Sarah L Kerns1, Ashley Amidon Morlang2, Sharon M Lee2, Derick R Peterson3, Brian Marples2, Hong Zhang2, Kevin Bylund2, Doug Rosenzweig2, William Hall4, Kim De Ruyck5, Barry S Rosenstein6, Richard G Stock7, Antonio Gómez-Caamaño8, Ana Vega9, Paloma Sosa-Fajardo10, Begoña Taboada-Valladares8, Miguel E Aguado-Barrera11, Chris Parker12, Liv Veldeman5, Valérie Fonteyne5, Renée Bultijnck5, Christopher J Talbot13, R Paul Symonds13, Kerstie Johnson13, Tim Rattay13, Adam Webb14, Maarten Lambrecht15, Dirk de Ruysscher16, Ben Vanneste16, Ananya Choudhury17, Rebecca M Elliott17, Elena Sperk18, Carsten Herskind18, Marlon R Veldwijk18, Tiziana Rancati19, Barbara Avuzzi20, Riccardo Valdagni21, David Azria22, Marie-Pierre Farcy Jacquet23, Jenny Chang-Claude24, Petra Seibold25, Catharine West17, Michelle Janelsins26, Yuhchyau Chen2, Edward Messing27, Gary Morrow26. 1. Department of Radiation Oncology, University of Rochester Medical Center, Rochester, United States. Electronic address: sarah_kerns@urmc.rochester.edu. 2. Department of Radiation Oncology, University of Rochester Medical Center, Rochester, United States. 3. Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, United States. 4. Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, United States. 5. Department of Radiation Oncology, Ghent University Hospital and Department of Human Structure and Repair, Ghent University, Ghent, Belgium. 6. Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, United States; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United States. 7. Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, United States. 8. Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain; Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain. 9. Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain; Fundación Pública Galega de Medicina Xenómica-Servizo Galego de Saude (SERGAS), Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain. 10. Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain; Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain; Fundación Pública Galega de Medicina Xenómica-Servizo Galego de Saude (SERGAS), Santiago de Compostela, Spain. 11. Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain; Fundación Pública Galega de Medicina Xenómica-Servizo Galego de Saude (SERGAS), Santiago de Compostela, Spain. 12. Department of Uro-oncology, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Sutton, United Kingdom. 13. Leicester Cancer Research Centre, University of Leicester, United Kingdom. 14. Department of Genetics and Genome Biology, University of Leicester, United Kingdom. 15. KU Leuven, Radiation Oncology, Leuven, Belgium. 16. KU Leuven, Radiation Oncology, Leuven, Belgium; Maastricht University Medical Center, Department of Radiation Oncology (Maastro Clinic), GROW School for Oncology and Developmental Biology, Maastricht, the Netherlands. 17. Division of Cancer Sciences, the University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester, the Netherlands. 18. Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. 19. Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 20. Department of Radiation Oncology 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 21. Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Radiation Oncology 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Oncology and Hemato-oncology, Università degli Studi di Milano, Milan, Italy. 22. Department of Radiation Oncology, Montpellier Cancer Institute, Université Montpellier, Inserm U1194, France. 23. ICG Cancer Institute, Centre Hospitalier Universitaire de Nîmes, Nimes, France. 24. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Cancer Epidemiology Group, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Germany. 25. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 26. Department of Surgery, University of Rochester Medical Center, Rochester, United States. 27. Department of Urology, University of Rochester Medical Center, Rochester, United States.
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.
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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