Higher blood concentrations of two common per- and polyfluoroalkyl substances (PFAS) were associated with an increased incidence of estrogen receptor (ER)-negative breast cancer among women participating in the Sister Study, according to research published by Chang et al in the Journal of Clinical Oncology.
PFAS are a large group of chemicals used in common consumer products. Often referred to as “forever chemicals,” PFAS do not break down easily in the environment and can remain in the body for years.
Study Details
The investigators conducted a case-cohort study within the Sister Study, a prospective cohort of 50,884 women aged 35 to 74 years who were free of breast cancer at enrollment but had a full or half-sister diagnosed with the disease. Participants were enrolled in the United States and Puerto Rico between 2003 and 2009. At baseline, investigators collected blood samples and information on sociodemographic characteristics, lifestyle, and breast cancer risk factors. Participants were subsequently followed for breast cancer diagnoses and other health outcomes.
For the present analysis, investigators initially identified 1,992 women who developed invasive breast cancer or ductal carcinoma in situ during follow-up and selected a stratified random subcohort of 2,328 women from the original Sister Study population. Black and Hispanic women were oversampled in the stratified random subcohort, and ER-negative breast cancer cases were oversampled to improve statistical power for subgroup analyses. After exclusions for quality-control issues and less than 2 years of follow-up, the analysis included 1,609 breast cancer cases and 2,269 subcohort participants, with 114 women represented in both groups.
The median follow-up was 5.9 years for breast cancer cases and 9.7 years for subcohort participants. Median age at enrollment was 57.2 and 55.6 years, respectively.
The investigators looked at risk associations by hormone receptor status and examined the effects of PFAS both as single chemicals as well as in a mixture with other PFAS. Seventeen PFAS were identified and quantified in blood samples.
The investigators also conducted a meta-analysis of previous studies that had prediagnostic blood samples which made evaluating PFAS exposure and breast cancer risk possible. Their latest meta-analysis builds on an earlier one and was expanded to capture additional publications from February 2023 to November 2025.
Key Findings
PFAS concentrations were similar between cases and subcohort participants. PFAS concentrations were generally higher among participants who were older, postmenopausal at the time they joined the study, or for those who were born before 1945.
There were negligible associations between 15 out of 17 individual PFAS and overall breast cancer incidence.
Perfluorooctanesulfonamide (PFOSA) showed a suggestive association with increased overall breast cancer incidence among participants with detectable vs nondetectable concentrations (HR = 1.29; 95% CI = 0.99–1.67), although the compound was detected in only 6.9% of subcohort participants. Perfluorodecanoic acid (PFDA) showed a suggestive positive association, with a 17% higher risk for each natural log-unit increase.
Compared with women in the lowest exposure quartile, those in the highest quartile had a 67% higher relative hazard of ER-negative breast cancer for PFOA and a 93% higher relative hazard for PFOS. No corresponding associations were observed for ER-positive tumors. In the meta-analysis, the association with ER-negative breast cancer was supported for PFOA (RR = 1.30; 95% CI = 1.05–1.62), whereas the association for PFOS was positive but less conclusive (RR = 1.20; 95% CI = 0.91–1.58).
Associations with progesterone receptor (PR)-positive tumors and tumors classified as ER-positive and/or PR-positive were generally negligible, with the exception of positive associations involving PFOSA.
In the meta-analysis, PFDA showed an elevated but statistically uncertain association with overall breast cancer incidence (RR = 1.35; 95% CI = 0.84–2.19). PFOA and PFOS showed no clear associations with overall breast cancer incidence.
ER-negative breast cancers lack estrogen receptors and therefore do not depend on estrogen receptor signaling for their growth. These tumors tend to be more aggressive and are associated with poorer clinical outcomes than ER-positive breast cancers.
“Our findings, which we confirmed using a meta-analysis of prior research, indicate that certain legacy PFAS, including PFOA and PFOS, are associated with a higher risk of ER-negative breast cancer, a more aggressive tumor type with few known risk factors,” explained NIH Stadtman Investigator Alexandra White, PhD, who led the study.
“These findings matter for women’s health broadly,” said first author Che-Jung Chang, PhD, a former research fellow at NIH and a current researcher at DLH, a scientific research organization. “Although PFAS are persistent in the environment and in our bodies, exposure to them is still potentially modifiable, meaning people can take steps to reduce their exposure, and these findings could open new avenues for prevention.”
Because the strongest associations generally involved hormone receptor–negative tumors, the authors suggest that PFAS may affect cancer risk through nonhormonal biologic pathways. Possible mechanisms include epigenetic alterations and immunosuppression. However, this study did not test those explanations. The authors say future studies should evaluate people with higher PFAS exposure and in groups more affected by ER-negative breast cancer.
Although most individuals have measurable levels of PFOA and PFOS in their bodies, these compounds have been largely phased out and replaced with new PFAS compounds. “More research is needed, particularly evaluating the risk of breast cancer associated with newer replacement PFAS chemicals,” Dr. White said.
The investigators noted that the study's findings may not be generalizable to all women because participants had a family history of breast cancer. Some subgroup analyses were also limited by small sample sizes. Although the prospective design and use of prediagnostic blood samples strengthened the analysis, the observational findings do not establish a causal relationship between PFAS exposure and breast cancer.
Disclosure: This research was supported by NIEHS grants: Z01ES044005; Z1AES103332; and R01ES032831. For full disclosures of the study authors, visit ascopubs.org.
