Use of Angiotensin Converting Enzyme Inhibitors and Risk of Late Bladder Toxicity Following Radiotherapy for Prostate Cancer

Abstract

Genome-wide association studies (GWAS) identified single nucleotide polymorphisms (SNPs) near AGT associated with late hematuria following radiotherapy (RT) for prostate cancer. AGT encodes angiotensinogen and, in pre-clinical models, angiotensin pathway inhibition protects against late radiation toxicity in some tissues. Effects on the bladder have not been investigated. We tested the hypothesis that angiotensin converting enzyme inhibitors (ACEi) reduce risk of late hematuria following RT. We additionally investigated the effect of genetically-defined hypertension on hematuria.Prostate cancer patients (N = 268) undergoing curative RT (alone or with surgery and/or androgen deprivation therapy) were enrolled from each of two cancer centers pre-RT and followed prospectively for development of hematuria for up to four years using patient reported outcome questionnaires. Hematuria was defined as gross bleeding or medication use for hematuria. Demographic, treatment, and medication data were abstracted from medical records. The cumulative probability of hematuria was estimated by Kaplan-Meier methods, and the log rank test assessed differences by ACEi/ARB, use stratified by enrollment center. Multivariable analyses used Cox models of time to onset of hematuria stratified by enrollment center. A polygenic risk score (PRS) comprising 882 SNPs previously associated with blood pressure was tested for association with time to onset of hematuria in our Radiogenomics Consortium GWAS cohorts (N = 3,608).The cumulative probability of hematuria among all participants was 17.1% (N = 19) at four years (median follow-up of two years). Hematuria was seen in 1.4% of those taking vs 22.9% in those not taking ACEi (P = 0.01) at the start of RT, resulting in a hazard ratio (HR) of 0.11 (95% CI 0.01 to 0.83). The protective effect of ACEi on hematuria remained when adjusted for factors associated with ACEi use, including body mass index, hypertension, or diabetes. The protective effect also remained after stratifying by risk factors for hematuria, including prior transurethral prostate resection, smoking status, or prior prostatectomy. A blood pressure PRS was strongly associated with hypertension (odds ratio per standard deviation 1.40, 95% CI 1.30 to 1.50, P < 0.001) but not with hematuria (HR per standard deviation 0.97, 95% CI 0.87 to 1.07, P = 0.52).Our study is the first to show a radioprotective effect of ACEi on bladder toxicity. This effect appears distinct from presence of hypertension, which is not itself a risk factor. These results point to a promising radioprotector readily available for testing in a randomized clinical trial. Mechanistic studies are needed to understand how targeting the angiotensin pathway protects normal tissues to reduce RT toxicity.