Abstract PS10-02: Association between Germline Mutation Status and Overall Survival among Women with Breast Cancer in Population-based Studies in the United States
Authors: Couch Fergus 
Published: May 2024

Abstract
Background:
The influence of germline pathogenic variants (PVs) in breast cancer predisposition genes on overall survival (OS) after breast cancer diagnosis is not well defined, particularly for PVs in genes other than BRCA1 and BRCA2, and in the context of estrogen-receptor (ER) positive breast cancer. Even for BRCA1/2, OS estimates in women with breast cancer have primarily been derived from high-risk women qualifying for genetic testing due to young age at diagnosis or family history of cancer, and OS estimates by germline PV status from population-based studies are lacking.
Methods:
The study included 16,797 prospectively followed women with locoregional breast cancer within the population-based CARRIERS study who underwent surgical resection of the primary tumor. OS was compared between germline PV carriers and non-carriers (negative for germline PVs in 12 breast cancer predisposition genes) from the time of breast cancer diagnosis in a multivariable Cox proportional hazard regression analysis adjusting for age and menopausal status at diagnosis, race/ethnicity, ER status, type of surgery, use of adjuvant radiation, chemotherapy and endocrine agents, and prophylactic oophorectomy. Further subset analyses by race/ethnicity ER status of the primary tumor and adjusting for relevant covariates were also performed.
Results:
Germline PVs in ATM, BRCA1, BRCA2, CHEK2, or PALB2 were detected in 5.6% of the women in the study [ATM: 142 (0.8%), BRCA1: 206 (1.2%), BRCA2: 260 (1.5%), CHEK2:167 (1.0%) and PALB2:116 (0.7%)]. Compared to non-carriers, a significant difference in OS was not observed for germline PV carriers in ATM, BRCA1, BRCA2, or CHEK2 in the overall study population. However, a trend towards worse OS was noted for PALB2 PV carriers compared to non-carriers although this was not statistically significant (Hazard Ratio (HR): 1.36, 95%CI: 0.98 – 1.89, p=0.06). Further subset analysis by race/ethnicity demonstrated that the OS was significantly worse among Black PALB2 PV carriers (HR: 3.11, 95%CI: 1.74 – 5.55, p&lt; 0.001) but not in non-Hispanic White PALB2 PV carriers (HR: 1.00, 95%CI: 0.59 – 1.70, p=0.98) compared to non-carriers within the same race/ethnicity. Among 12,780 women with ER+ breast cancer, compared to non-carriers, OS was significantly worse in BRCA2 PV carriers (HR: 1.51, 95%CI: 1.06 – 2.16, p=0.02) and a trend towards worse OS was observed in BRCA1 PV carriers (HR:1.53, 95%CI:0.93 – 2.51, p=0.09). Among women with ER-negative breast cancer, a significant difference in OS was not observed between PV carriers in each of the five genes and non-carriers.
Conclusions:
The differences in OS by race/ethnicity in PALB2 PV carriers and by ER status of the tumor in BRCA2 PV carriers warrant further investigation of underlying tumor biology and assessment of endocrine sensitivity of breast cancer in germline PV carriers.
Citation Format: Fergus Couch. Association between Germline Mutation Status and Overall Survival among Women with Breast Cancer in Population-based Studies in the United States [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS10-02.