Diabetes and Incidence of Breast Cancer and its Molecular Subtypes: A Systematic Review and Meta-Analysis

Diabetes mellitus (DM) has been proposed to be positively associated with breast cancer (BCa) risk due to shared risk factors, metabolic dysfunction, and use of antidiabetic medications. We conducted a systematic review and meta-analysis to evaluate the association between DM and BCa risk. We searched PubMed, Embase, and Web of Science for cohort and case-control studies assessing the association between DM and BCa published before December 10, 2021. Two reviewers independently screened the studies for inclusion, abstracted article data, and rated study quality. Random effects models were used to estimate summary risk ratios (RRs) and 95% confidence intervals (CIs). From 8396 articles identified in the initial search, 70 independent studies were included in the meta-analysis. DM was associated with an overall increased risk of BCa (RR=1.20, 95% CI: 1.11-1.29). The 24 case-control studies demonstrated a stronger association (RR=1.26, 95% CI: 1.13-1.40) than the 46 cohort studies (RR=1.15, 95% CI: 1.05-1.27). Studies reporting risk by menopausal status found that postmenopausal women had an elevated risk of developing BCa (RR=1.12, 95% CI: 1.07-1.17). No association between DM and BCa risk was observed among premenopausal women (RR=0.95, 95% CI: 0.85-1.05). In addition, DM was associated with significantly increased risks of estrogen receptor (ER)+ (RR=1.09, 95% CI: 1.00-1.20), ER- (RR=1.16, 95% CI: 1.04-1.30), and triple negative BCa (RR=1.41, 95% CI: 1.01-1.96). The association estimate for human epidermal growth factor 2- positive BCa was also positive (RR=1.21, 95% CI: 0.52-2.82), but the confidence interval was wide and crossed the null. Our meta-analysis confirms a modest positive association between DM and BCa risk. In addition, our results suggest that the DM and BCa association may be modified by menopausal status, and DM may be differentially associated with BCa subtypes defined by receptor status. Additional studies are warranted to investigate the mechanisms underlying these associations and any influence of DM on BCa receptor expression.