Long-Term Metformin Use Linked to Fewer ER+ Breast Cancers

Mitchel L. Zoler, PhD

February 03, 2021

Researchers say women with type 2 diabetes treated with metformin had a reduced rate of the most common type of breast cancer, estrogen receptor (ER)-positive tumors, during a median follow-up of nearly 9 years in a prospective study of more than 44,000 individuals in the United States.

Conversely, the results also showed higher rates of ER-negative and triple-negative breast cancer among women with type 2 diabetes who received metformin, although case numbers were small.

"Our conclusion that having type 2 diabetes increases the risk of developing breast cancer but taking metformin may protect against developing ER-positive breast cancer — but not other types of breast cancer — is biologically plausible and supported by our results even though some [endpoints] are not statistically significant," senior author Dale P. Sandler, PhD, chief of the epidemiology branch, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, North Carolina, said in an interview.

"Among our findings that are not statistically significant are several that helped us get a better picture of the relationships between type 2 diabetes, metformin treatment, and breast cancer risk," Sandler added.

The results were published online January 28 in Annals of Oncology by Yong-Moon Mark Park, MD, PhD, now an epidemiologist at the University of Arkansas for Medical Sciences in Little Rock, and colleagues.

Sara P. Cate, MD, a breast cancer surgeon at Mount Sinai Medical Center in New York City, who was not involved with the study, said: "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."

A Tangled Web...With No Clear Conclusions Yet

But in an accompanying editorial, Ana E. Lohmann, MD, PhD, and Pamela J. Goodwin, MD, say that while this is "a large, well-designed prospective cohort study," it tells a complicated story.

"The report by Park 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 observe.

The "largely negative" results of the new study perhaps in part occurred because the cohort included only 277 women with type 2 diabetes diagnosed with incident breast cancer, note Lohmann, of London Health Sciences Centre, University of Western Ontario, and Goodwin, of Mount Sinai Hospital, Toronto, Ontario, Canada.

"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," they write.

Examination of the effects of metformin in studies such as the Canadian Cancer Trial Group MA.32, a phase 3 trial of over 3500 women with hormone receptor-positive early stage breast cancer who are being randomized to metformin or placebo for up to 5 years in addition to standard adjuvant therapy, will provide further insights, they observe. The trial is slated to be completed in February 2022.

Study Followed Women Whose Sisters Had Breast Cancer 

The new data come from the Sister Study, which followed more than 50,000 women without a history of breast cancer who had sisters or half-sisters with a breast cancer diagnosis. The study, run by the NIEHS, enrolled women 35-74 years old from all 50 US states and Puerto Rico in 2003-2009.

The current analysis excluded women with a history of any other type of cancer, missing data about diabetes, or an uncertain breast cancer diagnosis during the study, which left 44,541 available for study. At entry, 7% of the women had type 2 diabetes, and another 5% developed new-onset type 2 diabetes during follow-up.

Among those with diabetes, 61% received treatment with metformin either alone or with other antidiabetic drugs.

During a median follow-up of 8.6 years, 2678 women received a diagnosis of primary breast cancer, either invasive or ductal carcinoma in situ.

In a series of multivariate analyses that adjusted for numerous potential confounders, the authors found that, overall, no association existed between diabetes and breast cancer incidence, with a hazard ratio of 0.99 compared to women without diabetes.

But, said Sandler, "there is a strong biological rationale to hypothesize that type 2 diabetes increases the risk for breast cancer, and results from earlier studies support this."

Association of Metformin and Breast Cancer

Women with type 2 diabetes who received metformin had a 14% lower rate of ER-positive breast cancer compared with women with diabetes not taking metformin, a nonsignificant association.

Among women taking metformin for at least 10 years, the associated reduction in ER-positive breast cancer compared with those who did not take it was 38%, a difference that just missed significance, with a 95% confidence interval of 0.38-1.01.

In contrast, cases of ER-negative and triple-negative breast cancers increased in the women with diabetes taking metformin. The hazard ratio for ER-negative tumors showed a nonsignificant 25% relative increase in women taking metformin and a significant 74% increase in triple-negative cancers.

The editorialists note, however, that "the number of patients who were found to have triple-negative breast cancer was small...[so] we cannot draw any practice-changing conclusions from it."

In conclusion, Park and colleagues reiterate: "Our analysis is consistent with a potential protective effect of metformin and suggests that long-term use of metformin may reduce breast cancer risk associated with type 2 diabetes."

The study received no commercial funding. Sandler, Park, Lohmann, Goodwin, and Cate have reported no relevant financial relationships.

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