Metformin May Affect Breast Cancer Risk In Women With Type 2 Diabetes

Women who took metformin to treat type 2 diabetes for a decade or more were at reduced risk of developing estrogen receptor positive breast cancer compared to women without diabetes, a new study finds.

In an analysis of data from nearly 45,000 women, researchers found that among those with type 2 diabetes there was a nearly 40% reduction in the risk of developing ER-positive breast cancer, according to the report published in the Annals of Oncology.

"Overall, women with type 2 diabetes for 15 or more years were less likely to be diagnosed with ER-positive breast cancer," study coauthor Dale Sandler, chief of the epidemiology branch at the U.S. National Institute of Environmental Sciences, said in a statement.

"We think this is most likely to be because of long term use of metformin," Sandler added. "We found that compared to non-diabetic women, the risk of ER-positive breast cancer was reduced by 38% among women with type 2 diabetes who had used metformin for 10 years or more. Taken together, these findings suggest that having type 2 diabetes may increase the risk of developing ER-positive breast cancer, the most common type of breast cancer."

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The authors did not respond to a request for comment.

Sandler and his colleagues also found that compared to women who did not have diabetes, those who had the disease and treated it with metformin had a higher risk of developing ER-negative (hazard ratio 1.25) and triple negative (HR 1.74) breast cancer.

"We can't say for sure if this increased risk of triple negative 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," Sandler said. "Since there are no mechanistic data supporting a causal effect of metformin, the former interpretation seems more likely."

To explore the impact of diabetes and metformin on breast cancer risk, Sandler and his colleagues turned to the Sister Study, which includes women with no previous diagnosis of breast cancer at baseline, but who had sisters or half-sisters who had been diagnosed with breast cancer. The women were aged 35 to 74 when they enrolled in the Sister Study.

The analysis focused on 44,451 participants, of whom 3,227 (7.2%) had prevalent diabetes and 2,389 (5.3%) had incident diabetes. Among the women with diabetes, 61% (3,386) were ever treated with metformin monotherapy or combination therapy.

During a median follow-up of 8.6 years, 2,678 incident primary cancer cases were identified. Among those without diabetes, there were 1,800 cases of ER-positive breast cancer, 303 cases of ER-negative breast cancer and 156 cases of triple negative breast cancer. Among those with diabetes, there were 184 cases of ER-positive breast cancer, 107 cases of ER-negative breast cancer, and 25 cases of triple negative breast cancer.

What is really interesting about the study is that while the relationship between type 2 diabetes and breast cancer was null, it looked like metformin, which was being taken by 60% to 70% of the women, might have been a confounder, said Dr. Adam Brufsky, a professor of medicine at the University of Pittsburgh School of Medicine, co-director of the Comprehensive Breast Cancer Center and associate chief of the division of hematology-oncology at the UPMC Hillman Cancer Center.

It's not known how metformin might protect against ER-positive breast cancer, said Dr. Brufsky, who was not involved in the study. Studies in cell culture and in animals have shown the medication has an impact on the immune system, he added.

"My personal bias, and this is rank speculation, is that there is something going on in the tumor microenvironment," Dr. Brufsky said.

The new study is "very interesting," said Dr. Sarah P. Cate, an assistant professor of surgery at the Icahn School of Medicine at Mount Sinai and director of the Special Surveillance and Breast Program at The Blavatnik Family - Chelsea Medical Center at Mount Sinai in New York City.

It "fits well in the context of the investigation of metformin and breast cancer risk," Dr. Cate said in an email. "The number of patients who were found to have TNBC was small, so we cannot draw any practice changing conclusions from it. Certainly, metformin helps with weight loss, which is linked with estrogen driven breast cancers, so this may explain why fewer patients on metformin got this type of breast cancer."

"There is currently a breast cancer prevention trial from the Alliance Cooperative Group looking at breast density and metformin, in high risk patients," Dr. Cate said. "Although the trial is still accruing, this is another area of study in the prevention of breast cancer. Metformin is likely to be in the cancer arena for a long time."

—Linda Carroll

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