ER-Negative Breast Cancer Risk Linked with Blood Levels of Two PFAS Forever Chemicals

Per- and polyfluoroalkyl substances (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.

The results of a study carried out by National Institutes of Health researchers has now found that women with higher blood levels of two common PFAS, perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), were more likely to develop estrogen receptor-negative (ER-negative) breast cancer. ER-negative tumors lack receptors that allow the hormone estrogen to help cancer cells grow. There was no clear association observed between the two chemicals and breast cancer risk overall.

“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,” said NIH Stadtman Investigator Alexandra White, PhD, who led the study. Although PFOA and PFOS compounds have been largely phased out and replaced with new PFAS compounds, most individuals have measurable levels of PFOA and PFOS in their bodies.

White is senior and corresponding author of the researchers’ published paper in Journal of Clinical Oncology, titled “Per- and Polyfluoroalkyl Substance Exposure and Breast Cancer Incidence in the Sister Study,” in which they concluded “Given the widespread exposure to PFAS and limited established risk factors for ER-negative tumors, these results have important public health implications.”

Breast cancer is the most common cancer among women, and incidence rates are rising in the U.S. and worldwide, the authors stated. Established breast cancer risk factors, such as reproductive history, exogenous hormone use and lifestyle factors, have been more strongly linked with hormone receptor–positive than with hormone receptor–negative tumors.

Scientists know less about what raises the risk of ER-negative breast cancer. “Evidence suggests that hormone receptor–negative tumors might have distinct etiologies, yet their risk factors remain largely unknown,” the researchers wrote. “This knowledge gap is concerning as hormone receptor–negative tumors are more aggressive with poorer clinical outcomes.”

The newly reported research drew on the Sister Study, which is led by NIH’s National Institute of Environmental Health Sciences (NIEHS). This larger study enrolled 50,884 women ages 35–74 in the U.S. and Puerto Rico from 2003 to 2009. None had breast cancer when they joined the Sister Study, but each had a full or half-sister who had been previously diagnosed with breast cancer.

For their PFAS study White and team included 1,609 women who developed breast cancer and a comparison sample of 2,269 women. “We oversampled estrogen receptor (ER)–negative cases (324 ER-negative, 1,120 ER-positive) to improve statistical power,” they explained in their paper. “To our knowledge, this is the largest study to date of PFAS exposure and breast cancer incidence, particularly for ER–tumors.”

The investigators measured 17 PFAS in blood, collected years before women were diagnosed with cancer. “Seventeen PFASs were quantified in prediagnostic plasma using liquid chromatography-high-resolution mass spectrometry,” they noted. The results of their studies showed that women in the group with the highest PFOA levels had a 67% higher rate of ER-negative breast cancer than those in the lowest group. For PFOS, the rate was 93% higher—nearly twice as high. These numbers describe relative differences between groups, not an individual woman’s chance of getting breast cancer.

The team also carried out meta-analyses, including the current and prior prospective studies, which showed consistent positive associations of PFOA and PFOS with ER-negative breast cancer. “Our meta-analyses of studies with prediagnostic blood measurements further support a positive association between PFOA and ER-tumors, with suggestive evidence for PFOS and ER-tumors,” they stated.

“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 involved tumors without hormone receptors, the authors suggest that PFAS may affect cancer risk through other non-hormonal biologic pathways. Possible pathways include changes in gene activity or immune system. The reported study did not test those potential explanations.

The authors say future studies should evaluate people with higher PFAS exposure and in groups more affected by ER-negative breast cancer. “More research is needed, particularly evaluating the risk of breast cancer associated with newer replacement PFAS chemicals,” White added.

In their paper the authors concluded, “Future studies should prioritize investigating these associations in populations with higher PFAS exposure and a greater burden of hormone receptor–negative breast cancer to better inform targeted prevention efforts. Research is also needed to assess the carcinogenic potential of newer PFAS replacement chemicals, which remain poorly characterized.”

Department of Health and Human Services (HHS) Secretary Robert F. Kennedy, Jr., commented, “Women deserve clear answers about how chemicals in their environment may affect their health. This NIH study links two forever chemicals to a higher risk of ER-negative breast cancer and demands further investigation. Under President Trump’s leadership, we will pursue the evidence, confront environmental health risks, and give women the information they need to protect their health.”

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