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.
