Genetic Testing in Breast Cancer Patients: Striking the Balance Between Over Versus Undertesting

This podcast summarizes and provides commentary on the recent article by Yadav et al. in which the authors demonstrate that expansion of the current NCCN guidelines for genetic testing in breast cancer patients to include all women diagnosed at or below the age of 65 markedly improves the sensitivity for detecting pathogenic germline variants without requiring the testing of all breast cancer patients.   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article "Evaluation of Germline Genetic Testing Criteria in a Hospital-Based Series of Women with Breast Cancer" by Yadav et al. My name is Erin Cobain, and I am a Clinical Lecturer at the University of Michigan Rogel Cancer Center in Ann Arbor, Michigan United States. My oncologic specialty is breast cancer. In this study, the authors sought to determine the sensitivity and specificity of current genetic testing criteria for the detection of pathogenic germline variants in women with breast cancer. Current national comprehensive cancer network (NCCN) guideline criteria, updated in January 2020, recommend that genetic testing be offered to all women diagnosed with breast cancer at age 45 or younger, those diagnosed with triple negative breast cancer at age 60 or younger as well as those with family history of breast, ovarian, prostate or pancreatic cancer that meet specific criteria. In addition, any patient with Ashkenazi Jewish ancestry is recommended to undergo testing. This most recent update to the guidelines also incorporates a recommendation to offer testing to individuals who have a greater than 5% risk of having a BRCA1 or BRCA2 mutation by prior probability models such as Tyrer-Cuzick or BRCAPro who would not otherwise meet criteria.  Prior to the publication of the present study by Yadav and colleagues, several recent articles including those by Beitsch et al. and Yang et al. indicate that many patients with pathogenic or likely pathogenic germline variants in genes associated with hereditary breast and ovarian cancer syndromes are missed by current testing criteria. The Beitsch et al. study analyzed results from a prospective registry whereby patients with previously or newly diagnosed breast cancer were consented and underwent genetic testing with an 80-gene panel test. Approximately 1,000 patients were enrolled and approximately half met NCCN guideline criteria for genetic testing. Among the patients who met NCCN guideline criteria, 9.4% had a pathogenic or likely pathogenic variant identified. For those patients not meeting NCCN guideline criteria for testing, 7.9% had a pathogenic or likely pathogenic variant. This led the authors to conclude that nearly half of breast cancer patients with pathogenic germline variants would be missed by NCCN criteria. Similarly, Yang and colleagues examined a cohort of patients with personal or family history of breast or gynecologic cancer from a Medicare database undergoing genetic testing. Data from over 4,000 patients tested indicated that the rate of identifying a likely pathogenic or pathogenic germline variant was nearly identical in the cohorts that met NCCN guideline criteria for testing versus those that did not, with the rate of pathogenic germline variants being approximately 10% in both groups. Indeed, the results from these studies lead the American Society of Breast Surgeons to issue a recommendation in October 2019 that all patients with personal history of breast cancer undergo genetic testing. While this recommendation would undoubtedly identify more patients with genetic susceptibility to breast cancer and other malignancies, the implications of this recommendation must be considered. Large scale testing would more readily identify patients with moderate penetrance genes that are without established cancer risk reduction guidelines. More testing also leads to increased identification of variants of uncertain significance, presenting challenges both for patients and their providers attempting to best counsel individuals with an ambiguous result. Finally, inequities in access to testing and genetic counseling resources as well as increased healthcare costs that result from broad testing are of major concern. If cost of testing is not covered by insurance, paying out of pocket may not be feasible for many patients.  In the present study, Yadav and colleagues attempted to address some of these apprehensions regarding the adoption of widespread genetic testing in breast cancer patients. The investigators enrolled patients with personal history of breast cancer over a 16 year period of time into a registry and evaluated for pathogenic germline variants in 9 cancer predisposition genes, including ATM, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53. These genes were selected because there are clear management recommendations in the NCCN guidelines when they are identified.  The authors found that among almost 4,000 women tested, those meeting current NCCN guideline criteria for testing (comprising 48% of the cohort) were more likely to harbor a pathogenic germline variant than those women who did not meet criteria. The rate of detection of pathogenic germline variants was 9% and 3.5% in these groups respectively. Despite the updated NCCN guideline criteria identifying patients with pathogenic germline variants more readily, there are undoubtedly still patients missed by these criteria. The authors conducted subsequent analysis to include all women diagnosed with breast cancer at age 65 or younger, which achieved 90% specificity for the 9 cancer predisposition genes selected and greater than 98% specificity for identification of pathogenic germline variants in BRCA1 and BRCA2. Given this, the authors concluded that expanding the NCCN genetic testing criteria to include all women diagnosed with breast cancer at or before the age of 65 will markedly improve the sensitivity of genetic testing and avoid the need to evaluate all patients with personal history of breast cancer. The major limitations of this study were that cost-effectiveness of this approach was not analyzed, and the majority of the patients included in the registry were White, limiting the applicability of these findings to a diverse patient population. Despite these limitations, this study offers a promising and considered approach to genetic testing in patients with personal history of breast cancer. While validation of this approach in additional study cohorts would be of great value, this data strongly suggests that testing all patients at or below age 65 at the time of breast cancer diagnosis achieves a balance between the two current testing paradigms, identifying the vast majority of patients at risk, and avoiding unnecessary testing of many. This concludes this JCO Podcast. Thank you for listening.