Abstract
Breast cancer is the most prevalent cancer and the leading cause of cancer-related death among women worldwide. Type 2 diabetes–associated metabolic traits such as hyperglycemia, hyperinsulinemia, inflammation, oxidative stress, and obesity are well-known risk factors for breast cancer. The insulin sensitizer metformin, one of the most prescribed oral antidiabetic drugs, has been suggested to function as an antitumoral agent, based on epidemiological and retrospective clinical data as well as preclinical studies showing an antiproliferative effect in cultured breast cancer cells and animal models. These benefits provided a strong rationale to study the effects of metformin in routine clinical care of breast cancer patients. However, the initial enthusiasm was tempered after disappointing results in randomized controlled trials, particularly in the metastatic setting. Here, we revisit the current state of the art of metformin mechanisms of action, critically review past and current metformin-based clinical trials, and briefly discuss future perspectives on how to incorporate metformin into the oncologist’s armamentarium for the prevention and treatment of breast cancer.
Highlights
Breast cancer is the most frequent neoplasia worldwide
These findings suggest an ER status-dependent link between type 2 diabetes (T2D) and breast cancer and that the associations between T2D and ER-positive breast cancer might be reduced by long-term usage of metformin [61]
Beyond the common “lost in translation” obstacles that characterize a successful transfer from the bench to clinical, bedside implementation of numerous anticancer candidates, it is becoming clearer that future large-scale trials should incorporate early dynamic monitoring of distinct metabolic adaptations to metformin
Summary
Breast cancer is the most frequent neoplasia worldwide. In 2020, over 2.3 million new cases were diagnosed, and there were 7.8 million living women with a breast cancer history in the previous five years [1]. T2D increases the incidence of breast cancer by 10–20% [6]. Since 15% of breast cancer patients suffer from T2D [7], it is not surprising that the interlinking metabolic pathways and the repurposing potential of antidiabetic drugs are steadily gaining momentum in cancer research. Metformin is a widely prescribed oral antidiabetic medication. This biguanide is considered a first-line drug for the management of T2D [12]. Metformin lowers blood glucose levels by reducing hepatic gluconeogenesis, improving peripheral insulin sensibility, and enhancing glucose uptake. In 2005, Scottish researchers found that T2D patients taking metformin seemed to have a lower cancer risk, indicating, for the first time, that metformin could have antitumoral properties [20]. The aim of this review is to revisit the current state of the art of metformin mechanisms of action, critically review past and current metformin-based clinical trials, and briefly discuss future perspectives on incorporating metformin for the prevention and treatment of breast cancer
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