How Metformin Influences Breast Cancer Risk

Study examines the complex relationship between type 2 diabetes, metformin use, and breast cancer subtype.  

Previous studies in women with type 2 diabetes found a 20% higher risk of breast cancer, which may be due to the activation of insulin and insulin-like growth factors on the breast tissue or through alterations in sex hormones.  The mechanism of action of metformin may provide a benefit in breast cancer reduction by improving insulin sensitivity. In addition, metformin may inhibit cancer cell proliferation and invasion and enhance resistance to chemotherapy. However, little evidence is currently available regarding the association between metformin use and breast cancer risk. As the first-line treatment option according to both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinology (AACE), the prevalent use of metformin may reveal a relationship between its use and the variable risk of developing different forms of breast cancer. 

Data were obtained from the Sister Study, which included 50,884 women, 35 – 74 years of age, with type 2 diabetes and no prior history of breast cancer. All women included in the study had a sister or half-sister with a breast cancer diagnosis. The study investigators further identified 44,541 women eligible for participation in the prospective cohort study. Statistical analysis was conducted using multivariable cox proportional hazard models to estimate hazard ratio and 95% confidence intervals. There were 3,227 (7.2%) women with prevalent type 2 diabetes and 2,389 (5.3%) women with incident type 2 diabetes. Of the women with type 2 diabetes, 3,386 (61%) had been treated with metformin therapy, either monotherapy or combination therapy (74% in the prevalent group and 42% in the incident group). Furthermore, women with a type 2 diabetes diagnosis had higher body mass indexes (BMI), were older, and had less physical activity and more deficient diets.  

This study found that over 8.6 years, 2,678 incidences of breast cancer were identified in women with and without type 2 diabetes. Although there was no overall relationship between breast cancer risk and type 2 diabetes, there was an increased risk of triple-negative breast cancer (HR 0.99, 95% CI 0.87–1.13) in women with type 2 diabetes. However, an inverse association was found between the duration of diabetes (15 years or longer) and estrogen-receptor-positive (ER+) breast cancer (HR 0.61, 95% CI 0.37-1.03). Compared to women without type 2 diabetes, those who used metformin and had type 2 diabetes did not report an increased breast cancer risk. However, use of metformin and a type 2 diabetes diagnosis was associated with a decrease in ER+ breast cancer (HR 0.86, 95% CI 0.70–1.05), most notably in women with the use of 10 years or more (HR 0.62, 95% CI 0.38–1.01), and an increase in ER– breast cancer (HR 1.25, 95% CI 0.84–1.88) and triple-negative breast cancer (HR 1.74, 95% CI 1.06–2.83). Analysis of incident type 2 diabetes showed that women on antihyperglycemic therapy other than metformin had a higher risk of overall breast cancer (HR 2.04, 95% CI 1.17-3.57) and ER+ breast cancer incidence (HR 2.62, 95% CI 1.46-4.70) when compared to women without a type 2 diabetes diagnosis.  

In conclusion, this study found that breast cancer incidence varies by hormone receptor status in women with type 2 diabetes using metformin. This study’s strengths were its large sample size, long duration of follow-up, and robust baseline characteristics analysis. This study’s limitations include the researchers’ inability to assess glycemic control and breast cancer risk, impacting this study’s results. Nevertheless, the positive association with ER- breast cancer and the inverse relationship with ER+ breast cancer may suggest that metformin use prevents estrogen receptors’ expression. However, because of the increase in ER- breast cancer incidence, there may be an underlying increased risk of the ER- subtype in women with a type 2 diabetes diagnosis.  Altogether, this study highlights the potential benefit that metformin therapy offers in breast cancer risk.  

Practice Pearls 

• Long-term metformin use may have a protective effect on breast cancer risk in women with type 2 diabetes.  
• Other antihyperglycemic medications may be associated with an increased risk of breast cancer.  
• Breast cancer subtype may affect the relationship between type 2 diabetes, metformin use, and the incidence of developing breast cancer.  

Park, Y-M M et al. “A prospective study of type 2 diabetes, metformin use, and risk of breast cancer.” Annals of oncology: official journal of the European Society for Medical Oncology vol. 32,3 (2021): 351-359.  

Roshan, Mohsin Hk et al. “Metformin as an adjuvant in breast cancer treatment.” SAGE open medicine vol. 7 2050312119865114. July 16. 2019 

Wu JW, Azoulay L, Majdan A, Boivin JF, Pollak M, Suissa S. Long-term use of long-acting insulin analogs and breast cancer incidence in women with type 2 diabetes. J Clin Oncol. 2017;35:3647-3653.  

Macrina Ghali, PharmD Candidate 2021, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences