• Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
• Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
• Integrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

Per- and polyfluoroalkyl substances (PFAS) are highly persistent endocrine-disrupting chemicals that may contribute to breast cancer development; however, epidemiologic evidence is limited. We investigated associations between prediagnostic serum levels of perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) and postmenopausal breast cancer risk, overall and by hormone receptor status, in a nested case-control study of 621 cases and 621 matched controls in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. PFOS and PFOA levels were determined based on serum metabolomic profiling performed using ultra-performance liquid chromatography-tandem mass spectrometry. We used multivariable conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between each PFAS and breast cancer risk, overall, by estrogen receptor (ER) or progesterone receptor (PR) status, and by joint ER/PR status. We found little evidence of association between PFOS or PFOA and breast cancer risk overall. However, in subtype-specific analyses, we observed statistically significant increased risks of ER+, PR+, and ER+/PR+ tumors for the third vs. lowest quartile of serum PFOS (ORs [95% CIs]=1.59 [1.01-2.50], 2.34 [1.29-4.23], and 2.19 [1.21-3.98], respectively) and elevated but non-statistically significant ORs for the fourth quartile. Conversely, for PFOA, modest positive associations with ER-, PR-, ER+/PR-, and ER-/PR- tumors were generally seen in the upper quartiles. Our findings contribute evidence supporting positive associations between serum PFOS and hormone receptor-positive tumors, and possibly between PFOA and receptor-negative tumors. Future prospective studies incorporating tumor hormone receptor status are needed to better understand the role of PFAS in breast cancer etiology. This article is protected by copyright. All rights reserved.