Abstract P5-09-08: Germline variants in non-BRCA homologous recombination genes detected in HER2-negative breast cancer patients

Abstract

Abstract Background: PARP inhibitors (PARPi) are FDA approved for a subset of metastatic human epidermal growth factor receptor 2-negative (H2N) breast cancer patients who harbor a germline pathogenic or likely pathogenic variant (PV) in BRCA1/2, two of the most well-described breast cancer susceptibility genes in the homologous recombination (HR) pathway. While the NCCN guidelines recommend consideration of BRCA1/2 testing for patients with H2N disease that are eligible for single-agent therapy, there are currently clinical trials available for women with advanced H2N breast cancer who have PVs in HR genes beyond BRCA1/2 to investigate outcomes of receiving PARPi. The yield of germline PVs in other HR genes in the H2N population is not well-described. Methods: Clinical histories and test results were reviewed for women with a diagnosis of H2N breast cancer who underwent multi-gene hereditary cancer panel testing that included a minimum of 10 homologous recombination (HR) genes in addition to BRCA1/2 (ATM, BARD1, BRIP1, CHEK2, FANCC, NBN, PALB2, PTEN, RAD51C, RAD51D). Those with prior BRCA1/2 testing were excluded. We assessed the yield of PVs in non-BRCA1/2 HR genes in the H2N breast cancer population. In addition, we compared the yield of PVs in non-BRCA1/2 HR genes in a “low risk” population (probands with H2N breast cancer with no reported personal history of ovarian or pancreatic cancer and no reported family history of breast, ovarian, pancreatic, or prostate cancer) to a “high risk” population (probands with H2N breast cancer who also have a personal history of ovarian or pancreatic cancer and/or a reported family history of breast, ovarian, pancreatic, or prostate cancer) via a two-tailed Fisher's exact test. Results: A total of 6179 women with H2N breast cancer were identified. Of these, BRCA1/2 PVs were identified in 4.8% (299/6179), while 5.7% (351/6179) carried PVs in HR genes other than BRCA1/2. These included CHEK2 (145), ATM (62), PALB2 (59), BRIP1 (26), FANCC (18), BARD1 (17), RAD51C (12), NBN (11), RAD51D (6), and PTEN (2). No statistically significant difference in the likelihood to harbor a PV in one of the 10 non-BRCA1/2 HR genes was observed between those with a “low risk” presentation (4.8% (53/1096) as compared to those with a “high risk” presentation (5.9% (298/5083)) (p=0.1956). Conclusions: Our findings show that the yield of PVs in HR genes other than BRCA1/2 is appreciable in the H2N breast cancer population. As such, it may be beneficial to include all HR genes when testing H2N breast cancer patients, regardless of other personal or family history, if and/or when a patient develops metastatic disease. Citation Format: Vogel Postula KJ, McGill AK, Sutcliffe E, Murphy PD, Klein RT, Hruska KS. Germline variants in non-BRCA homologous recombination genes detected in HER2-negative breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-08.