| Verf.angabe: | Sarah L. Kerns, Ashley Amidon Morlang, Sharon M. Lee, Derick R. Peterson, Brian Marples, Hong Zhang, Kevin Bylund, Doug Rosenzweig, William Hall, Kim De Ruyck, Barry S. Rosenstein, Richard G. Stock, Antonio Gómez-Caamaño, Ana Vega, Paloma Sosa-Fajardo, Begoña Taboada-Valladares, Miguel E. Aguado-Barrera, Chris Parker, Liv Veldeman, Valérie Fonteyne, Renée Bultijnck, Christopher J. Talbot, R. Paul Symonds, Kerstie Johnson, Tim Rattay, Adam Webb, Maarten Lambrecht, Dirk de Ruysscher, Ben Vanneste, Ananya Choudhury, Rebecca M. Elliott, Elena Sperk, Carsten Herskind, Marlon R. Veldwijk, Tiziana Rancati, Barbara Avuzzi, Riccardo Valdagni, David Azria, Marie-Pierre Farcy Jacquet, Jenny Chang-Claude, Petra Seibold, Catharine West, Michelle Janelsins, Yuhchyau Chen, Edward Messing, Gary Morrow, REQUITE Consortium, David Azria, Erik Briers, Jenny Chang-Claude, Ananya Choudhury, Alison Dunning, Rebecca M. Elliott, Sara Gutiérrez-Enríquez, Tiziana Rancati, Tim Rattay, Barry S. Rosenstein, Dirk De Ruysscher, Petra Seibold, Elena Sperk, R. Paul Symonds, Hilary Stobart, Christopher J. Talbot, Ana Vega, Liv Veldeman, Tim Ward, Adam Webb, Catharine M. West |
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| Abstract: | Background and purpose - Genome-wide association studies (GWAS) of late hematuria following prostate cancer radiotherapy identified single nucleotide polymorphisms (SNPs) near AGT, encoding angiotensinogen. We tested the hypothesis that patients taking angiotensin converting enzyme inhibitors (ACEi) have a reduced risk of late hematuria. We additionally tested genetically-defined hypertension. - Materials and methods - Prostate cancer patients undergoing potentially-curative radiotherapy were enrolled onto two multi-center observational studies, URWCI (N = 256) and REQUITE (N = 1,437). Patients were assessed pre-radiotherapy and followed prospectively for development of toxicity for up to four years. The cumulative probability of hematuria was estimated by the Kaplan-Meier method. Multivariable grouped relative risk models assessed the effect of ACEi on time to hematuria adjusting for clinical factors and stratified by enrollment site. A polygenic risk score (PRS) for blood pressure was tested for association with hematuria in REQUITE and our Radiogenomics Consortium GWAS. - Results - Patients taking ACEi during radiotherapy had a reduced risk of hematuria (HR 0.51, 95%CI 0.28 to 0.94, p = 0.030) after adjusting for prior transurethral prostate and/or bladder resection, heart disease, pelvic node radiotherapy, and bladder volume receiving 70 Gy, which are associated with hematuria. A blood pressure PRS was associated with hypertension (odds ratio per standard deviation 1.38, 95%CI 1.31 to 1.46, n = 5,288, p < 0.001) but not hematuria (HR per standard deviation 0.96, 95%CI 0.87 to 1.06, n = 5,126, p = 0.41). - Conclusions - Our study is the first to show a radioprotective effect of ACEi on bladder in an international, multi-site study of patients receiving pelvic radiotherapy. Mechanistic studies are needed to understand how targeting the angiotensin pathway protects the bladder. |
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