PracticeUpdate Oncology February 2019

EDITOR’S PICKS 15

Underdiagnosis of Hereditary Breast Cancer Journal of Clinical Oncology Take-home message • This study evaluated the capability of the National Comprehensive Cancer Network (NCCN) guidelines to identify patients with breast cancer with pathogenic variants in expanded panel testing. Eligibility criteria included patients with a previously or newly diagnosed breast cancer who had not undergone either single- or multigene testing. Approximately 1000 patients 18 to 90 years of age underwent an 80-gene panel test. • Approximately 50% of patients with breast cancer with a pathogenic/likely pathogenic variant who meet NCCN criteria for genetic testing and/or who would have a clinically actionable genetic test result are missed by current testing guidelines. The authors strongly suggest that major revision of the scope and intent of existing guidelines for genetic testing be undertaken and recommend that all patients with a diagnosis of breast cancer undergo expanded panel testing. Jeffrey Wiisanen MD

COMMENT By Lee S. Schwartzberg MD, FACP H ow should we determine who should be tested for a hereditary predisposition to breast cancer? Opinions range from testing all women to only testing those who fall into a very specific set of criteria as elucidated by the current NCCN guidelines. The guidelines recognize multiple scenar- ios that are generally accepted by insurers willing to cover the cost of testing. However, some of them are arbitrary (up to 45 years of age with no family history, for instance – what if you are adopted?) and they are confusing. A study published in the Journal of Clinical Oncology by Beitsch et al tested 1000 breast cancer patients with a large, 80-gene panel to determine how many had a pathogenic alter- ation in one of these genes, broadly defined as increasing the risk of hereditary cancer. Those who met NCCN criteria were marginally more likely to have a pathogenic mutation, 9.39% compared with those who did not meet criteria, 7.92%, and there was no statistical difference. For a commonly accepted, 11-gene hereditary breast and ovarian cancer subset of genes, the positivity rates were 6.26% for those meeting NCCN criteria and 3.54% for those not meeting criteria. Given the relatively large absolute number of patients who could have manage- ment decisions made on these results, the authors advocate for a wholesale change in criteria to do panel testing and to cover the cost for all patients with a diagnosis of breast cancer. I agree with this approach, but at this point it seems that an 80-gene panel may be too large. Many of the genes tested do not have evidence-based management decisions associ- ated with them. In addition, variants of unknown significance are more often found in these genes because of less pop- ulation-based information on outcomes. Such a large panel will generate many concerns and questions by patients that have no answers at the moment, and will consume a great deal of genetic counselor and provider time that is already at a premium. It would make sense for payers to reimburse more broadly for actionable panels in most, if not all, breast cancer patients. As the authors state, the cost of these panels is reducing rapidly, and the actionable information becomes very cost-effective. Perhaps these data will prompt the NCCN panel to streamline and expand the guidelines so more breast cancer patients can receive this pertinent germline information.

Abstract PURPOSE An estimated 10% of breast and ovarian cancers result from hereditary causes. Current testing guidelines for germ line susceptibility genes in patients with breast carcinoma were developed to identify car- riers of BRCA1/2 variants and have evolved in the panel-testing era. We evaluated the capability of the National Comprehensive Cancer Network (NCCN) guidelines to identify patients with breast cancer with pathogenic variants in expanded panel testing. METHODS An institutional review board-approved multicenter prospective registry was initiated with 20 community and academic sites experienced in cancer genetic testing and counseling. Eligibility criteria included patients with a previously or newly diagnosed breast cancer who had not undergone either single- or multigene testing. Consecutive patients 18 to 90 years of age were consented and underwent an 80-gene panel test. Health Insurance Portability and Accountability Act-compliant elec- tronic case report forms collected information on patient demographics, diagnoses, phenotypes, and test results. RESULTS More than 1,000 patients were enrolled, and data records for 959 patients were analyzed; 49.95% met NCCN criteria, and 50.05% did not. Overall, 8.65% of patients had a pathogenic/likely pathogenic (P/LP) var- iant. Of patients who met NCCN guidelines with test results, 9.39% had a P/LP variant. Of patients who did not meet guidelines, 7.9% had a P/LP variant. The difference in positive results between these groups was not statistically significant (Fisher's exact test P = .4241). CONCLUSION Our results indicate that nearly half of patients with breast cancer with a P/LP variant with clinically actionable and/or management guidelines in development are missed by current testing guidelines. We recommend that all patients with a diagnosis of breast cancer undergo expanded panel testing. Underdiagnosis of Hereditary Breast Cancer: Are Genetic Testing Guide- lines a Tool or an Obstacle? J Clin Oncol 2018 Dec 07;[EPub Ahead of Print], PD Beitsch, PW Whitworth, K Hughes, et al. www.practiceupdate.com/c/77382

VOL. 3 • NO. 1 • 2019