Metformin Shows Survival Benefit in Patients With HER2-Positive Breast Cancer

Metformin, a widely prescribed antidiabetic medication, is gaining attention with promising implications for breast cancer prevention and treatment. A review of randomized clinical trials published in BMC Cancer provides a comprehensive landscape of metformin investigations across various stages and modalities of breast cancer management. Among breast cancer subtypes, HER2-positive disease has been a particular focus, as research shows moderate increases in pathologic complete response (pCR) in these patients when treated with metformin.¹

Metformin prescription bottle | Image Credit: © Sherry Young - stock.adobe.com

The scoping review in mapped out 40 clinical trials assessing metformin in breast cancer patients, including several that examined HER2-positive populations. The majority of these studies evaluated metformin in the neoadjuvant or adjuvant setting, where treatment aims to reduce tumor burden before surgery or prevent recurrence afterward. pCR—a critical end point in HER2-positive disease—was frequently assessed.^1,2

Results from the neoadjuvant trials suggest that metformin may modestly increase pCR rates when added to standard regimens, particularly in patients with HER2-positive breast cancer. For example, exploratory analyses have found that HER2-positive tumors may be more sensitive to the metabolic effects of metformin. Observational evidence also supports this—patients with diabetes and breast cancer on metformin have shown improved survival, with hazard ratios suggesting nearly a 50% reduction in breast cancer–specific mortality compared with non-users.^1,2

Research suggests that metformin activates AMP-activated protein kinase (AMPK), which in turn inhibits the mammalian target of rapamycin (mTOR) pathway. This is significant because HER2 signaling promotes cell proliferation partly through the PI3K/AKT/mTOR pathway—a driver of resistance in HER2-positive disease. By dampening this pathway, metformin may enhance the effectiveness of HER2-targeted agents such as trastuzumab (Herceptin; Genentech Inc) or pertuzumab (Perjeta; Genentech Inc).^1,2

Additionally, metformin lowers systemic insulin and insulin-like growth factor (IGF) levels. Preclinical work shows that high insulin levels may reduce the efficacy of HER2-targeted therapies, suggesting that metformin’s metabolic effects could counteract this resistance mechanism.^1,2

The scoping review noted that many metformin trials suffered from limitations, including small sample sizes, heterogeneous patient populations, and insufficient stratification by HER2 status. Few studies have incorporated biomarker-driven analyses to directly link AMPK or mTOR activity to treatment outcomes. Moreover, most phase 3 data to date have not shown statistically significant improvements in survival with metformin, underscoring the need for more rigorous, subtype-focused investigations.^1,2

Given metformin’s low cost, favorable safety profile, and well-established use in other chronic diseases, even modest efficacy could make it an attractive adjunct therapy in HER2-positive breast cancer. With HER2-positive disease accounting for roughly 15% to 20% of breast cancers—and with ongoing challenges of resistance and recurrence—the potential of repurposing a familiar drug like metformin continues to generate significant scientific and clinical interest.³

REFERENCES

1. Araujo CFM, Nunes LC, Murta-Nascimento C, et al. Metformin for the treatment of breast cancer: a scoping review of randomized clinical trials. BMC Cancer. August 21, 2025. Doi:10.1186/s12885-025-14468-3

2. Metformin’s potential role in breast cancer. Bioengineering.org. August 21, 2025. Accessed August 22, 2025. https://bioengineer.org/metformins-potential-role-in-breast-cancer/

3. Gerlach A. Neoadjuvant chemotherapy improves survival in HER2-positive breast cancer. Pharmacy Times. August 20, 2025. Accessed August 22, 2025. https://www.pharmacytimes.com/view/neoadjuvant-chemotherapy-improves-survival-in-her2-positive-breast-cancer