Past research has provided evidence that metformin, a commonly prescribed drug for type 2 diabetes, may have anti-cancer properties; however, a recent study casts doubt on its ability to reduce breast cancer mortality specifically.
Early recognition that metformin stimulates production of the protein kinase LKB1, a tumor suppressor, sparked interest in its potential as an anticancer agent.1 As a result, epidemiological studies followed in effort to determine whether regular users of the drug have a lower risk of cancer; systematic reviews and meta-analyses have suggested that they do.
In 2010, a meta-analysis of case-control and cohort studies found that subjects with pre-existing diabetes taking metformin had a 31% lower risk of developing cancer compared with subjects taking other antidiabetic agents; the association was significant for pancreatic and hepatocellular cancer but nonsignificant for breast, colon, and prostate cancer.2
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A systematic review of six studies, published as of October 12, 2011, included more than 20,000 individuals with diabetes found that those taking metformin had a 33% lower risk of cancer—including lower risks of colorectal, hepatocellular, and lung cancer—and a 34% reduction in cancer mortality.3 Once again, there was no reduction in the risk for breast cancer.
Another meta-analysis, published in 2012, reviewed seven studies that focused on breast cancer in patients taking metformin and found a 17% reduction in risk.4 There was evidence of greater risk reduction with longer duration of use of metformin, with a 25% risk reduction in subjects who had taken metformin for 3 years or longer and a 32% risk reduction in studies that had begun observation before 1997.
To gain insight into the relationship between metformin use and breast cancer mortality, a population-based study consisted of women with diabetes who were diagnosed with breast cancer was conducted.5 Data were obtained from administrative health care databases in Ontario, Canada. A total of 2,361 women who had been diagnosed with diabetes after age 66 and diagnosed with breast cancer between 1997 and 2008 were included in the analysis.
The study population was restricted to women diagnosed with diabetes after age 66 so that drug use data, which is collected starting at age 65, would be available. The subjects’ mean age at diagnosis was 77 years and they had a mean duration of diabetes of 3.6 years. During follow-up, 46% were prescribed metformin, 12% were prescribed other hypoglycemic agents, and 42% received no prescription for antidiabetic medication. There were 1,101 deaths overall, 386 of which were associated with breast cancer.
When the researchers examined time-specific variables, they found no relationship between the duration of metformin use and all-cause survival (hazard ratio [HR], 0.97; 95% CI: 0.92-1.02) or breast cancer–specific survival (HR, 0.91; 95% CI: 0.81-1.03). There was a 9% decrease in breast cancer mortality for each year of metformin use, but this association did not reach statistical significance. Given that only 150 women with long-term use of metformin were included and that the follow-up period was only 3.7 years, it is possible that the study was underpowered to detect a protective effect of metformin.
Alternatively, metformin may confer a survival advantage only in certain types of breast cancer. In previous studies, the drug had no effect on mortality among women with triple-negative breast cancer6; on the other hand, metformin was associated with a 48% reduction in mortality in women with HER2+ tumors.7
References
1. Evans JMM, Donnelly LA, Emslie-Smith AM, et al. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330:1304-5.
2. DeCensi A, Puntoni M, Goodwin P, et al. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res. 2010;3:1451-61.
3. Noto H, Goto A, Tsujimoto T, Noda M. Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PLoS One. 2012;7(3):e33411.
4. Col NF, Ochs L, Springmann V, et al. Metformin and breast cancer risk: a meta-analysis and critical literature review. Breast Cancer Res Treat. 2012;135:639-46.
5. Lega IC, Austin PC, Gruneir A, et al. Association between metformin therapy and mortality after breast cancer. Diabetes Care. 2013; DOI: 10.2337/dc12-2535.
6. Bayraktar S, Hernadez-Aya LF, Lei X, et al. Effect of metformin on survival outcomes in diabetic patients with triple receptor–negative breast cancer. Cancer. 2012; 118:1202–11.
7. He X, Esteva FJ, Ensor J, et al. Metformin and thiazolidinediones are associated with improved breast cancer-specific survival of diabetic women with HER2+ breast cancer. Ann Oncol. 2012;23:1771-80.
