Abstract PD4-03: Physical Activity, Reproductive Factors, and Breast Cancer Risk: A Prospective Cohort Study using data from the UK Biobank

Abstract Introduction: Reproductive factors such as early menarche, late menopause, nulliparity, and exogenous hormone use are well-established risk factors for breast cancer. Physical activity is associated with a lower risk of breast cancer, but whether this protective effect varies across reproductive risk factors is not well characterized. Objective: To investigate whether reproductive risk factors modify the association between physical activity and breast cancer risk. Methods: Females ≥40 years without a history of cancer from UK Biobank provided self-reported data on moderate-to-vigorous intensity physical activity and reproductive factors (2007-2010). Physical activity levels were categorized based on reported metabolic equivalent hours per week (MET-hrs/week), with high levels of physical activity defined as ≥50 MET-hrs/week, moderate levels of physical activity as 10 to <50 MET-hrs/week, and low levels of physical activity as <10 MET-hrs/week. Incident cancers were ascertained to 13 May 2022. Multivariable Cox regressions were used to examine the association between baseline physical activity and breast cancer risk, adjusting for sociodemographic variables, lifestyle factors, and reproductive risk factors. Reproductive risk strata were defined by age at menarche (≤ vs. >12 years), parity (number of live births [<2 vs. 2+ live births]; age at first birth [within vs. more than 10 years from menarche]), age at menopause (≤ vs. >50 years), use of oral contraceptive and use of menopausal hormone therapy (ever use vs. never use). Additive and multiplicative interactions were assessed using interaction terms within Cox regression and Relative Excess Risk due to Interaction (RERI), respectively. Subgroup analyses were conducted for pre-menopausal and post-menopausal breast cancer risk. Results: The study followed 242 721 participants for a mean of 12.53 years (SD: 2.55). During the study period, 8397 breast cancer cases were identified, including 748 pre-menopausal cases. Participants with high level of physical activity had significantly lower breast cancer risk (HR=0.87, 95%CI=0.82-0.93) compared to those with low level of physical activity. This association was observed for both pre- and post-menopausal breast cancer (HR [95% CI] = 0.78 [0.62-0.97] & 0.88 [0.83-0.94], respectively). The association between increased physical activity and decreased breast cancer risk was consistent across reproductive risk strata defined by age at menarche, parity, age at menopause, and use of oral contraceptive or menopausal hormone therapy (all p-values>0.05 for interaction terms and RERI estimates). Conclusions: Physical activity is a useful breast cancer risk reduction strategy for women, regardless of their reproductive history. Citation Format: H. Harsanyi, A. Harper, H. Freisling, N. Slot, S. Lupichuk, A. Toriola, L. Yang. Physical Activity, Reproductive Factors, and Breast Cancer Risk: A Prospective Cohort Study using data from the UK Biobank [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD4-03.