiar with commonly encountered dilemmas; it is imperative, however, that the clinician evaluate each patient and his or her situation on a case-by-case basis. These case scenarios were adopted from “Counseling about Cancer: Strategies for Genetic Counseling;” the in-depth case examples are extensively discussed in the original text.
Duty to warn versus privacy
A patient with known family history of breast cancer is interested in testing for and pathogenic variant. In reviewing her family history, the health care provider realizes that the patient is not aware of an additional rare but hereditary cancer pathogenic variant in a second-degree relative, which the health center tested and confirmed in the past. After talking with her family, the patient is unable to confirm the details of the second hereditary cancer pathogenic variant and again expresses interest in testing. Does the health care provider have a “duty to warn” the patient of the unknown cancer susceptibility gene in the family, at the risk of disclosing private patient information? The following issues are important to consider in resolving this case.
Patient’s right to know versus family member’s autonomy
A patient with a family history of a hereditary cancer is interested in predictive genetic testing and convinces an affected family member, who initially expresses unwillingness, to be tested in order to establish the familial pathogenic variant. In this scenario, the surviving family member admits to feeling pressured into consenting for genetic testing. Both the patient and the affected family member are patients. What takes precedence—the patient’s right to know or the family member’s autonomy? The following issues are important to consider in resolving this case.
Right to know versus right not to know
A hereditary cancer syndrome has been identified in a family. Within that family, an adult child wants a cancer susceptibility test that her parent declined, and one identical twin wants testing but the other does not. Even though the uninterested parties have declined testing and do not want to know the results, it is possible that testing one relative can disclose results for the other family members. Do the rights of the family members interested in predictive testing take precedence over the rights of the relatives who do not want to know? The following issues are important to consider in resolving this case.
Beneficence versus paternalism
A psychological assessment of a patient interested in predictive testing for an autosomal dominant cancer reveals a history of depression and suicidal attempts. The health care provider is considering denying or deferring testing because of concerns for the patient’s emotional well-being even though the patient refuses a referral to a psychologist because he reports feeling emotionally stable. Is deferring or denying predictive genetic testing a beneficent gesture or an act of paternalism? The following issues are important to consider in resolving this case.
Professional guidelines and other resources
(Refer to the Genetic Resources section of the PDQ Cancer Genetics Overview summary for more information about the ELSI of genetic testing and counseling.)
Changes to This Summary (11/30/2017)
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.
Identification of Candidates for Referral to Genetic Counseling
Added this new section.
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 cancer genetics risk assessment and counseling. 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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- Kathleen A. Calzone, PhD, RN, AGN-BC, FAAN (National Cancer Institute)
- Suzanne M. O'Neill, MS, PhD, CGC (Northwestern University)
- 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)
- Susan T. Vadaparampil, PhD, MPH (H. Lee Moffitt Cancer Center & Research Institute)
- Catharine Wang, PhD, MSc (Boston University School of Public Health)
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