Abstract
BACKGROUND: Oral contraceptive (OC) use is widespread globally. Despite their significant benefits, concerns persist about a potential rise in breast cancer risk linked to their use. Genetic predisposition also influences breast cancer risk; however, its interaction with OC use remains inconclusive. This study aims to explore the association between OC use and breast cancer risk in women with varying genetic predispositions to breast cancer, as measured by polygenic risk scores (PRS). METHOD: A total of 257,185 white female participants from the UK Biobank were included. Time-varying Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) to examine the association between OC and invasive breast cancer events, stratified by PRS. Age was used as the primary time scale, and analyses were adjusted for year of birth, Townsend Deprivation Index, body mass index, smoking status, age at menarche, menopausal status, family history of breast cancer, parity, hormone replacement therapy use, history of hysterectomy, as well as genetic principal components. RESULTS: Current use of OC was associated with an increased risk of breast cancer, with a HR of 1.21 (95% CI: 1.03–1.41). In contrast, previous use showed no association (HR = 0.99, 95% CI: 0.92–1.05). Genetic risk, as measured by the PRS, was strongly associated with breast cancer risk (P < 0.001). Individuals in the highest PRS decile had approximately three times higher risk compared to those in the mid deciles. Importantly, for the association between current OC use and breast cancer risk, a statistically significant trend was observed across both PRS deciles (P = 0.04) and tertiles (P = 0.05), with decreasing HRs as genetic risk increased. Specifically, the HR for current OC use was 1.43 (95% CI: 1.02–2.01) in the lowest PRS tertile, 1.14 (95% CI: 0.89–1.45) in the middle tertile, and 0.96 (95% CI: 0.80–1.14) in the highest tertile. CONCLUSION: Both OC use and a high PRS increase the risk of breast cancer. There is a trend toward a decreased relative risk associated with OC use among those with higher genetic predisposition. Therefore, there is no evidence to suggest that women with a high genetic risk for breast cancer are more adversely affected by OC use. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13058-025-02177-5.