Per- and Polyfluoroalkyl Substance Exposure and Breast Cancer Incidence in the Sister Study

Purpose Although mechanistic evidence suggests that some per- and polyfluoroalkyl substances (PFASs) may be carcinogenic, epidemiologic findings for PFAS and breast cancer remain inconsistent, partly because of differing study designs and limited evaluation by hormone receptor status. Methods We conducted a case-cohort study within the Sister Study that included 1,609 breast cancer cases and 2,269 subcohort participants. We oversampled estrogen receptor (ER)–negative cases (324 ER-negative, 1,120 ER-positive) to improve statistical power. Seventeen PFASs were quantified in prediagnostic plasma using liquid chromatography-high-resolution mass spectrometry. Sampling-weighted Cox models were used to estimate associations with overall breast cancer incidence and by hormone receptor status, adjusting for confounders and coexposures. We conducted a meta-analysis of seven studies with prediagnostic blood PFAS measurements. Results We observed associations between certain PFAS and ER-negative tumors. Positive associations were observed for perfluoro-n-octanoic acid (PFOA; hazard ratio [HR] Q4 v Q1 , 1.67 [95% CI, 1.10 to 2.53], P trend = .09), perfluorooctane-1-sulfonic acid (PFOS; HR Q4 v Q1 , 1.93 [95% CI, 1.15 to 3.22], P trend = .01), and potentially n-methylperfluoro-1-octanesulfonamidoacetic acid (N-MeFOSAA; HR Q4 v Q1 , 1.42 [95% CI, 0.99 to 2.04], P trend = .12). By contrast, perfluoro-n-tridecanoic acid was inversely associated with ER-negative tumors (PFTrDA; HR Q4 v Q1 , 0.63 [95% CI, 0.41 to 0.97], P trend = .05). Perfluorooctane sulfonamide (PFOSA), which was infrequently detected (6.9%), was positively associated with ER+ tumors (HR detectable v nondetectable , 1.36 [95% CI, 1.03 to 1.81]). The meta-analysis further supported associations for both PFOA (relative risk [RR], 1.30 [95% CI, 1.05 to 1.62]) and PFOS with ER-negative breast cancer (RR, 1.20 [95% CI, 0.91 to 1.58]). Conclusion Findings from this large prospective study, together with meta-analyses, suggest that PFOA and PFOS may increase ER-negative breast cancer risk. Given the widespread exposure to PFAS and limited established risk factors for ER-negative tumors, these results have important public health implications.