SHBG as a breast cancer risk biomarker in premenopausal women? Results from an individual patient's pooled analysis and a meta-analysis

BACKGROUND: Low levels of sex hormone-binding globulin (SHBG) have been associated with increased breast cancer (BC) risk, particularly in postmenopausal women. Whether this association extends to premenopausal women remains uncertain. We therefore performed an individual-patient pooled analysis and a meta-analysis to evaluate SHBG's role as a biomarker across menopausal status. METHODS: The pooled analysis included women at increased BC risk enrolled in two low-dose tamoxifen trials. The meta-analysis included 11 independent published studies assessing the association of SHBG with BC risk in healthy premenopausal women. RESULTS: Among premenopausal women in the pooled high-risk cohort, SHBG levels above the lowest tertile were associated with a 40% lower hazard of subsequent breast cancer events (HR = 0.60; 95% CI, 0.38-0.96; p = 0.03). In the meta-analysis, comprising 35,167 premenopausal women and 2,302 BC events, the summary estimate in premenopausal women showed a non-significant 8% risk reduction (SOR=0.92; 95% CI, 0.78-1.09). On the other hand, among the seven studies reporting stratified data by menopausal status, postmenopausal women experienced a significant 28% risk reduction (SOR=0.77; 95% CI, 0.69-0.87), with no statistically significant heterogeneity by menopausal status (P = 0.28). CONCLUSIONS: In a selected high-risk population, higher baseline SHBG was associated with fewer subsequent BC events. However, the meta-analysis did not provide statistically significant evidence of an inverse association with breast cancer occurrence in premenopausal women. These findings suggest that SHBG may be a biomarker of subsequent breast events in high-risk settings but do not confirm its role as a risk biomarker in the general premenopausal population.