A nested case-control study of perfluoroalkyl and polyfluoroalkyl substances (PFAS) and breast cancer risk in the Multiethnic Cohort

ABSTRACT. Per- and poly-fluoroalkyl substances (PFAS) are a class of persistent, ubiquitous, and endocrine disrupting synthetic chemicals commonly used in consumer products and industrial processes. While they are detected in >97% of the US population, residents of low-income communities and racial-ethnic minorities show greater concentrations of many PFAS substances. Experimental and animal data support PFAS as potential mammary carcinogens. Epidemiologic data have been mixed, but results from a limited number of prospective studies among primarily European white women suggest that several PFAS compounds are associated with increased risk of breast cancer and that metabolic alterations linked to PFAS might underlie the associations. However, no prospective data from diverse racial-ethnic populations are available. The primary goal of this study is to investigate whether higher PFAS exposure increases the risk of breast cancer in a diverse US population and whether integration of PFAS levels, metabolic alterations, genetic predisposition, and epidemiologic risk factors of breast cancer identifies subgroups of women at increased risk. We propose the first and largest prospective multi-ethnic study to examine PFAS as novel risk factors of breast cancer. Leveraging the pre- diagnostic blood samples and comprehensive data on breast cancer risk factors and genomics in the Multiethnic Cohort (MEC), an ethnically diverse prospective cohort in California and Hawaii, we propose a nested case- control study of 1,600 female invasive breast cancer patients and 1,600 matched control women (12% African American, 16% Latina, 11% Native Hawaiian, 40% Asian American, and 21% White). We will utilize state-of-the- art laboratory technologies based on untargeted liquid chromatography with high resolution mass spectrometry to measure plasma PFAS and metabolome profiles, and combine these comprehensive measurements with innovative statistical methods to evaluate the integrated associations of PFAS, metabolome, genetics, risk factors, and breast cancer risk. Our specific aims are: (1) To examine the association between pre-diagnostic plasma levels of PFAS and risk of invasive breast cancer; (1a) Evaluate the associations of individual PFAS and PFAS mixture in pre-diagnostic plasma samples with breast cancer risk; (1b) Examine whether genetic predisposition determined by a polygenic risk score (PRS) modifies the association of individual PFAS and the PFAS mixture with breast cancer risk; (2) To examine the association between pre-diagnostic metabolomic profiles (a) with PFAS exposures and (b) with invasive breast cancer risk; (3) To integrate PFAS concentrations, metabolomic measures, PRS, and other breast cancer risk factors to identify subgroups of women at increased risk for breast cancer using an innovative latent variable analysis. This research relies on a multidisciplinary team of internationally-recognized investigators with expertise in environmental and cancer epidemiology, and state- of-the-art high-resolution metabolomics, genomics and statistical methods. Findings have the potential to inform precision medicine approaches for breast cancer prevention for diverse populations, and to impact policy change.