The Option of Genetic Testing
Factors to Consider When 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:[1,2]
- 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.[1]
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.[1]
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.
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.[3] 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.[4]
Insurance coverage
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 BRCA1/BRCA2 or Lynch syndrome testing) are able to obtain insurance coverage for multigene testing.[5] 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 BRCA1/BRCA2 testing for unaffected women meeting United States Preventive Services Task Force guidelines.[6,7] 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.[8] 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.[9-11] For individuals with autosomal dominant cancer syndromes (e.g., those associated with APC, BRCA1/BRCA2, PTEN, or TP53 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:[10]
- Does the cancer syndrome include childhood malignancies or significant morbidity or mortality at an early age?
- What is the penetrance associated with the genetic variant?
- How severe is the syndrome phenotype?
- Are there interventions available that decrease the pathogenic variant-associated cancer risk or are proven to detect cancer early when it is in a treatable form?
- Is there evidence of a different phenotype if an individual is a heterozygous or homozygous carrier?[12,13]
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.[14] 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 BRCA1 pathogenic variants (185delAG and 5382insC) and one BRCA2 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 BRCA1 and BRCA2pathogenic variants that occur among Ashkenazim are nonfounder pathogenic variants.[15] 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 adenomatous polyposis coli (APC) pathogenic variants are associated with hundreds or thousands of colonic polyps and colon cancer of the classical FAP syndrome, some APCpathogenic variants cause a milder clinical picture, with fewer polyps and lower colorectal cancer risk.[16,17] In addition, other disorders may be part of the FAP spectrum. Pathogenic variants in a certain portion of the APC gene also predispose to retinal changes, for example, when pathogenic variants in a different region of APC 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 [18] 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.[2,19] Yet, the use of multigene testing requires modification of traditional approaches to genetic counseling.[20,21] 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.[2]
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.[22]
- Testing methodologies also differ among laboratories regarding exon /introncoverage, read depth, Sanger sequencing confirmation, and variant interpretation.[23]
- 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.[24]
- 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.[25,26]
- In the studies that replicated previous BRCA testing with a panel, 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 BRCA testing and multigene testing.[25,26]
In high-risk individuals who meet criteria for hereditary cancer genetic testing but in whom no pathogenic variant was identified from single-gene testing, panel testing may identify other clinically actionable variants.[27,28] For example, the additional yield of multigene testing in individuals in whom a BRCA1/BRCA2 pathogenic variant was not detected currently seems to be approximately 4%.[26,29,30] The most common non-BRCApathogenic variants found are in CHEK2, ATM, and PALB2.[26,29-31] 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.[30,32-34]
Selected reports from 2014 to 2016, which included 1,000 to 10,000 tested individuals, showed variation in pathogenic variant and VUS rates.[23,24,26,30,35-37] Pathogenic variant rates ranged from 7% to 14%; VUS rates ranged from 19% to 41% and increased with the number of genes included on the panel, but decreased in the later studies, likely because of larger data pools and refinements in variant interpretation.
A large study published by a commercial laboratory included more than 252,000 individuals who were tested with a 25-gene panel between 2013 and 2016.[38] The study reported an overall pathogenic variant rate of 6.7% (9.8% in affected individuals and 4.7% in unaffected individuals), with an overall VUS rate of 30%. The study population was 97% female, had no prior cancer genetic testing, and 93% met NCCN criteria for hereditary breast and ovarian cancer (HBOC) or Lynch syndrome testing. It was noted that half of the pathogenic variants found for HBOC or Lynch syndrome were not in the expected genes associated with these syndromes (BRCA1, BRCA2, MLH1, MSH2, MSH6, and PMS2).
Outcomes of multigene testing
Results from multigene tests have several possible outcomes, including the following:[19]
- No variant detected.
- VUS detected.
- Pathogenic variant in a high-penetrance gene concordant with the existing personal/family history (e.g., a germline MSH2 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 CDH1 pathogenic variant in an individual with no personal/family history of gastric cancer).
- Pathogenic variant in a moderate-penetrance gene (e.g., CHEK2, ATM).
- Pathogenic variant in a gene with uncertain cancer risks and/or cancer associations.
Results can also reveal more than one finding given that multiple genes are being tested simultaneously and the elevated rate of VUS.[21] 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.[39] 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.[21,39] (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.[40,41] 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),[24] higher rates of VUS in some minority populations,[32,42] 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.[2,39,40,43]
Overall, there is insufficient evidence to determine superiority of multigene testing over phenotype-guided testing or sequential gene testing.[19] As a consequence, practice guidelines for optimal clinical use of multigene tests continue to evolve.[2,44] 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.[2,44] 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.[44]
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.[1,2] 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.[45] (Refer to the Penetrance of Inherited Susceptibility to Hereditary Breast and/or Gynecologic Cancerssection 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.[46] 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.[47] 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.[46,48] 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.[46]
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.[48] Laboratory-developed tests are performed in a laboratory that assembles its own testing materials in-house;[48] 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.[46,48] 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.[48]
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.[46] 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.[48] 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.[49] 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.[46] 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.[46] 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.[50] 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.[50]
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.[51] 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.
Genotyping for carrier status and disease risks
In 2015, the FDA provided clearance for a large DTC company (23andMe) to market carrier screening for Bloom syndrome, which is associated with increased cancer risks in homozygotes as well as other phenotypic features. Subsequently, DTC carrier testing for several conditions became available. In 2017, the FDA allowed 23andMe to market DTC tests for ten diseases or conditions including late-onset Alzheimer disease, Parkinson disease, and hereditary thrombophilia.[52] It is important to note that the carrier and health tests authorized for marketing by the FDA are performed by genotyping, which means that only specific nucleotides or bases are targeted for analysis; sequencing is not performed.[53] Thus, while the false-positive or false-negative rate for a specific genotype is very low (i.e., analytic validity is high), other pathogenic variants are not analyzed, nor is the entire sequence of the gene. Thus, the false-negative rate due to untested pathogenic variants as well as other gene abnormalities is high.
Genotyping for founder pathogenic variants in BRCA1 and BRCA2
In March 2018, the FDA authorized 23andMe to market DTC testing for three founder pathogenic variants in the BRCA1 and BRCA2 genes that are common in individuals of Ashkenazi Jewish descent.[54] These three variants are rare among high-risk individuals who are not of this ethnicity and in the general population of non-Jewish individuals. However, Jewish individuals whose family history is suggestive of hereditary breast/ovarian cancer who test negative for these three variants warrant additional testing.
It is crucial for individuals who obtain a BRCA1/BRCA2 (or any health-related) positive result from DTC testing to pursue clinical confirmation of such a result. Clinical confirmation entails repeating the test in a CLIA-certified lab, as well as individual review and verification of the result by laboratory personnel.
A potential advantage of DTC testing of these three BRCA1/BRCA2 pathogenic variants is that it will identify individuals who would not have been otherwise aware of their increased risk of associated cancers, for example if they have no personal or family history of breast, ovarian, or prostate cancer. This is one of the main arguments for population-based screening for BRCA1/BRCA2 pathogenic variants. (Refer to the Population screening section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.)
However, a negative result does not rule out other hereditary factors or account for other clinical indicators, genetic and nongenetic, of increased cancer risk. Thus, for most individuals who test negative for the three BRCA1/BRCA2 variants, the results do not provide reassurance about their cancer risks. For high-risk individuals in particular (i.e., those with a history suggestive of hereditary breast/ovarian cancer) a negative result from this limited testing is incomplete, given that it does not assess the presence or absence of other pathogenic variants in BRCA1/BRCA2 or in many other cancer-associated genes.
Testing for SNPs
In the past, several DTC companies offered only single nucleotide polymorphism (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.[55] (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 BRCA1/BRCA2 founder pathogenic variants).[56] 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.[57,58]
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.[59-61] 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.[59]
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) [62] may improve the accuracy of risk assessment.[63,64] 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 whole-genome sequencing (WGS) or whole-exome sequencing (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 may have access to their raw sequence data and may consult with other companies, websites, and open-access databases for interpretation.[65,66] However, these data must be interpreted with caution. A clinical lab found that 40% of variants reported in DTC raw data were false positives (i.e., low analytic validity because the identified variant was not present).[67] In addition, several variants that were designated as “increased risk” in the raw data were classified as benign by clinical laboratories and public databases.[67] Given the potential for misinterpretation, which may lead to unnecessary medical procedures or testing, these findings underscore the importance of clinical confirmation of all potentially medically actionable gene variants identified by DTC testing.
Some factors to consider when determining the accuracy and utility of 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,[68] and DTC companies have varying protocols for classification, which may or may not be consistent with national guidelines (e.g., refer to [69]). 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.
Considerations
There may be potential benefits associated with DTC testing. DTC marketing and provision of genetic tests may promote patient autonomy.[56] 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.[70] 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,[71-74] 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.[75,76] Further, psychological distress has not been widely reported among consumers who have undergone DTC testing for a variety of conditions.[73] However, little is known about how individuals respond after learning that they carry pathogenic variants in high-risk genes such as BRCA1/BRCA2 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.[1] 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.[2]
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.[77] 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
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.[78] 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.[79] 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.[80] 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,[1,2,81,82] 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 [83] and providers [84] 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 y or older) because of concerns about autonomy, potential discrimination, and possible psychosocial effects.[85-87] 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).[88,89] 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.[1] 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., TP53 pathogenic variants). The decision to test in such circumstances is particularly controversial.[1]
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.[1,90] Counseling under these circumstances incorporates a discussion of how test results will be shared with the child when he or she is older.[1] Children aged 10 to 17 years may have more involvement in the decision-making process.[91] 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.[91] 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.[90] 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.[90] 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.[90] 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.[92,93]
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.[1] 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.[86] 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.[94] 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.[95]
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.[96-98] 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.[99-103] 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.[104] 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.[105,106]
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.[107,108]
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,[109] the Profile of Mood States,[110] the Hospital Anxiety and Depression Scale,[111] and the Brief Symptom Inventory.[112] 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.[113]
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.[114-116]
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.[117]
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.[118-120] 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.
- Potential burdens of a test result that is uninformative or of uncertain significance.In the absence of a known pathogenic variant in the family, a negative test result is not informative. In this situation, the tested person’s risk status remains the same as it was prior to testing. One study of 183 women with an uninformative BRCA test result found that most women understood the implications of the test result, and it did not alter their intention to undergo a high-risk screening regimen.[121,122] If the test identifies a new variant of unknown clinical significance, the test result is of uncertain significance and cannot be used to revise the tested person’s risk estimate. Subsequent research, however, may provide information about the variant's effect (or lack of effect) on cancer risk.Potential burdens
- Need to evaluate other family members to determine the significance of variants not known to be disease related.
- Persistent uncertainty about risk status, which may result in a recommendation for intensive monitoring if a hereditary predisposition cannot be ruled out with certainty.
- Lack of evidence-based guidance regarding prevention or surveillance strategies.
- Continuing anxiety, frustration, and other adverse psychological sequelae associated with uncertainty because no definitive answer has been provided.
- High monetary cost of testing.
- Potential benefits and burdens of a positive test in an unaffected, at-risk individual when a disease-related pathogenic variant has been previously identified in the family.Potential benefits
- Elimination of uncertainty about inherited susceptibility for an individual.
- Potential for reduction in future morbidity and mortality through enhanced cancer risk management strategies (i.e., increased screening, adoption of a healthy lifestyle, and avoidance of risk factors).
- Opportunity to reduce cancer risk through chemoprevention and risk-reducing surgery.
- Opportunity to inform relatives about the likelihood that they have the family pathogenic variant and about the availability of genetic testing, cancer risk assessment, and management services.
Potential burdens- Neglect of screening and surveillance resulting from increased anxiety about being a carrier of a pathogenic variant.
- Psychological distress, including anxiety, depression, reduced self-esteem.
- Increased worry about cancer due to unproven effectiveness of current interventions to reduce risk.
- Risks and costs of increased screening or prophylaxis.
- Strained/altered relationships within family.
- Guilt about possible transmission of genetic risk to children.
- Potential insurance, employment, or social discrimination.
- Potential benefits and burdens of a negative test result when a disease-related pathogenic variant has been identified in the family.Potential benefits
- Reassurance and reduction of anxiety about personal cancer risk due to heredity.
- Avoidance of unnecessary intensive monitoring and prevention strategies.
- Avoidance of aggressive interventions such as risk-reducing surgery.
- Relief that children are not at increased risk.
Potential burdens- Neglect of routine surveillance resulting from misunderstanding of a negative test result. The patient remains at the general population risk and may be at increased risk depending on his or her personal risk factors and any risk associated with the other branch of the family.
- Adjustment to the change in expected life course.
- Survivor guilt.
- Strained relationship with others in family.
- Regret over previous decisions (e.g., having had risk-reducing surgery prior to being tested).
- Potential benefits and burdens of a positive test result in an individual who is the first identified carrier in a family.[4]Potential benefits
- No need to rely on other family members for informative test results.
- Potential for risk reduction in future morbidity and mortality through enhanced cancer risk management strategies (i.e., increased screening and surveillance, chemoprevention, and risk-reducing surgery).
- Opportunity to inform relatives about the likelihood that they have the family pathogenic variant and about the availability of genetic testing, cancer risk assessment, and management services.
Potential burdens- Confronting ethical dilemmas about who should receive the information, what should be conveyed, and when it should be conveyed to specific family members.
- Coping with potential personal distress in conveying the information.
- Coping with family members' potential distress and reaction to the information.
- Feeling unprepared for the tasks associated with disseminating genetic information through the family.
- Loss of privacy.
- Coping with potential personal psychological distress and reaction to the information.
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.[123] 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.[124] 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 BRCA1/BRCA2 pathogenic variant testing [125] 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.
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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 Usedsection 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.
Beneficence
The concept of beneficence dictates that the primary goal of medical care is to provide benefit through appropriate health care.[1] 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.[1] Consideration of the patient’s psychological and emotional ability to handle the testing and results disclosure process can help avoid doing harm.[2] (Refer to the Psychological Impact of Genetic Testing/Test Results on the Individual section of this summary for more information.)
Nonmaleficence
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.[1] 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.[2]
Autonomy
Autonomous decision making respects individual preferences by incorporating informed consent and education.[1] 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.[1]
Justice
Justice refers to the equitable distribution of the benefits and risks of health care.[1] 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.[2] Equitable distribution balances individual rights with responsibilities of community membership.[1]
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.[2,3] 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.[4] One practical suggestion for facilitating family-based communication is providing patients with education and information materials to facilitate disease susceptibility discussions with family members.[1] 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.[5] 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.[6] 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.[6]
“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).[7] There are four state case laws that apply to duty to warn.[8] 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 4 summarizes the cases.
At the federal level, there are strict nondisclosure policies governing private health information.[8] 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;[15,16] therefore, under certain conditions, there are exceptions to the nondisclosure policy include the following:
- There is serious or imminent threat to the health or safety of a person or the public.
- The threat constitutes an imminent, serious threat to an identifiable third party.
- The physician has the capacity to avert significant harm.
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.[4,8,17]
The Council on Ethical and Judicial Affairs of the American Medical Association (AMA) and the American Society of Clinical Oncology (ASCO) [18,19] encourage discussing the importance of patients sharing genetic information with family members.[4] 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.”[18] These organizations recommend that family members disclose genetic information.
The National Society of Genetic Counselors [20] and the International Society of Nurses in Genetics [21] support the release of any genetic information upon request to third parties including relatives but only with the patient's consent.[4] 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.[4,20]
Similar to the Privacy Rule, the U.S. Bioethics Commission,[22] American Society of Human Genetics,[23] and National Human Genome Research Institute (NHGRI) recommend the following guidelines to identify exceptional circumstances under which it is ethically acceptable to breach confidentiality.[4,8]
- There is a high likelihood of harm if the relative is not warned.[4,22,23]
- The patient, despite encouragement, refuses to inform family members.[4,22,23]
- The relative is identifiable.[23]
- The harm of nondisclosure is greater than the harm of disclosure.[23]
- Current medical technology renders the disease preventable, treatable, or manageable.[23]
- Only the information necessary to prevent harm is released.[4,24]
- There is no other reasonable way to avert harm.[4]
At an international level, the World Health Organization and World Medical Association have similar guidelines.[4] 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.[4]
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.[25,26] 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.[27] In a 2014 survey of 1,479 U.S. adults, 79% indicated that they were unaware of the law.[28] 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.[28]
(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.[24]
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.[12] 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.[24] 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.[24] 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) [29,30] 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.[32]
- 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.[32]
- Prohibits employers from using genetic information to refuse employment, and prohibits them from collecting employees’ personal genetic information without their explicit consent.[32]
- Prohibits employment agencies from failing or refusing to refer a candidate on the basis of genetic information.[33]
- Prohibits labor organizations from refusing membership based on a member's genetic make-up.[33]
- Does not mandate coverage for medical tests or treatments.[34]
- Does not prohibit medical underwriting based on current health status.[34]
- Does not limit a treating health provider, including those employed by or affiliated with health plans, from requesting or notifying individuals about genetic tests.[35]
- 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.[36]
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.[29] 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.
- GINA does not apply to members of the United States military, to veterans obtaining health care through the Veteran’s Administration, or to the Indian Health Service because the laws amended by GINA do not apply to these groups and programs.
- The legislation does not apply to life insurance, long-term care insurance, or disability insurance. Even though GINA does not provide protection for employer-provided disability and life insurance, some states do encompass these arenas in addition to employment, genetic privacy, health insurance, health insurance enforcement, life, disability, and long term care. NHGRI's Genome Status and Legislation Databaseprovides a searchable listing of state statutes and bills related to the following topics: direct-to-consumer genetic testing, employment and insurance nondiscrimination, health insurance coverage, privacy, research, and the use of residual newborn screening specimens.
- GINA’s employment provisions generally do not apply to employers with fewer than 15 employees.[34]
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.[37]
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.[38] 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.[39]
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 BRCA 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 BRCA 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 preexisting condition 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.[39]
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.[18,19] 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.[5] 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.[2]
Duty to warn versus privacy
A patient with known family history of breast cancer is interested in testing for BRCA1 and BRCA2 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 BRCA1/BRCA2 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.
- Preserving the confidentiality of the relative and informing the patient of her cancer risk are both important goals. In general, the health care professional has a “Duty to warn” when there is a high likelihood of harm if not warned, the person at risk is identifiable, the harm of nondisclosure is greater than disclosure, and only the information necessary to prevent harm is released. (Refer to the Privacy and Confidentiality: Disclosure of Patient’s Genetic Information section of this summary for more information.)
- It is possible that the benefit outweighs the harm of informing the patient of the second cancer syndrome because the monitoring and management of the rare cancer are different from guidelines for the general population. Additionally both parties are identifiable. An option is to contact the relative for permission to disclose the genetic test result to the patient in question.
- If it is not possible to obtain permission to disclose, it is possible to inform the patient that she meets clinical criteria for the hereditary cancer syndrome without releasing specific information about the genetic test results of the relative.
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.
- Explore, with the patient, alternatives to testing that do not involve the participation of the unwilling family member, such as testing stored tissue of a deceased relative. (Refer to the Value of Testing an Affected Family Member First section of this summary for more information).
- If the patient does not want to consider other options and the family member has agreed to be tested without coercion or interference, inform the family member of the implications of the test results, including risks and benefits, and assess her emotional well-being prior to testing.[20] (Refer to the Informed Consent section of this summary for more information.)
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.
- In hereditary cancer syndromes, an individual’s right to know takes precedence over an individual’s right not to know especially if there are early detection and prevention strategies to reduce the likelihood of morbidity and mortality.
- Since the family has a documented pathogenic variant, standard of care recommendations include guidelines for screening and monitoring. In the event that testing is not done, it is important to take “reasonable steps” to guarantee immediate family members are warned of the hereditary cancer risk. (Refer to the Privacy and Confidentiality: Disclosure of Patient’s Genetic Information section of this summary for more information.)
- Pretest and posttest discussions can include the possibility of medical, psychological, and social impact on family members and strategies on how to lessen any negative impact. The patient should honor the wishes of relatives who request not to know and attempt to keep the results secret.[20]
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.
- Despite the patient’s refusal to speak with a psychologist, the health care provider can discuss the details of the case with a mental health professional to determine suicidal risk. (Refer to the Psychological Impact of Genetic Information/Test Results on the Individual section of this summary for more information.)
- If there is risk of psychosocial disturbances because of test results, it is possible to defer testing. Conditions under which testing can resume are explained to the patient. For example, the NSGC Code of Ethics recommends that clients be referred to other qualified professionals when the patient requires additional services.[20]
- Denying a test does not seem justifiable under any circumstances because it implies that the client will never be able to undergo testing.
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.)
References
- Burke W, Press N: Genetics as a tool to improve cancer outcomes: ethics and policy. Nat Rev Cancer 6 (6): 476-82, 2006. [PUBMED Abstract]
- Schneider K: The ethical issues. In: Schneider KA: Counseling About Cancer: Strategies for Genetic Counseling. 2nd ed. New York, NY: Wiley-Liss, 2002, pp 291-312.
- Offit K: Clinical Cancer Genetics: Risk Counseling and Management. New York, NY: John Wiley and Sons, 1998.
- Godard B, Hurlimann T, Letendre M, et al.: Guidelines for disclosing genetic information to family members: from development to use. Fam Cancer 5 (1): 103-16, 2006. [PUBMED Abstract]
- Offit K: Psychological, ethical, and legal issues in cancer risk counseling. In: Offit K: Clinical Cancer Genetics: Risk Counseling and Management. New York, NY: John Wiley and Sons, 1998, pp 287-315.
- Beskow LM, Botkin JR, Daly M, et al.: Ethical issues in identifying and recruiting participants for familial genetic research. Am J Med Genet A 130A (4): 424-31, 2004. [PUBMED Abstract]
- Tantravahi U, Wheeler P: Molecular genetic testing for prenatal diagnosis. Clin Lab Med 23 (2): 481-502, 2003. [PUBMED Abstract]
- Offit K, Groeger E, Turner S, et al.: The "duty to warn" a patient's family members about hereditary disease risks. JAMA 292 (12): 1469-73, 2004. [PUBMED Abstract]
- California requires psychiatrists to warn about dangerous patients - Tarasoff v. Regents of University of California, 17 Cal. 3d 425, 551 P.2d 334, 131 Cal. Rptr. 14 (Cal. 1976). 1976. Also available online. Last accessed December 07, 2018.
- Harris M, Winship I, Spriggs M: Controversies and ethical issues in cancer-genetics clinics. Lancet Oncol 6 (5): 301-10, 2005. [PUBMED Abstract]
- Pate v. Threlkel, 661 So. 2d 278 (Florida 1995). 1995. Also available online. Last accessed December 07, 2018.
- Sankar P: Genetic privacy. Annu Rev Med 54: 393-407, 2003. [PUBMED Abstract]
- Safer v. Estate of Pack, 677 A2d 1188 (NJ App), appeal denied, 683 A2d 1163 (NJ 1996). 1996. Also available online. Last accessed December 07, 2018.
- Molloy v. Meier, Nos. C9-02-1821, C2-02-1837 (Minn 2004). 2004. Also available online. Last accessed December 07, 2018.
- Health Insurance Portability and Accountability Act of 1996, Public Law 104-191, 104th Congress. Washington, DC: 1996. Also available online. Last accessed December 07, 2018.
- US Department of Health and Human Services: OCR Privacy Brief: Summary of the HIPAA Privacy Rule. Washington, DC: US Department of Health and Human Services, 2002. Also available online. Last accessed December 07, 2018.
- Gordijn B: Genetic diagnosis, confidentiality and counseling: an ethics committee's potential deliberations about the do's and don'ts. HEC Forum 19 (4): 303-12, 2007. [PUBMED Abstract]
- Robson ME, Storm CD, Weitzel J, et al.: American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 28 (5): 893-901, 2010. [PUBMED Abstract]
- Robson ME, Bradbury AR, Arun B, et al.: American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J Clin Oncol 33 (31): 3660-7, 2015. [PUBMED Abstract]
- National Society of Genetic Counselors: National Society of Genetic Counselors Code of Ethics. Chicago, Il: National Society of Genetic Counselors, 2006. Also available online. Last accessed December 07, 2018.
- International Society of Nurses in Genetics: Position Statements: Privacy and Confidentiality of Genetic Information: The Role of the Nurse. Pittsburgh, Pa: International Society of Nurses in Genetics, 2010. Also available online. Last accessed December 07, 2018.
- US President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research: Screening and Counseling for Genetic Conditions: The Ethical, Social, and Legal Implications of Genetic Screening, Counseling, and Education Programs. Washington, DC: Government Printing Office, 1983. Also available online. Last accessed December 07, 2018.
- ASHG statement. Professional disclosure of familial genetic information. The American Society of Human Genetics Social Issues Subcommittee on Familial Disclosure. Am J Hum Genet 62 (2): 474-83, 1998. [PUBMED Abstract]
- Lowrey KM: Legal and ethical issues in cancer genetics nursing. Semin Oncol Nurs 20 (3): 203-8, 2004. [PUBMED Abstract]
- Wauters A, Van Hoyweghen I: Global trends on fears and concerns of genetic discrimination: a systematic literature review. J Hum Genet 61 (4): 275-82, 2016. [PUBMED Abstract]
- Prince AE, Roche MI: Genetic information, non-discrimination, and privacy protections in genetic counseling practice. J Genet Couns 23 (6): 891-902, 2014. [PUBMED Abstract]
- Parkman AA, Foland J, Anderson B, et al.: Public awareness of genetic nondiscrimination laws in four states and perceived importance of life insurance protections. J Genet Couns 24 (3): 512-21, 2015. [PUBMED Abstract]
- Green RC, Lautenbach D, McGuire AL: GINA, genetic discrimination, and genomic medicine. N Engl J Med 372 (5): 397-9, 2015. [PUBMED Abstract]
- National Conference of State Legislatures: Summary: Selected Health Legislation 110th Congress. Washington, DC: National Conference of State Legislatures, 2008. Also available online. Last accessed December 07, 2018.
- National Human Genome Research Institute: National Human Genome Research Institute Genome Statute and Legislation Database. Bethesda, Md: National Humokayan Genome Research Institute, 2008. Also available online. Last accessed December 07, 2018.
- Leib JR, Hoodfar E, Haidle JL, et al.: The new genetic privacy law: how GINA will affect patients seeking counseling and testing for inherited cancer risk. Community Oncology 5 (6): 351-4, 2008.
- American Society of Human Genetics: Genetic Scientists Applaud U.S. Senate Passage of the Genetic Information Nondiscrimination Act: American Society of Human Genetics Supports Important New Legislation [Press Release - April 25, 2008]. Bethesda, Md: American Society of Human Genetics, 2008. Also available online.Last accessed December 07, 2018.
- Asmonga D: Getting to know GINA. An overview of the Genetic Information Nondiscrimination Act. J AHIMA 79 (7): 18, 20, 22, 2008. [PUBMED Abstract]
- National Human Genome Research Institute: "GINA": The Genetic Information Nondiscrimination Act of 2008: Information for Researchers and Health Care Professionals. Bethesda, MD: National Human Genome Research Institute, 2009. Available online. Last accessed December 07, 2018.
- United States Department of Labor: Frequently Asked Questions Regarding the Genetic Information Nondiscrimination Act. Washington, DC: United States Department of Labor, 2010. Available online. Last accessed December 07, 2018.
- U.S. Equal Employment Opportunity Commission: The Genetic Information Nondiscrimination Act of 2008. Washington, DC: U.S. Equal Employment Opportunity Commission, 2008. Available online. Last accessed December 07, 2018.
- Allain DC, Friedman S, Senter L: Consumer awareness and attitudes about insurance discrimination post enactment of the Genetic Information Nondiscrimination Act. Fam Cancer 11 (4): 637-44, 2012. [PUBMED Abstract]
- Hudson KL, Holohan MK, Collins FS: Keeping pace with the times--the Genetic Information Nondiscrimination Act of 2008. N Engl J Med 358 (25): 2661-3, 2008. [PUBMED Abstract]
- Baruch S, Hudson K: Civilian and military genetics: nondiscrimination policy in a post-GINA world. Am J Hum Genet 83 (4): 435-44, 2008. [PUBMED Abstract]
Changes to This Summary (03/01/2019)
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.
Updated National Comprehensive Cancer Network (NCCN) as reference 12.
Updated NCCN as reference 12.
Updated NCCN as reference 2.
Updated NCCN as reference 33.
The Research examining multigene testing subsection was extensively revised.
Updated NCCN as reference 44.
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).
Board members review recently published articles each month to determine whether an article should:
- be discussed at a meeting,
- be cited with text, or
- replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Cancer Genetics Risk Assessment and Counseling are:
- Kathleen A. Calzone, PhD, RN, AGN-BC, FAAN (National Cancer Institute)
- Suzanne M. O'Neill, MS, PhD, CGC
- 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)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Cancer Genetics Editorial Board. PDQ Cancer Genetics Risk Assessment and Counseling. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/causes-prevention/genetics/risk-assessment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389258]
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