Use of angiotensin converting enzyme inhibitors is associated with reduced risk of late bladder toxicity following radiotherapy for prostate cancer

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

doi:10.1016/j.radonc.2022.01.014

Use of angiotensin converting enzyme inhibitors is associated with reduced risk of late bladder toxicity following radiotherapy for prostate cancer

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 FonteyneRenée 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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	75-82
Number of pages	8
Journal	Radiotherapy and Oncology
Volume	168
Early online date	22 Jan 2022
DOIs	https://doi.org/10.1016/j.radonc.2022.01.014
Publication status	Published - Mar 2022

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10.1016/j.radonc.2022.01.014

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Kerns, S. L., Amidon Morlang, A., Lee, S. M., Peterson, D. R., Marples, B., Zhang, H., Bylund, K., Rosenzweig, D., Hall, W., De Ruyck, K., Rosenstein, B. S., Stock, R. G., Gómez-Caamaño, A., Vega, A., Sosa-Fajardo, P., Taboada-Valladares, B., Aguado-Barrera, M. E., Parker, C., Veldeman, L., ... REQUITE consortium (2022). Use of angiotensin converting enzyme inhibitors is associated with reduced risk of late bladder toxicity following radiotherapy for prostate cancer. Radiotherapy and Oncology, 168, 75-82. https://doi.org/10.1016/j.radonc.2022.01.014

@article{d05d7d1deb7f4722bfe5d38b8e13e2bc,

title = "Use of angiotensin converting enzyme inhibitors is associated with reduced risk of late bladder toxicity following radiotherapy for prostate cancer",

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.",

author = "Kerns, {Sarah L} and {Amidon Morlang}, Ashley and Lee, {Sharon M} and Peterson, {Derick R} and Brian Marples and Hong Zhang and Kevin Bylund and Doug Rosenzweig and William Hall and {De Ruyck}, Kim and Rosenstein, {Barry S} and Stock, {Richard G} and Antonio G{\'o}mez-Caama{\~n}o and Ana Vega and Paloma Sosa-Fajardo and Bego{\~n}a Taboada-Valladares and Aguado-Barrera, {Miguel E} and Chris Parker and Liv Veldeman and Val{\'e}rie Fonteyne and Ren{\'e}e Bultijnck and Talbot, {Christopher J} and Symonds, {R Paul} and Kerstie Johnson and Tim Rattay and Adam Webb and Maarten Lambrecht and {de Ruysscher}, Dirk and Ben Vanneste and Ananya Choudhury and Elliott, {Rebecca M} and Elena Sperk and Carsten Herskind and Veldwijk, {Marlon R} and Tiziana Rancati and Barbara Avuzzi and Riccardo Valdagni and David Azria and {Farcy Jacquet}, Marie-Pierre and Jenny Chang-Claude and Petra Seibold and Catharine West and Michelle Janelsins and Yuhchyau Chen and Edward Messing and Gary Morrow and {REQUITE consortium}",

year = "2022",

month = mar,

doi = "10.1016/j.radonc.2022.01.014",

language = "English",

volume = "168",

pages = "75--82",

journal = "Radiotherapy and Oncology",

issn = "0167-8140",

publisher = "Elsevier Ireland Ltd",

}

Kerns, SL, Amidon Morlang, A, Lee, SM, Peterson, DR, Marples, B, Zhang, H, Bylund, K, Rosenzweig, D, Hall, W, De Ruyck, K, Rosenstein, BS, Stock, RG, Gómez-Caamaño, A, Vega, A, Sosa-Fajardo, P, Taboada-Valladares, B, Aguado-Barrera, ME, Parker, C, Veldeman, L, Fonteyne, V, Bultijnck, R, Talbot, CJ, Symonds, RP, Johnson, K, Rattay, T, Webb, A, Lambrecht, M, de Ruysscher, D, Vanneste, B, Choudhury, A, Elliott, RM, Sperk, E, Herskind, C, Veldwijk, MR, Rancati, T, Avuzzi, B, Valdagni, R, Azria, D, Farcy Jacquet, M-P, Chang-Claude, J, Seibold, P, West, C, Janelsins, M, Chen, Y, Messing, E, Morrow, G & REQUITE consortium 2022, 'Use of angiotensin converting enzyme inhibitors is associated with reduced risk of late bladder toxicity following radiotherapy for prostate cancer', Radiotherapy and Oncology, vol. 168, pp. 75-82. https://doi.org/10.1016/j.radonc.2022.01.014

TY - JOUR

T1 - Use of angiotensin converting enzyme inhibitors is associated with reduced risk of late bladder toxicity following radiotherapy for prostate cancer

AU - Kerns, Sarah L

AU - Amidon Morlang, Ashley

AU - Lee, Sharon M

AU - Peterson, Derick R

AU - Marples, Brian

AU - Zhang, Hong

AU - Bylund, Kevin

AU - Rosenzweig, Doug

AU - Hall, William

AU - De Ruyck, Kim

AU - Rosenstein, Barry S

AU - Stock, Richard G

AU - Gómez-Caamaño, Antonio

AU - Vega, Ana

AU - Sosa-Fajardo, Paloma

AU - Taboada-Valladares, Begoña

AU - Aguado-Barrera, Miguel E

AU - Parker, Chris

AU - Veldeman, Liv

AU - Fonteyne, Valérie

AU - Bultijnck, Renée

AU - Talbot, Christopher J

AU - Symonds, R Paul

AU - Johnson, Kerstie

AU - Rattay, Tim

AU - Webb, Adam

AU - Lambrecht, Maarten

AU - de Ruysscher, Dirk

AU - Vanneste, Ben

AU - Choudhury, Ananya

AU - Elliott, Rebecca M

AU - Sperk, Elena

AU - Herskind, Carsten

AU - Veldwijk, Marlon R

AU - Rancati, Tiziana

AU - Avuzzi, Barbara

AU - Valdagni, Riccardo

AU - Azria, David

AU - Farcy Jacquet, Marie-Pierre

AU - Chang-Claude, Jenny

AU - Seibold, Petra

AU - West, Catharine

AU - Janelsins, Michelle

AU - Chen, Yuhchyau

AU - Messing, Edward

AU - Morrow, Gary

AU - REQUITE consortium

PY - 2022/3

Y1 - 2022/3

N2 - 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.

AB - 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.

U2 - 10.1016/j.radonc.2022.01.014

DO - 10.1016/j.radonc.2022.01.014

M3 - Article

C2 - 35077710

SN - 0167-8140

VL - 168

SP - 75

EP - 82

JO - Radiotherapy and Oncology

JF - Radiotherapy and Oncology

ER -