Abstract PS10-01: Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Pathogenic Variants in BRCA1 and BRCA2

Abstract BACKGROUND: Current use of hormonal contraception is associated with a 20-30% relative increase in the risk of breast cancer (BC) for women in the general population compared with never using. Longer duration of use is associated with higher risk, and the risk remains elevated above that of never users for at least 5 years after cessation. Most published data are for various formulations of the combined oral contraceptive pill, but associations are similar for progestogen-only contraceptives, including intrauterine devices. For women in the general population who use hormonal contraceptives in their 20s and 30s, when baseline BC risk for most women is low, these increased relative risks translate into only small increases in absolute risk. It is unclear whether use of hormonal contraceptives increases BC risk for women carrying a germline BRCA1 or BRCA2 pathogenic variant (PV). These women are at markedly higher risk of early-onset BC, so even slightly increased relative risks could translate to important increases in their absolute risk of BC. This study assessed the association between use of any hormonal contraception and BC risk for BRCA1 and BRCA2 PV carriers using individual participant data from four prospective cohorts. METHODS: Data from females born after 1920 with a PV in BRCA1 or BRCA2 and no history of cancer or bilateral mastectomy at cohort entry were analyzed. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for BC (invasive disease or ductal carcinoma in situ) associated with use of hormonal contraceptives for at least 1 year, with age as the timescale, entry at cohort enrolment, and censoring at the earlier of bilateral mastectomy, death, diagnosis of another cancer or last follow-up. Analyses were adjusted for study, birth cohort, first-degree family history of BC, parity, premenopausal bilateral oophorectomy and menopausal status. Current use of hormonal contraceptives was defined as use within the previous year, to account for cessation of use due to BC symptoms or clinical investigation. RESULTS: Of 3,882 BRCA1 and 1,509 BRCA2 PV carriers, 53% and 71%, respectively had ever used hormonal contraceptives (for at least one year). The median cumulative duration of hormonal contraceptive use was 4.8 and 5.7 years, respectively. Overall, 488 BRCA1 and 191 BRCA2 PV carriers developed incident BC during a median of 5.9 and 5.6 years of follow-up, respectively. For BRCA1 PV carriers, use of hormonal contraceptives for at least 1 year was associated with increased BC risk (HR 95% CI: 1.29 1.04-1.60 p=0.019). BC risk increased with longer cumulative duration of hormonal contraceptive use (HR 95% CI: 1.13 0.88-1.45 p=0.35, 1.48 1.11-1.96 p=0.007 and 1.56 1.13-2.17 p=0.007 for 1-5, 6-10 and 10 years of use, respectively), with an estimated proportional increase in risk of 3% (1%-5%, p=0.002) for each additional year of use. For BRCA2 PV carriers, there was no evidence that current or past use, or cumulative duration of use, were associated with increased risk of BC, but confidence intervals on the HRs were wide. CONCLUSION: Hormonal contraceptive use is associated with an increased risk of BC for women carrying PVs in BRCA1 and risk increases with cumulative duration of use. Hormonal contraceptives are an important healthcare option for women; they provide excellent contraceptive efficacy and reduce risks of ovarian and endometrial cancer. Decisions about use of hormonal contraceptives in women at increased risk for BC due to BRCA1 PVs need to carefully weigh the risks and benefits; while shorter-term use may result in only small increases, prolonged cumulative use may result in larger increases in absolute BC risk that may not be acceptable to some women. Citation Format: Kelly-Anne Phillips, Joanne Kotsopoulos, Susan Domchek, James Chamberlain, Julie Bassett, Amber Aeilts, Irene Andrulis, Saundra Buys, Wanda Cui, Mary Daly, Andrea Eisen, William Foulkes, Michael Friedlander, Jacek Gronwald, John Hopper, Esther John, Beth Karlan, Raymond Kim, Jan Lubiński, Kelly Metcalfe, Katherine Nathanson, Christian F. Singer, Heather Symecko, Nadine Tung, Steven Narod, Mary Beth Terry, Roger Milne. Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Pathogenic Variants in BRCA1 and BRCA2 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 PS10-01.