Effect of estradiol as a continuous variable on breast cancer survival by menopausal status: a cohort study in China

High levels of circulating estradiol (E2) are associated with increased risk of breast cancer, whereas its relationship with breast cancer prognosis is still unclear. We evaluated the effect of E2 concentration on survival endpoints among 8766 breast cancer cases diagnosed between 2005 and 2017 from the Tianjin Breast Cancer Cases Cohort. Levels of serum E2 were measured in pre-menopausal and post-menopausal women. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) between quartile of E2 levels and overall survival (OS) and progression-free survival (PFS) of breast cancer. The penalized spline was then used to test for non-linear relationships between E2 (continuous variable) and survival endpoints. 612 deaths and 982 progressions occurred over follow-up through 2017. Compared to women in the quartile 3, the highest quartile of E2 was associated with reduced risk of both PFS in pre-menopausal women (HR 1.79, 95% CI 1.17-2.75, P = 0.008) and OS in post-menopausal women (HR 1.35, 95% CI 1.04-1.74, P = 0.023). OS and PFS in pre-menopausal women exhibited a nonlinear relation ("L-shaped" and "U-shaped", respectively) with E2 levels. However, there was a linear relationship in post-menopausal women. Moreover, patients with estrogen receptor-negative (ER-negative) breast cancer showed a "U-shaped" relationship with OS and PFS in pre-menopausal women. Pre-menopausal breast cancer patients have a plateau stage of prognosis at the intermediate concentrations of E2, whereas post-menopausal patients have no apparent threshold, and ER status may have an impact on this relationship.