Metformin, a drug primarily prescribed to manage type 2 diabetes, has increasingly captured the attention of oncologists and cancer researchers seeking innovative approaches to breast cancer treatment. Known for its safety profile and widely understood mechanisms, metformin’s potential anti-cancer properties have sparked numerous clinical investigations worldwide. Despite decades of research into breast cancer therapeutics, a comprehensive understanding of metformin’s role, especially across the varied phenotypes of breast cancer, has been lacking—until now.
This gap is precisely what a recent scoping review published in BMC Cancer aims to address. Conducted by an international team of researchers, the study consolidates findings from randomized clinical trials (RCTs) that assessed metformin’s effects on breast cancer patients. By meticulously synthesizing data from 40 separate RCTs encompassing over 5,600 participants, this review offers a panoramic view of the current evidence base and importantly underscores gaps demanding future inquiry.
Breast cancer is a heterogeneous disease with multiple phenotypes, including hormone receptor-positive, HER2-positive, and triple-negative subtypes, each responding differently to existing treatments. This heterogeneity complicates the translation of therapeutic findings across patient groups, often leading to generalized conclusions that fail to capture treatment nuances. The reviewed RCTs predominantly neglected to stratify outcomes by breast cancer phenotype, a critical oversight that limits clinical applicability—the review thus insists on a paradigm shift emphasizing phenotype-specific reporting.
Intriguingly, within the vast dataset, a salient finding emerged from subgroup analyses of a large-scale RCT suggesting that metformin may confer tangible benefits for patients with HER2-positive breast cancer. These benefits included improvements in overall survival and disease-free survival rates, contrasting sharply with the absence of statistically significant effects among other phenotypes. Although promising, this observation is preliminary and requires rigorous validation through additional focused trials.
Mechanistically, metformin’s anti-cancer effects are thought to arise from multiple pathways. Beyond its glucose-lowering actions, metformin activates AMP-activated protein kinase (AMPK), a cellular energy sensor, which in turn inhibits the mammalian target of rapamycin (mTOR) pathway—a central regulator of cell growth and proliferation often dysregulated in tumors. Furthermore, metformin decreases insulin and insulin-like growth factor levels, hormones implicated in tumor progression. The reviewed trials, however, have rarely delved into these biochemical pathways with sufficient granularity, highlighting an urgent need for mechanistic explorations intertwined with clinical assessments.
The review also points out the methodological challenges inherent in the current body of research. Variability in dosing regimens, treatment durations, and concomitant therapies across trials complicates cross-study comparisons. Some trials combined metformin with chemotherapy or hormonal therapies, while others investigated metformin as a monotherapy. Such heterogeneity underscores the necessity for standardized protocols to unravel true drug efficacy and optimal therapeutic windows.
Another compelling recommendation from the authors pertains to the retrospective determination of breast cancer phenotypes in existing trial datasets. This strategy could enable powerful individual participant data (IPD) meta-analyses that leverage patient-level information to discern nuanced effects obscured in aggregate data. IPD meta-analyses can illuminate subgroup-specific benefits and identify predictors of treatment response, propelling personalized oncology forward in a cost-effective and time-efficient manner.
The review’s call for journals and funding agencies to mandate comprehensive phenotype-based result reporting is a clarion for transparency and scientific rigor. Such policies would foster richer datasets, enabling clinicians and researchers to tailor therapies to the biological intricacies of breast cancer subtypes, ultimately enhancing patient outcomes.
Despite the wealth of data accumulated, the authors caution against premature clinical adoption of metformin as a breast cancer treatment outside research contexts. The inconsistency in findings and the paucity of phenotype-specific evidence mandate cautious optimism. Future research must be designed with stratification at its core, integrating biomarker studies and exploring drug interactions in multi-modal treatment regimens.
This endeavor arrives at a pivotal moment as oncologists strive to repurpose established drugs with favorable safety profiles and affordability to address unmet clinical needs. Metformin exemplifies such a candidate, but unlocking its full potential hinges on overcoming current knowledge gaps and methodological shortcomings identified by this exhaustive review.
In addition to survival metrics, the diverse range of 107 distinct outcomes assessed across trials reflects an evolving understanding of what constitutes meaningful clinical benefit. Incorporating patient-reported outcomes, quality of life measures, and long-term adverse effects will provide a holistic appreciation of metformin’s therapeutic value.
Translational research avenues are particularly promising when coupled with this comprehensive scoping review. Preclinical models can explore metformin’s effects on cancer stem cells, tumor microenvironment modulation, and immune responses, guiding the design of future RCTs that are mechanistically informed and phenotype adaptive.
In summary, this scoping review by Araujo and colleagues crystallizes our current understanding of metformin’s role in breast cancer treatment, highlighting significant heterogeneity and urging focused investigations. While metformin’s promise in HER2-positive breast cancer offers a glimpse of potential breakthroughs, the overall field must pivot toward precision medicine approaches that respect tumor biology diversity. The next chapter in oncological therapeutics might very well include this decades-old diabetes drug—if science can navigate the complexities and deliver actionable insights from rigorous, phenotype-conscious trials.
Such a transition from tantalizing potential to clinical standard will require collaboration across disciplines, robust data-sharing frameworks, and sustained commitment from the research community. The findings encapsulated in this review provide a roadmap for these efforts—with the ultimate goal of enhancing survival, reducing morbidity, and improving the lives of millions affected by breast cancer globally.
Subject of Research: Use of metformin in the treatment of breast cancer, focusing on randomized clinical trials and consideration of breast cancer phenotypes.
Article Title: Metformin for the treatment of breast cancer: a scoping review of randomized clinical trials.
Article References:
Araujo, C.F.M., Nunes, L.C., Murta-Nascimento, C. et al. Metformin for the treatment of breast cancer: a scoping review of randomized clinical trials. BMC Cancer 25, 1352 (2025). https://doi.org/10.1186/s12885-025-14468-3
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