Metformin may prevent ER+ breast cancer

Use of metformin in patients with type 2 diabetes (T2D) appears to reduce their risk of developing oestrogen receptor (ER)-positive breast cancer, especially with long-term use, although there is no change in overall breast cancer risk — suggesting that the protective benefit of metformin may vary by hormone receptor status, according to the Sister Study.

During a median follow-up of 8.6 years, T2D was not associated with any significant change in overall breast cancer risk (adjusted hazard ratio [HR], 0.99, 95 percent confidence interval [CI], 0.87–1.13). [Ann Oncol 2021;32:351-359]

However, when stratified by specific breast cancer type, T2D was associated with a 40 percent higher risk of triple negative breast cancer (TNBC; HR, 1.40, 95 percent CI, 0.90–2.16) but an 8 percent lower risk of ER-positive breast cancer (HR, 0.92, 95 percent CI, 0.78–1.07), although both did not reach statistical significance.

When analysing the data by the type of antidiabetic treatment, T2D patients who took metformin had a 14 percent lower risk of developing ER-positive breast cancer (HR, 0.86, 95 percent CI, 0.70–1.05); but this risk became 12 percent greater in women who took medications other than metformin (HR, 1.20, 95 percent CI, 0.82–1.76), compared with the reference group who did not have T2D. 

In particular, the association between metformin use and decreased risk of ER-positive breast cancer was stronger with longer duration of metformin use (≥10 years; HR, 0.62, 95 percent CI, 0.38–1.01; p-trend=0.09).   

On the other hand, metformin use was associated with excess risk of developing ER-negative breast cancer (HR, 1.25; 95 percent CI, 0.84–1.88) and TNBC (HR, 1.74, 95 percent CI, 1.06–2.83), the latter which was significant, compared with the reference group without T2D.

“Taken together, these findings suggest that having T2D may increase the risk of developing breast cancer, but that taking metformin may protect against developing ER-positive breast cancer, the most common type of breast cancer,” concluded study principal investigator Professor Dale Sandler from the National Institute of Environmental Health Sciences, National Institutes of Health in Durham, North Carolina, US.

“Metformin did not appear to protect against ER-negative or TNBC. We can’t say for sure if the increased risk of TNBC is because metformin doesn’t protect women against the negative effects of having T2D or because metformin use can cause TNBC,” he added. “Since there are no mechanistic data supporting a causal effect of metformin, the former interpretation seems more likely.”

The current analysis of the Sister Study involved 44,541 women aged 35–74 who were never diagnosed with breast cancer at baseline, but were sisters or half-sisters of those who had been diagnosed with breast cancer.

“It’s important to note that some of our findings, especially for TNBC, were based on a small number of cases and those results need replication,” said lead author Dr Yong-Moon Mark Park, University of Arkansas for Medical Sciences, Little Rock, Arkansas, US.

Noting the small number of participants in the TNBC subgroup who used metformin (n=20), Drs Ana Lohmann  and Pamela Goodwin from the University of Western Ontario and the University of Toronto, Canada, respectively, commented that the significant association between metformin use and TNBC “may have reflected chance and/or uncontrolled bias and confounding.” [Ann Oncol 2021;32:285-286]

“[This study] adds to the growing evidence linking T2D and its treatment to breast cancer risk but definitive conclusions regarding these associations are not yet possible,” they wrote, suggesting the need for further studies with bigger sample size to validate these associations.