Disclosures: The researchers reported no relevant financial disclosures. Goodwin and Lohmann reported research funding from Epic Sciences.
February 01, 2021
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Type 2 diabetes, metformin use impact risk for breast cancer subtypes

Disclosures: The researchers reported no relevant financial disclosures. Goodwin and Lohmann reported research funding from Epic Sciences.
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Women with type 2 diabetes and those who used metformin did not demonstrate an overall increased risk for breast cancer, according to an analysis of the Sister Study published in Annals of Oncology.

However, type 2 diabetes appeared associated with an increased risk for triple-negative breast cancer. Also, use of metformin for type 2 diabetes appeared associated with increased risk for ER-negative breast cancer and triple-negative breast cancer, but decreased risk for ER-positive breast cancer, results showed.

Women with type 2 diabetes and those who used metformin did not demonstrate an overall increased risk for breast cancer.

“Our most important finding is that although type 2 diabetes may increase risk for developing breast cancer, the use of metformin appears to prevent this risk — at least for ER-positive breast cancer, which is the type of breast cancer that is most common,” Dale Sandler, PhD, chief of epidemiology at U.S. National Institute of Environmental Health Sciences (NIEHS) of NIH, and Yong-Moon Mark Park, MD, MS, PhD, a postdoctoral fellow at NIEHS during the conduct of the study and now an assistant professor in the department of epidemiology at University of Arkansas for Medical Sciences, said in a joint statement to Healio.

“It was somewhat surprising to see a significant association of metformin treatment for diabetes (compared with not having diabetes) with increased risk for triple-negative breast cancer because there is no mechanistic data to support this,” Sandler and Park continued. “More research is needed to understand this finding.”

Previous studies had reported an increased risk for breast cancer among women with type 2 diabetes, but there had been conflicting evidence on the association between metformin and breast cancer. Sandler, Park and colleagues sought to evaluate the association between type 2 diabetes and metformin use and incident breast cancer to “disentangle [the] potentially opposite effects,” they said.

The analysis included 44,541 women aged 35 to 74 years from the United States and Puerto Rico enrolled between 2003 and 2009 in the Sister Study, a cohort study of women who had no previous diagnosis of breast cancer but who were sisters or half-sisters of women with breast cancer. Researchers assessed the women for type 2 diabetes, antidiabetic medications and covariates at baseline and via follow-up questionnaires conducted every 3 years through Sept. 15, 2017, and they used medical records to confirm incident breast cancer cases.

Of the women, 7.2% (n = 3,227) had prevalent type 2 diabetes and 5.3% (n = 2,389) had incident type 2 diabetes, and 61% (n = 3,386) of these women had been treated with metformin.

During median follow-up of 8.6 years, 2,678 breast cancers were diagnosed at least 1 year after enrollment. Although researchers found no overall association of type 2 diabetes with breast cancer risk (HR = 0.99; 95% CI, 0.87-1.13), type 2 diabetes was associated with an increased risk for triple-negative breast cancer (HR = 1.4; 95% CI, 0.9-2.16).

Women with type 2 diabetes who received metformin also did not have an increased overall breast cancer risk compared with women without type 2 diabetes (HR = 0.98; 95% CI, 0.83-1.15). Additionally, type 2 diabetes with metformin use appeared associated with a decreased risk for ER-positive breast cancer (HR = 0.86; 95% CI, 0.7-1.15) and increased risk for both ER-negative (HR = 1.25; 95% CI, 0.84-1.88) and triple-negative (HR = 1.74; 95% CI, 1.06-2.83) breast cancer.

Moreover, the reduction in risk for ER-positive cancer appeared stronger with longer use (10 or more years) of metformin (HR = 0.62; 95% CI, 0.38-1.01).

“Although our study provides evidence that type 2 diabetes with metformin use may be associated with increased risk for developing ER-negative and triple-negative breast cancer, it is still not conclusive,” Sandler and Park said. “We can’t say for sure if the increased risk for 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.

“Because there are no mechanistic data supporting a causal effect of metformin, the former interpretation seems more likely,” they added.

Because women self-reported type 2 diabetes and medication use, researchers could not account for glucose control and type 2 diabetes progression or improvement, which could affect breast cancer risk, the researchers noted.

Also, Sandler and Park noted that some of their findings, especially those for triple-negative breast cancer, were based on a small number of cases.

“Thus, further studies are needed to provide a clinical practice guideline for women with type 2 diabetes to prevent ER-negative and triple-negative breast cancer,” they said.

However, additional studies may be challenging because metformin is usually the first line of treatment for type 2 diabetes, and there is a need for a larger sample size to examine breast cancer subgroup associations, according to an editorial accompanying the study by Ana Elisa Lohmann, MD, PhD, of the department of oncology at London Health Sciences Center and University of Western Ontario, and Pamela J. Goodwin, MD, MSc, FRCPC, of the department of medicine at Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital and University of Toronto.

“The report by Park [and colleagues] adds to the growing evidence linking type 2 diabetes and its treatment to breast cancer risk but definitive conclusions regarding these associations are not yet possible,” they wrote. “Clearly, this is an important area and additional research is needed to untangle the web of inter-related associations of type 2 diabetes, its treatment and breast cancer risk.”

References:

Lohmann AE and Goodwin PJ. Ann Oncol. 2021;doi:10.1016/j.annonc.2020.12.014.
Park Y-MM, et al. Ann Oncol. 2021;doi10.1016/j.annonc.2020.12.008
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For more information:

Yong-Moon “Mark” Park, MD, MS, PhD, can be reached at National Institute of Environmental Health Sciences, Mail Drop A3-05, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709; email: mark.park@nih.gov.

Dale Sandler, PhD, can be reached at Epidemiology Branch, National Institute of Environmental Health Sciences, PO Box 12233, Mail Drop A3-05, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709; email: sandler@niehs.nih.gov.