Background
It is well-established that higher body mass index (BMI) is associated with reduced risk of breast cancer before menopause, but increased risk after menopause. However, it remains unclear how weight change impacts breast cancer risk and whether the timing of such change matters. In this study, we examined the association between BMI change and breast cancer risk, both overall and by the timing of weight change relative to menopause. 
Methods
Within the Generations Study, a prospective cohort of UK women with median age 48 (range: 16–102 years) at recruitment, we investigated changes in BMI comparing follow-up with baseline assessments (median 6.2 years apart, IQR: 5.9–6.5 years) in relation to breast cancer risk. The analysis included 79,228 women, who were classified according to menopausal status at each BMI assessment: premenopausal at both, postmenopausal at both, or transitioning through menopause between measurements. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between BMI change, modelled as a continuous variable, and breast cancer. All models were adjusted for potential confounders. We examined the overall association of BMI change and breast cancer risk, tested for effect modification by time-varying menopausal status, and fitted group-specific models examining associations with breast cancer diagnosed before and after menopause. Sensitivity analyses excluding the first three years of follow-up were performed to address potential reverse causation.
Results
Between exposure assessments, weight remained stable (±0.5 kg/m²) in 28% of women, while 28% lost weight (<-5.0 kg/m²), 28% gained moderately (0.5–2.0 kg/m²), and 16% gained >2.0 kg/m². Over a median follow-up period of 6.7 years (IQR: 3.8–8.1 years), starting from the date of the second BMI assessment, 1,451 incident breast cancers were diagnosed. Overall, compared to stable BMI, a 5 kg/m² increase was positively associated with breast cancer risk (HR: 1.16, 95% CI: 1.02–1.31), while a 5 kg/m² decrease was inversely associated with breast cancer risk (HR: 0.87, 95% CI: 0.76–0.98). There was no evidence that this association varied by menopausal status. Premenopausal BMI change was not associated with breast cancer risk (HR per 5kg/m²: 1.09, 95% CI: 0.88–1.35) and there was no evidence of effect modification by menopausal status. Postmenopausal BMI change was not associated with breast cancer risk (HR per 5 kg/m²: 1.09, 95% CI: 0.90–1.31). BMI change spanning the menopausal transition was associated with breast cancer risk: relative to stable BMI, a 5 kg/m² increase was associated with a higher risk (HR: 1.46, 95% CI: 1.09–1.94), whereas a 5 kg/m² decrease was associated with a lower risk (HR: 0.69, 95% CI: 0.52–0.91).
Conclusion
In this study, weight gain during the menopausal transition was associated with higher risk of breast cancer, whilst weight loss during this period was associated with lower risk. This suggests that the menopausal transition may represent a critical window when weight management could be particularly effective for breast cancer prevention.