ASCO and the Society of Surgical Oncology (SSO) recently published a joint guideline to provide formal consensus-based recommendations on the role of germline mutation testing in patients with breast cancer.48 The guideline addressed
BRCA1/2 testing in patients with newly diagnosed breast cancer and among those with local recurrence, contralateral primary breast cancer, or metastatic disease;
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BRCA1/2 testing in persons with a personal history of breast cancer (and no active disease);
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the value of testing patients with a diagnosis of breast cancer for breast cancer predisposition genes other than BRCA1/2; and
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how patients with breast cancer considering genetic testing should be counseled.
This companion Q and A article addresses some of the questions clinicians may face as they implement the recommendations (Fig 1) into clinical practice.
Question: What Patients Are Appropriate for Testing for Genes Beyond Brca1/2?
Epidemiologic studies of patients with breast cancer have found a comparable prevalence of pathogenic variants in other breast cancer–associated genes (including moderate-penetrance genes such as ATM and CHEK2 and high-penetrance genes such as PALB2, TP53, and PTEN) as in BRCA1/2.1–6 In contrast to BRCA1/2, the frequency of pathogenic variants in moderate-penetrance genes does not decline as steeply with age at diagnosis.1,5 Pathogenic variants in genes other than BRCA1/2 may also confer an increased risk of contralateral breast cancer.7,8 Furthermore, studies have shown that testing criteria developed for BRCA1/2 often miss other pathogenic variants2 and that the extent of family cancer history does not correlate with pathogenic variants in particular genes (eg, BRCA1/2 versus others).9 Testing breast cancer–associated genes other than BRCA1/2 approximately doubles the yield of pathogenic variants in patients with breast cancer.
As noted in Recommendation 4.2 of the ASCO-SSO guideline, testing additional genes does not inform decision-making for surgical treatment of the diagnosed breast cancer. It may, however, inform the management of future contralateral breast cancer risk. Patients may consider risk-reducing mastectomy at the same time as surgical treatment for the diagnosed cancer, if they carry a high-penetrance pathogenic variant that may confer contralateral breast cancer risk. Moderate-penetrance pathogenic variants are not an indication for risk-reducing mastectomy. However, moderate-penetrance variants may support recommendations for secondary breast cancer screening incorporating magnetic resonance imaging.10 Currently, there are no approved systemic therapies for pathogenic variants in genes other than BRCA1/2 although two small clinical trials suggest that patients with PALB2 pathogenic variants may benefit from poly (ADP-ribose) polymerase (PARP) inhibitor treatment for metastatic breast cancer.11,12 Identifying some pathogenic variants may enable prevention and/or targeted screening for second cancers of other organs (eg, risk-reducing salpingo-oophorectomy with BRIP1, PALB2, RAD51C, and RAD51D and pancreatic cancer screening with ATM, PALB2, and STK11).10,13 Finding pathogenic variants in other genes also enables prediagnosis testing, targeted screening, and prevention for patients’ relatives. Thus, a case can be made for testing breast cancer–associated genes beyond BRCA1/2 in most patients with breast cancer.
Reasons not to test genes beyond BRCA1/2 might include the higher probability of a variant of uncertain significance result when more genes are tested14 and the possibility that a patient who is undergoing BRCA1/2 testing might lack all criteria discussed previously (ie, may be uninterested in additional screening or risk reduction and may lack living relatives). Pretesting informed consent is essential and should include discussion of genes to be tested and the implication of potential results for the patient and family. A provider experienced in clinical cancer genetics may help to guide gene selection, consent, and interpretation of testing results.
Question: What Is an Appropriate Gene Panel? Broader Gene Testing or More Tailored Gene Testing?
As noted in the response to question 1, there is reason to consider testing most patients for breast cancer–associated genes other than BRCA1/2, such as the high-penetrance genes PALB2, PTEN, STK11, and TP53 and the moderate-penetrance genes ATM, BARD1, CHEK2, NF1, RAD51C, and RAD51D. Including genes associated with cancers other than breast may be considered based on family cancer history (eg, CDKN2A with a family history of pancreatic cancer and melanoma). While some laboratories offer large germline testing panels that incorporate genes associated with other cancer syndromes (eg, Lynch Syndrome), testing such genes in a patient with breast cancer but no other suggestive personal or family history is essentially population screening and warrants pretest counseling on the possibility of unexpected pathogenic variants (eg, in CDH1, which might prompt discussion of prophylactic gastrectomy).15 Some panels contain genes for which cancer associations are not well-established, and studies suggest that including these genes increases the probability of a variant of uncertain significance result without an increase in clinically useful findings.14 A provider with expertise in clinical cancer genetics may help to select appropriate genes to evaluate, taking into consideration patient and family cancer history and patient preferences.
Question: How Can Clinical Oncologists Appropriately Manage Patients Identified as Carriers by Commercial, Direct-to-consumer Tests?
Studies have shown that direct-to-consumer laboratories differ in the validity of results, and some direct-to-consumer laboratories do not identify many, or even most, of the pathogenic variants that are found with traditional clinician-ordered genetic testing.16,17 Direct-to-consumer laboratories also vary in their results disclosure process: some require a video or telephone appointment with a licensed genetic counselor for pathogenic variant disclosure, while others use e-mail notification.17 Thus, patients’ needs after direct-to-consumer testing may vary from a worst-case scenario in which confirmatory genetic testing and post-test counseling are required to a best-case scenario of valid results and sufficient counseling to guide follow-up care.
A recent survey of patients with breast cancer found that direct-to-consumer genetic testing use is low (3.5%)18; however, providers should ask patients if they have undergone such testing and seek results for review. A provider with expertise in clinical cancer genetics may be helpful in determining the quality and sufficiency of direct-to-consumer testing and counseling received; in some cases, the scope of testing may not have been appropriate for the patient’s personal and family history. If review confirms a pathogenic variant, patients should be followed by a provider with expertise in managing pathogenic variants in the affected gene. Appropriate follow-up care may include addition of PARP inhibitor therapy, consideration of risk-reducing surgeries, and/or escalation of secondary cancer screening approaches.10 Educating patients about notification of their family members, with the ultimate goal of facilitating cascade genetic testing for the familial pathogenic variant, is another important component of post-test care.19
Question: How Can Clinical Oncologists Connect Patients with Professionals Qualified to Counsel Patients Regarding Germline Mutations?
Germline genetic testing is increasingly incorporated into the care of patients with cancer without the step of pretest counseling with a genetic counselor. Educational tools, automated workflows, and discussions with members of the cancer treatment team (point-of-care testing) are well received and can help increase access to genetic testing of patients with cancer. Point-of-care testing20–25 during regular cancer treatment appointments may also reduce disparities in access to genetic testing.26,27
However, genetic test results have implications beyond the treatment of the patient’s current cancer, and addressing these issues can fall outside the oncology setting. Post-test referral to a cancer genetics specialist is recommended for individuals with pathogenic variants, variants of uncertain or conflicting interpretation, possible mosaicism or clonal hematopoiesis, and negative results but a highly suspicious personal and/or family history.10
Individuals with the types of test results noted previously can benefit from access to cancer genetics specialists who can provide tailored follow-up of non–treatment-related aspects of post-testing care. Individuals found to have a pathogenic variant may need screening or management of other cancer risks. The finding of a pathogenic variant provides an opportunity to identify at-risk relatives and initiate proactive screening and prevention; however, rates of cascade testing among at-risk relatives are persistently low.19,24,28,29 Ongoing family communication and strategies to actively facilitate genetic testing for relatives are needed to overcome barriers.30,31 Clinical management hinges on accurate variant classification, but variants with uncertain or conflicting interpretations are commonly identified by multigene panel testing.32,33 Rates of reclassification of uncertain variants have been reported to be 6%-15% over 5- to 10-year periods, and the rate of reclassification is likely to increase with advances in variant interpretation.34 Consensus about the optimal approaches for identifying conflicting interpretations and communicating about reclassifications is lacking, but overall, there is agreement that a provider who becomes aware of a clinically significant reclassification has a responsibility to inform their patients of it.33,34 Finally, even a multigene panel test may not identify the cause of cancer risk in all families. Patients with significant personal and/or family histories may need other specialized testing, enrollment in research, and cancer screening recommendations based on empiric risks.
Providers offering germline genetic testing should be prepared to return results, including complex results as previously noted. Ultimately, the management of patients with hereditary cancer syndromes is often multidisciplinary, and patients may need to be connected to several specialists with expertise in managing specific cancer risks as well as to genetic counselors. Genetic counselors are resources for variant information, cancer risk and management recommendations, family member testing, and coordinating care between providers. The rapid increase in telemedicine genetic counseling is helping to overcome historic geographical barriers and making genetic counseling more accessible.35,36 Genetic counseling resources can be found at the National Society of Genetic Counselors website.37 However, efforts for broader provider education on cancer genetics are also needed (Table 1). Provider education resources are offered by ASCO and other professional societies. National consensus guidelines for managing patients with hereditary cancer syndromes are also available. There is a need for continued development and evaluation of patient-facing tools to help support post-test follow-up issues such as family communication and adherence to screening. These efforts will increase the number of providers who are proficient at post-genetic testing follow-up.Table 1. Patient and Provider Resources for Cancer Genetics Education, Counseling, and Testing
Organization | Services | Website |
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Genetic Counseling and Patient Resources | ||
National Society of Genetic Counselors (NSGC) | Search for certified genetic counselor providing in-person or telemedicine services by specialty and geographic location | NSGC37 |
Facing Hereditary Cancer Empowered (FORCE) | Education, support, and advocacy resources for people with hereditary breast or ovarian cancer and other syndromes | FORCE38 |
Provider Cancer Genetics Education | ||
American Society of Clinical Oncology | Cancer genetics toolkit Provides links to several ASCO courses and training materials | ASCO39 |
City of Hope: Cancer Screening and Prevention Intensive Course in Cancer Risk Assessment | Continuing Education Unit/Continuing Medical Education-approved course for providers who want to incorporate hereditary cancer risk assessment and genetic testing into practice | City of Hope40 |
Collaborative Group of the Americas on Hereditary Gastrointestinal Cancers (CCA-IGC) | Provider education via podcasts, webinars, and annual conference on hereditary GI and pancreatic cancers | CGA-IGC41 |
National Cancer Institute Cancer Genetics Overview (PDQ) | Provider education on cancer genetics and links to additional resources | National Cancer Institute42 |
National Comprehensive Cancer Network (NCCN) | Regularly updated guidelines regarding genetic testing and management of hereditary cancer syndromes | NCCN43 |
Gene and Variant Curation | ||
BRCA Exchange | BRCA1/2 variant classification information | BRCA Exchange44 |
ClinVar | Publicly available information about individual genetic variants and reported classifications | ClinVar45 |
ClinGen | Publicly available database of the data regarding the clinical actionability of cancer predisposition genes | ClinGen46 |
International Society for Gastrointestinal hereditary tumors (InSiGHT) | Curation of variants in the mismatch repair genes Provider education and research opportunities |