Contrary to previous research, a new study examining how genetic variations impact the effect of metformin suggests that this drug commonly used for glycemic control may not be an effective agent for the chemoprevention of prostate cancer (PCa).
In fact, the new study found an increased risk of PCa associated with metformin use.
The study, by Robert Hamilton, MD, MPH, a clinician investigator at the Princess Margaret Cancer Centre in Toronto, and colleagues, is the first to examine pharmacogenetic interaction and PCa chemoprevention. He and his colleagues noted that genetic variation in metformin metabolism pathways may modify metformin glycemic control and help protect against some cancers.
The investigators collected clinical data and germline DNA from a prostate biopsy database and conducted a genome-wide association study. They examined 27 single nucleotide polymorphisms (SNPs) implicated in metformin metabolism. The team analyzed the associations between metformin use and risk of high-grade disease (Grade Group 2 or higher) and overall PCa with a case-control design.
The study included 3481 men, of whom 132 (4%) were taking metformin at diagnosis. A total of 2061 men (59%) were diagnosed with PCa, with 922 (45%) of them diagnosed with high-grade disease. After adjusting for baseline characteristics, metformin use was significantly associated with 76% and 77% increased odds of high-grade PCa and overall PCa, respectively, the investigators reported in Prostate Cancer and Prostatic Diseases.1
The investigation showed that none of the 27 candidate SNPs in metformin metabolic pathways had significant interaction with the metformin-cancer association. In the genome-wide scan, one SNP (rs149137006) had a significant interaction with metformin for high-grade PCa, and a second SNP (rs115071742) was found to have an interaction with metformin for overall PCa. These SNPs, however, occurred in parts of the genome with no known function (introns or intergenic) or association with prostate cancer.
“It could be possible that metformin users were at increased risk for prostate cancer for other reasons, such as diabetes, and only a randomized controlled trial could truly tease this out,” Dr Hamilton told Renal & Urology News. “The genetic factors we studied did not seem to modify the metformin prostate cancer risk, suggesting that how a patient’s body metabolizes metformin doesn’t seem to alter how metformin affects the prostate gland.”
He added, “By no means does this mean men taking metformin should stop for fear of causing prostate cancer. Our study must be put in the context of the many other studies published on metformin and prostate cancer risk. Some have shown metformin to be protective, others no effect, and others, like ours, suggest it may be associated with increased risk.”
The investigators said their study findings must be viewed cautiously because there was a heterogeneous mixture of metformin duration and dose in this cohort. This could potentially dilute any genetic signal. Also, data were not available on other anti-diabetic agents or concurrent medication use.
Brock O’Neil, MD, an Assistant Professor in the Division of Urology at the University of Utah School of Medicine and the Huntsman Cancer Institute in Salt Lake City, said the new study is a thoughtful attempt to understand the relationship between metformin and PCa. Still, he pointed out that the sample of men taking metformin was too small and there were too few events (99 PCa cases and 62 high-grade PCa cases) “to have enough degrees of freedom relative to the number of covariates included in the multivariable models to make meaningful conclusions about whether metformin use is associated with prostate cancer.”
Although the authors report that metformin use was associated with a higher risk of any PCa and high-risk PCa, they were unable to account for a possible selection bias, Dr O’Neil said. In addition, he noted metformin could have an impact on PSA kinetics that leads to a greater likelihood that a prostate biopsy is performed.
“Given the small size of the study, it is too early to conclude that none of the 27 candidate SNPs in the metformin pathway are not associated with prostate cancer,” he said. “Additionally, it is too early to conclude that 2 SNPs from the GWAS are indeed meaningfully related to prostate cancer development or risk.”
Amar U. Kishan, MD, Vice Chair of Clinical and Translational Research and Chief of the Genitourinary Oncology Service at the David Geffen School of Medicine at UCLA and the UCLA Jonsson Comprehensive Cancer Center, said that despite the study’s limitations, it provides new insight into how genetic factors may play a role.
“This is a well-done case-control study,” Dr Kishan said. “The dataset is well curated and their methods are robust. Limitations are well acknowledged by the authors and relate to unknowns and heterogeneity in metformin use, duration, and dose. The authors did do a sensitivity analysis showing that when focusing on men who started metformin soon after biopsy, there was a small increased risk of cancer, implying that there might simply be an association between diabetes/prediabetes and prostate cancer that metformin is a proxy for.”
Michael S. Leapman, MD, Assistant Professor of Urology at the Yale School of Medicine in New Haven, Connecticut, said this study is important because all of the men underwent a prostate biopsy for clinical suspicion of PCa. “It is often difficult to fully disentangle potential biases associated with which patients are screened and referred for a biopsy as well, length of metformin exposure, or potential interactions with other drugs,” Dr Leapman said.
A systematic review and meta-analysis published last year found metformin therapy appeared to exhibit advantages in improving the prognosis of PCa. The study showed no association between metformin usage and PCa incidence, however.2 The review included 30 cohort studies with 1,660,795 patients, and it showed that metformin treatment improved overall survival, recurrence-free survival, cancer-specific survival in PCa compared with non-metformin treatment.
“By recent estimates, approximately 10% of Americans have diabetes and metformin is commonly prescribed for type 2 diabetics,” Dr Leapman said. Subsequently, continued investigation into the relationship between metformin and risk of PCa is paramount. In a review of existing literature regarding the numerous mechanisms of action of metformin on PCa, investigators found that it may have a role in the treatment protocol as a monotherapy or in combination with other agents.3 They analyzed the molecular impact of metformin as well as adjunct therapies such as androgen deprivation therapy, aspirin use, statin use, and chemotherapy.
A French prospective multicenter randomized controlled phase 2 study comparing docetaxel plus metformin versus docetaxel plus placebo in metastatic castration-resistant prostate cancer found no meaningful clinical benefit in this setting.4
- Lee MJ, Jayalath VH, Xu W, et al. Association between metformin medication, genetic variation and prostate cancer risk. Prostate Cancer Prostatic Dis (2020). doi: 10.1038/s41391-020-0238-y
- He K, Hu H, Ye S, et al. The effect of metformin therapy on incidence and prognosis in prostate cancer: A systematic review and meta-analysis. Sci Rep. 2019;9:2218.
- Zaidi S, Gandhi J, Joshi G, et al. The anticancer potential of metformin on prostate cancer. Prostate Cancer Prostatic Dis. 2019;22:351-361. doi: 10.1038/s41391-018-0085-2
- Pujalte Martin M, Borchiellini D, Viotti J, et al. TAXOMET: A French prospective multicenter randomized controlled phase II study comparing docetaxel plus metformin versus docetaxel plus placebo in mCRPC. J Clin Urol. 2019;37. Abstract 5004. doi: 10.1200/JCO.2019.37.15_suppl.5004