Metformin and reduction of cancer risk

Metformin and reduction of cancer risk

• diabetes is a common disease that may occur throughout human life, and can increase the likelihood of the occurrence of various types of cancer, such as colon, rectum, pancreas and liver cancers, compared to non-diabetic patients
• metformin inhibits mTOR activity by activating ATM (ataxia telangiectasia mutated) and LKB1 (liver kinase B1) and then adenosine monophosphate-activated kinase (AMPK), and thus prevents protein synthesis and cell growth
  • TOR is a protein kinase regulating cell growth, survival, metabolism, and immunity
• metformin can activate p53 by activating AMPK and thereby ultimately stop the cell cycle
• it has been hypothesised that metformin may be of benefit in the treatment of cancer

Metformin in nondiabetic, unresectable stage III non-small cell lung cancer (NSCLC) treated with chemoradiation (2)

• trial that included 170 patients, survival exceeded expectations in both groups (those who received chemoradiation alone vs chemoradiation and metformin); however, the addition of metformin to chemoradiation did not improve overall or progression-free survival

Addition of metformin to chemoradiotherapy, as a concurrent treatment as well as consolidation therapy, in patients without diabetes who have locally advanced non-small cell lung cancer (3)

• addition of metformin to chemoradiotherapy was associated with worse treatment efficacy and increased toxic effects compared with chemoradiotherapy alone. The proportion of patients who experienced a failure event within 1 year (ie, locoregional disease progression, distant metastases, death, or withdrawal) was 69.2% in the metformin arm vs 42.9% in the control arm
• based on the results of this trial, metformin is not recommended as an adjunct to chemoradiotherapy for the treatment of unresected locally advanced non-small cell lung cancer in patients who do not have diabetes

Addition of metformin to standard breast cancer treatment (4)

• a randomised controlled trial (RCT) (n=3,469) found addition of metformin to standard breast cancer treatment did not improve invasive disease free survival vs placebo among patients with high-risk operable disease who did not have diabetes (2.78 vs 2.74 events per 100 patients years, HR 1.01, 95%CI 0.84-1.21)
  • an editorial notes that a number of observational studies have reported improved outcomes for individuals with type-2 diabetes receiving metformin while undergoing cancer treatment, and notes the potential pharmacological rationale for this noting the increased risk of cancer in patients with metabolic syndrome
  • highlights however that the negative results of this study may not be surprising as it is already known that there is strong evidence for a lack of benefit from metformin treatment in metabolically healthy individuals
  • points to other research suggesting there are strong hypothesis-generating data about potential benefits from metformin in ERBB2-positive breast cancer disease, and that trials investigating metformin in additional serum biomarker studies are eagerly awaited

A review (27 RCTs; n=20,720) found metformin use did not have a significant effect on cancer incidence in subjects with overweight/obesity and/or prediabetes/diabetes (relative risk 1.07; 95% CI 0.87–1.31; no evidence of publication bias; low risk of bias in most studies) (5)

Reference:

1. Saraei P, Asadi I, Kakar MA, Moradi-Kor N. The beneficial effects of metformin on cancer prevention and therapy: a comprehensive review of recent advances. Cancer Manag Res. 2019;11:3295-3313. Published 2019 Apr 17. doi:10.2147/CMAR.S200059
2. Skinner H, Hu C, Tsakiridis T, et al. Addition of Metformin to Concurrent Chemoradiation in Patients With Locally Advanced Non-Small Cell Lung Cancer: The NRG-LU001 Phase 2 Randomized Clinical Trial. JAMA Oncol. Published online July 29, 2021. doi:10.1001/jamaoncol.2021.2318
3. Tsakiridis T, Pond GR, Wright J, et al. Metformin in Combination With Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer: The OCOG-ALMERA Randomized Clinical Trial. JAMA Oncol. Published online July 29, 2021. doi:10.1001/jamaoncol.2021.2328
4. Goodwin PJ, Chen BE, Gelmon KA, et al. Effect of Metformin vs Placebo on Invasive Disease–Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial. JAMA. 2022;327(20):1963-1973. doi:10.1001/jama.2022.6147
5. Mesquita LA, Spiazzi BF, Piccoli GF, et al. Does metformin reduce the risk of cancer in obesity and diabetes? A systematic review and meta-analysis. Diabetes Obes Metab. 2024; 1-12. doi:10.1111/dom.15509 (https://doi.org/10.1111/dom.15509)