Bethesda, MD—A confounder might be responsible for the lack of an obvious link between type 2 diabetes and higher risk of developing certain types of breast cancer, according to new research.

Affecting the results, according to a report in Annals of Oncology, is that most of the 44,541 women in a study finding no association between type 2 diabetes (T2D) and developing breast cancer overall were taking metformin.

National Institutes of Health researchers point out that metformin, the most commonly prescribed drug for T2D, might help to reduce the risk of developing estrogen-positive (ER-positive) breast cancer. ER-positive breast cancer, which has receptors on cell surfaces for the hormone estrogen, makes up about 80% of breast cancer diagnosed in the United States, the authors explain.

The study, which had an average of more than 8 years of follow-up, reveals that T2D was associated with a 40% increased risk of triple negative breast cancer (TNBC), which lacks receptors for the hormones estrogen and progesterone and the HER2 protein.

That conclusion was reached in comparison with women who did not have diabetes. At the same time, a small, 8%, decrease was detected in risk for ER-positive breast cancer, although the results were not considered statistically significant.

Grouping women by diabetes treatment, researchers determined that T2D treated with metformin was associated with a 14% decreased risk of developing ER-positive breast cancer but a 25% increased risk of developing ER-negative breast cancer, when compared to nondiabetic women, although not statistically significant.

On the other hand, the report found a statistically significant 74% increased risk of developing TNBC among those treated with metformin.

“We also found that having type 2 diabetes for 15 years or more seemed to be associated with a 39% reduced risk of ER-positive breast cancer, and we think this is most likely to be because of long-term use of metformin,” explained lead investigator Dale Sandler, PhD, chief of the Epidemiology Branch at the NIH’s National Institute of Environmental Health Sciences (NIEHS). “We found that, compared to non-diabetic women, the risk of developing ER-positive breast cancer was reduced by 38% among women with type 2 diabetes who had used metformin for ten years or more.

“Taken together, these findings suggest that having type 2 diabetes 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,” Dr. Sandler added.

Yet, he continued, “Metformin did not appear to protect against ER-negative or triple negative breast cancer. We can’t say for sure if the increased risk of triple negative breast cancer is because metformin doesn’t protect women against the negative effects of having type 2 diabetes or because metformin use can cause triple negative breast cancer. Since there are no mechanistic data supporting a causal effect of metformin, the former interpretation seems more likely.”

The current study analyzed data from the Sister Study, which enrolled U.S. women between 2003 and 2009 using follow-up data through to the end of 2017. Researchers sought to resolve conflicting evidence of T2D on risk of breast cancer. At the study’s enrollment, participants ranged from age 35 years to age 74 years and had no previous diagnosis of breast cancer, although they were sisters or half-sisters of women diagnosed with breast cancer. The women completed annual health updates and follow-up questionnaires every 3 years.

Researchers posit that metformin might reduce breast cancer risk by improving insulin sensitivity, correcting high insulin levels, which can activate cell signals involved in cancer. They also say it might activate adenosine monophosphate-activated protein kinase (AMPK), an enzyme that inhibits a pathway involved in the proliferation of cancer cells and/or reduce the risk of ER-positive breast cancer by inhibiting estrogen receptors.

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