CASE Woman with BRCA2 mutation
An 80-year-old woman presents for evaluation of newly diagnosed metastatic pancreatic adenocarcinoma. Her medical history is notable for breast cancer. Genetic testing of pancreatic tumor tissue detected a pathogenic variant in BRCA2. Family history revealed a history of melanoma as well as bladder, prostate, breast, and colon cancer. The patient subsequently underwent germline genetic testing with an 86-gene panel and a pathogenic mutation in BRCA2 was identified.
Watch a video of this patient and her clinician, Dr. Andrea Hagemann: https://www.youtube.com/watch?v=0x1jUG2u51c&t=21s.
Methods of genetic testing
It is estimated that 1 in 300 to 1 in 500 women in the United States carry a deleterious mutation in BRCA1 or BRCA2. This equates to between 250,000 and 415,000 women who are at high risk for breast and ovarian cancer.1 Looking at all women with cancer, 20% with ovarian,2 10% with breast,3 2% to 3% with endometrial,4 and 5% with colon cancer5 will have a germline mutation predisposing them to cancer. Identification of germline or somatic (tumor) mutations now inform treatment for patients with cancer. An equally important goal of germline genetic testing is cancer prevention. Cancer prevention strategies include risk-based screening for breast, colon, melanoma, and pancreatic cancer and prophylactic surgeries to reduce the risk of breast and ovarian cancer based on mutation type. Evidence-based screening guidelines by mutation type and absolute risk of associated cancers can be found on the National Comprehensive Cancer Network (NCCN).6,7
Multiple strategies have been proposed to identify patients for germline genetic testing. Patients can be identified based on a detailed multigenerational family history. This strategy requires clinicians or genetic counselors to take and update family histories, to recognize when a patient requires referral for testing, and for such testing to be completed. Even then the generation of a detailed pedigree is not very sensitive or specific. Population-based screening for high-penetrance breast and ovarian cancer susceptibility genes, regardless of family history, also has been proposed.8 Such a strategy has become increasingly realistic with decreasing cost and increasing availability of genetic testing. However, it would require increased genetic counseling resources to feasibly and equitably reach the target population and to explain the results to those patients and their relatives.
An alternative is to test the enriched population of family members of a patient with cancer who has been found to carry a pathogenic variant in a clinically relevant cancer susceptibility gene. This type of testing is termed cascade genetic testing. Cascade testing in first-degree family members carries a 50% probability of detecting the same pathogenic mutation. A related testing model is traceback testing where genetic testing is performed on pathology or tumor registry specimens from deceased patients with cancer.9 This genetic testing information is then provided to the family. Traceback models of genetic testing are an active area of research but can introduce ethical dilemmas. The more widely accepted cascade testing starts with the testing of a living patient affected with cancer. A recent article demonstrated the feasibility of a cascade testing model. Using a multiple linear regression model, the authors determined that all carriers of pathogenic mutations in 18 clinically relevant cancer susceptibility genes in the United States could be identified in 9.9 years if there was a 70% cascade testing rate of first-, second- and third-degree relatives, compared to 59.5 years with no cascade testing.10
Gaps in practice
Identification of mutation carriers, either through screening triggered by family history or through testing of patients affected with cancer, represents a gap between guidelines and clinical practice. Current NCCN guidelines outline genetic testing criteria for hereditary breast and ovarian cancer syndrome and for hereditary colorectal cancer. Despite well-established criteria, a survey in the United States revealed that only 19% of primary care providers were able to accurately assess family history for BRCA1 and 2 testing.11 Looking at patients who meet criteria for testing for Lynch syndrome, only 1 in 4 individuals have undergone genetic testing.12 Among patients diagnosed with breast and ovarian cancer, current NCCN guidelines recommend germline genetic testing for all patients with epithelial ovarian cancer; emerging evidence suggests all patients with breast cancer should be offered germline genetic testing.7,13 Large population-based studies have repeatedly demonstrated that testing rates fall short of this goal, with only 10% to 30% of patients undergoing genetic testing.9,14
Among families with a known hereditary mutation, rates of cascade genetic testing are also low, ranging from 17% to 50%.15-18 Evidence-based management guidelines, for both hereditary breast and ovarian cancer as well as Lynch syndrome, have been shown to reduce mortality.19,20 Failure to identify patients who carry these genetic mutations equates to increased mortality for our patients.
Barriers to cascade genetic testing
Cascade genetic testing ideally would be performed on entire families. Actual practice is far from ideal, and barriers to cascade testing exist. Barriers encompass resistance on the part of the family and provider as well as environmental or system factors.
Family factors
Because of privacy laws, the responsibility of disclosure of genetic testing results to family members falls primarily to the patient. Proband education is critical to ensure disclosure amongst family members. Family dynamics and geographic distribution of family members can further complicate disclosure. Following disclosure, family member gender, education, and demographics as well as personal views, attitudes, and emotions affect whether a family member decides to undergo testing.21 Furthermore, insurance status and awareness of and access to specialty-specific care for the proband’s family members may influence cascade genetic testing rates.
Provider factors
Provider factors that affect cascade genetic testing include awareness of testing guidelines, interpretation of genetic testing results, and education and knowledge of specific mutations. For instance, providers must recognize that cascade testing is not appropriate for variants of uncertain significance. This can lead to unnecessary surveillance testing and prophylactic surgeries. Providers, however, must continue to follow patients and periodically update testing results as variants may be reclassified over time. Additionally, providers must be knowledgeable about the complex and nuanced nature of the screening guidelines for each mutation. The NCCN provides detailed recommendations by mutation.7 Patients may benefit from care with cancer specialists who are aware of the guidelines, particularly for moderate-penetrance genes like BRIP1 and PALB2, as discussions about the timing of risk-reducing surgery are more nuanced in this population. Finally, which providers are responsible for facilitating cascade testing may be unclear; oncologists and genetic counselors not primarily treating probands’ relatives may assume the proper information has been passed along to family members without a practical means to follow up, and primary care providers may assume it is being taken care of by the oncology provider.
Continue to: Environmental or system factors...