Metformin may offer no protective effect in men undergoing external beam radiation therapy for prostate cancer

• Published in: BJU international Vol. 123; no. S5; pp. 36 - 42
• Main Authors: Ranasinghe, Weranja K.B., Williams, Scott, Ischia, Joseph, Wetherell, David, Baldwin, Graham, Shulkes, Arthur, Sengupta, Shomik, Bolton, Damien, Patel, Oneel
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01-05-2019
• Subjects: Adenocarcinoma - complications; Adenocarcinoma - drug therapy; Adenocarcinoma - pathology; Adenocarcinoma - radiotherapy; Androgen Antagonists - therapeutic use; Antidiabetics; Cancer therapies; Cell survival; Cell Survival - drug effects; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; HIF1α; Humans; Hydrogen peroxide; Hypoglycemic Agents - therapeutic use; Hypoxia; hypoxia inducible factor 1‐α; Hypoxia-Inducible Factor 1, alpha Subunit - drug effects; Male; Metastases; Metastasis; Metformin; Metformin - therapeutic use; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Oxidative Stress; PC-3 Cells - drug effects; PCSM; Prostate cancer; Prostate-Specific Antigen - blood; ProstateCancer; Prostatic Neoplasms - complications; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; Prostatic Neoplasms - radiotherapy; Radiation therapy; radiotherapy; Radiotherapy Dosage; Rapamycin; Regression analysis; Risk Factors; Survival Analysis; TOR protein; Treatment Failure; prostate cancer; PCSM; radiotherapy; ProstateCancer; Metformin; hypoxia inducible factor 1-α; HIF1α
• ISSN: 1464-4096; 1464-410X
• DOI: 10.1111/bju.14709

Objectives
To assess whether metformin reduces radio‐resistance and increases survival in men undergoing external beam radiation therapy (EBRT) for prostate cancer (PCa), and to determine its effect on hypoxia inducible factor 1‐α (HIF1α).
Patients and Methods
All patients treated with curative intent with EBRT for PCa at a major cancer centre between 2000 and 2007 were included in this study. The outcome measures of time to biochemical failure (BF), metastasis, PCa‐specific mortality and overall survival (OS) were analysed in those taking metformin vs those not, using competing risk and Cox regression models. To determine metformin's effect on HIF1α expression and survival in vitro, PC3 cells with high basal HIF1α levels were subjected to increasing doses of metformin after H2O2‐induced oxidative stress.
Results
A total of 2055 eligible cases, including 113 who were on metformin, were identified, with a median follow‐up of 95.7 months. There were no differences in age, initial prostate‐specific antigen level, Gleason score, T‐stage, D'Amico risk class or duration of androgen deprivation therapy (ADT) between patients who were or were not on metformin. Treatment with metformin did not result in any apparent improvement in time to BF, time to metastasis detection or OS, but there was a 1.5‐fold increase in PCa‐specific deaths (P = 0.045) in patients on metformin and ADT when adjusted for cancer risk and comorbidities. When comparing patients on high‐dose metformin (>1 g/d) with those on low‐dose metformin (≤1 g), there was no difference in either time to metastases or time to BF. In vitro metformin at a high concentration of 100 μM did not reduce HIF1α expression, nor did metformin affect the PC3 cell survival when exposed to oxidative stress (H2O2).
Conclusions
No association was found between the use of metformin and time to metastasis detection, time to BF or OS in patients undergoing radiation therapy with or without ADT for PCa. In vitro, low therapeutic concentrations of metformin had no effect on HIF1α, and this observation could explain the conflicting evidence for the effectiveness of metformin in men undergoing EBRT for PCa. Higher, more toxic doses of metformin may be required to inhibit the mammalian target of rapamycin‐HIF1α pathway in this patient group.