Rise in serum folate after androgen deprivation associated with worse prostate cancer-specific survival

Abstract

IntroductionHigh folate has an association with advanced prostate cancer and levels of testosterone. Herein, we perform a translational study to investigate the inverse response of serum folate in prostate cancer patients initiating androgen deprivation therapy (ADT) and a mirrored animal model. MethodsA retrospective study was performed using the South Texas Veterans Healthcare System to identify patients with prostate cancer on ADT. We documented testosterone and folate levels before and after ADT initiation (defined by a reduction in testosterone by 50 ng/ml) as compared to those already on ADT (maintenance). Our primary outcome was overall mortality with secondary outcome of prostate cancer-specific mortality. In parallel, we tested castration of C57BL/6J mice on folate-defined diet to determine if folate levels change with response to androgen deprivation. Students’ t test on continuous variables and Chi-squared test on dichotomous variables was performed along with Kaplan-Meier for time to event analysis. ResultsWe identified 56 men with prostate cancer undergoing androgen deprivation in which folate levels had been determined. 15 out of 16 (94%) men initiating ADT had increases in their folate, which is substantially more than 67% in maintenance group (P = 0.04). We identified more rapid time to death from prostate cancer if folate levels increased to levels >200 ng/ml above their baseline (P = 0.03). Mice models demonstrated a significant rise in serum red blood cell folate after mice were castrated (P = 0.03) by an average of 1.5x over pre-castrated baseline level. By contrast, sham-castrated mice showed no increase in serum folate levels over baseline. ConclusionOur study suggests that men with substantial rises in folate after initiating ADT may be associated with worse prostate cancer-specific and overall survival. Our translational experiments in mice confirmed correlation between rising in folate levels post-castration. Given this study, further investigation is warranted on the role of dietary folate consumption during initiation of ADT and progression to castrate-resistant prostate cancer.