Clinical Outcome of Prostate Cancer Patients with Germline DNA Repair Mutations: Retrospective Analysis from an International Study

Germline DNA damage repair gene mutation (gDDRm) is found in >10% of metastatic prostate cancer (mPC). Their prognostic and predictive impact relating to standard therapies is unclear. To determine whether gDDRm status impacts benefit from established therapies in mPC. This is a retrospective, in...

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Veröffentlicht in:European urology 2018-05, Vol.73 (5), p.687-693
Hauptverfasser: Mateo, Joaquin, Cheng, Heather H., Beltran, Himisha, Dolling, David, Xu, Wen, Pritchard, Colin C., Mossop, Helen, Rescigno, Pasquale, Perez-Lopez, Raquel, Sailer, Verena, Kolinsky, Michael, Balasopoulou, Ada, Bertan, Claudia, Nanus, David M., Tagawa, Scott T., Thorne, Heather, Montgomery, Bruce, Carreira, Suzanne, Sandhu, Shahneen, Rubin, Mark A., Nelson, Peter S., de Bono, Johann S.
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container_end_page 693
container_issue 5
container_start_page 687
container_title European urology
container_volume 73
creator Mateo, Joaquin
Cheng, Heather H.
Beltran, Himisha
Dolling, David
Xu, Wen
Pritchard, Colin C.
Mossop, Helen
Rescigno, Pasquale
Perez-Lopez, Raquel
Sailer, Verena
Kolinsky, Michael
Balasopoulou, Ada
Bertan, Claudia
Nanus, David M.
Tagawa, Scott T.
Thorne, Heather
Montgomery, Bruce
Carreira, Suzanne
Sandhu, Shahneen
Rubin, Mark A.
Nelson, Peter S.
de Bono, Johann S.
description Germline DNA damage repair gene mutation (gDDRm) is found in >10% of metastatic prostate cancer (mPC). Their prognostic and predictive impact relating to standard therapies is unclear. To determine whether gDDRm status impacts benefit from established therapies in mPC. This is a retrospective, international, observational study. Medical records were reviewed for 390 mPC patients with known gDDRm status. All 372 patients from Royal Marsden (UK), Weill-Cornell (NY), and University of Washington (WA) were previously included in a prevalence study (Pritchard, NEJM 2016); the remaining 18 were gBRCA1/2m carriers, from the kConFab consortium, Australia. Response rate (RR), progression-free survival (PFS), and overall survival (OS) data were collected. To account for potential differences between cohorts, a mixed-effect model (Weibull distribution) with random intercept per cohort was used. The gDDRm status was known for all 390 patients (60 carriers of gDDRm [gDDRm+], including 37 gBRCA2m, and 330 cases not found to carry gDDRm [gDDRm–]); 74% and 69% were treated with docetaxel and abiraterone/enzalutamide, respectively, and 36% received PARP inhibitors (PARPi) and/or platinum. Median OS from castration resistance was similar among groups (3.2 vs 3.0 yr, p=0.73). Median docetaxel PFS for gDDRm+ (6.8 mo) was not significantly different from that for gDDRm– (5.1 mo), and RRs were similar (gDDRm+=61%; gDDRm–=54%). There were no significant differences in median PFS and RR on first-line abiraterone/enzalutamide (gDDRm+=8.3 mo, gDDRm–=8.3 mo; gDDRm+=46%, gDDRm–=56%). Interaction test for PARPi/platinum and gDDRm+ resulted in an OS adjusted hazard ratio of 0.59 (95% confidence interval 0.28–1.25; p=0.17). Results are limited by the retrospective nature of the analysis. mPC patients with gDDRm appeared to benefit from standard therapies similarly to the overall population; prospective studies are ongoing to investigate the impact of PARPi/platinum. Patients with inherited DNA repair mutations benefit from standard therapies similarly to other metastatic prostate cancer patients. Metastatic prostate cancer patients carrying germline mutations in DNA damage repair genes derive similar benefit from standard of care taxanes and androgen receptor signalling inhibitors to the overall population. Moreover, this exploratory analysis supports further investigation of the impact of PARP inhibitors and platinum chemotherapy in this subset of patients.
doi_str_mv 10.1016/j.eururo.2018.01.010
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Their prognostic and predictive impact relating to standard therapies is unclear. To determine whether gDDRm status impacts benefit from established therapies in mPC. This is a retrospective, international, observational study. Medical records were reviewed for 390 mPC patients with known gDDRm status. All 372 patients from Royal Marsden (UK), Weill-Cornell (NY), and University of Washington (WA) were previously included in a prevalence study (Pritchard, NEJM 2016); the remaining 18 were gBRCA1/2m carriers, from the kConFab consortium, Australia. Response rate (RR), progression-free survival (PFS), and overall survival (OS) data were collected. To account for potential differences between cohorts, a mixed-effect model (Weibull distribution) with random intercept per cohort was used. The gDDRm status was known for all 390 patients (60 carriers of gDDRm [gDDRm+], including 37 gBRCA2m, and 330 cases not found to carry gDDRm [gDDRm–]); 74% and 69% were treated with docetaxel and abiraterone/enzalutamide, respectively, and 36% received PARP inhibitors (PARPi) and/or platinum. Median OS from castration resistance was similar among groups (3.2 vs 3.0 yr, p=0.73). Median docetaxel PFS for gDDRm+ (6.8 mo) was not significantly different from that for gDDRm– (5.1 mo), and RRs were similar (gDDRm+=61%; gDDRm–=54%). There were no significant differences in median PFS and RR on first-line abiraterone/enzalutamide (gDDRm+=8.3 mo, gDDRm–=8.3 mo; gDDRm+=46%, gDDRm–=56%). Interaction test for PARPi/platinum and gDDRm+ resulted in an OS adjusted hazard ratio of 0.59 (95% confidence interval 0.28–1.25; p=0.17). Results are limited by the retrospective nature of the analysis. mPC patients with gDDRm appeared to benefit from standard therapies similarly to the overall population; prospective studies are ongoing to investigate the impact of PARPi/platinum. Patients with inherited DNA repair mutations benefit from standard therapies similarly to other metastatic prostate cancer patients. Metastatic prostate cancer patients carrying germline mutations in DNA damage repair genes derive similar benefit from standard of care taxanes and androgen receptor signalling inhibitors to the overall population. 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Their prognostic and predictive impact relating to standard therapies is unclear. To determine whether gDDRm status impacts benefit from established therapies in mPC. This is a retrospective, international, observational study. Medical records were reviewed for 390 mPC patients with known gDDRm status. All 372 patients from Royal Marsden (UK), Weill-Cornell (NY), and University of Washington (WA) were previously included in a prevalence study (Pritchard, NEJM 2016); the remaining 18 were gBRCA1/2m carriers, from the kConFab consortium, Australia. Response rate (RR), progression-free survival (PFS), and overall survival (OS) data were collected. To account for potential differences between cohorts, a mixed-effect model (Weibull distribution) with random intercept per cohort was used. The gDDRm status was known for all 390 patients (60 carriers of gDDRm [gDDRm+], including 37 gBRCA2m, and 330 cases not found to carry gDDRm [gDDRm–]); 74% and 69% were treated with docetaxel and abiraterone/enzalutamide, respectively, and 36% received PARP inhibitors (PARPi) and/or platinum. Median OS from castration resistance was similar among groups (3.2 vs 3.0 yr, p=0.73). Median docetaxel PFS for gDDRm+ (6.8 mo) was not significantly different from that for gDDRm– (5.1 mo), and RRs were similar (gDDRm+=61%; gDDRm–=54%). There were no significant differences in median PFS and RR on first-line abiraterone/enzalutamide (gDDRm+=8.3 mo, gDDRm–=8.3 mo; gDDRm+=46%, gDDRm–=56%). Interaction test for PARPi/platinum and gDDRm+ resulted in an OS adjusted hazard ratio of 0.59 (95% confidence interval 0.28–1.25; p=0.17). Results are limited by the retrospective nature of the analysis. mPC patients with gDDRm appeared to benefit from standard therapies similarly to the overall population; prospective studies are ongoing to investigate the impact of PARPi/platinum. Patients with inherited DNA repair mutations benefit from standard therapies similarly to other metastatic prostate cancer patients. Metastatic prostate cancer patients carrying germline mutations in DNA damage repair genes derive similar benefit from standard of care taxanes and androgen receptor signalling inhibitors to the overall population. 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Cheng, Heather H. ; Beltran, Himisha ; Dolling, David ; Xu, Wen ; Pritchard, Colin C. ; Mossop, Helen ; Rescigno, Pasquale ; Perez-Lopez, Raquel ; Sailer, Verena ; Kolinsky, Michael ; Balasopoulou, Ada ; Bertan, Claudia ; Nanus, David M. ; Tagawa, Scott T. ; Thorne, Heather ; Montgomery, Bruce ; Carreira, Suzanne ; Sandhu, Shahneen ; Rubin, Mark A. ; Nelson, Peter S. ; de Bono, Johann S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-861ff874fa0e2b274d93c24f6b0252de61d6592a4b742155dce571575fad32693</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Aged</topic><topic>Androgen Antagonists - therapeutic use</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Biomarkers</topic><topic>Biopsy, Needle</topic><topic>BRCA</topic><topic>Cohort Studies</topic><topic>Disease-Free Survival</topic><topic>DNA repair</topic><topic>DNA Repair - drug effects</topic><topic>DNA Repair - genetics</topic><topic>Genomics</topic><topic>Germ-Line Mutation - genetics</topic><topic>Germline</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Internationality</topic><topic>Kaplan-Meier Estimate</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Neoplasm Grading</topic><topic>Precision medicine</topic><topic>Prognosis</topic><topic>Proportional Hazards Models</topic><topic>Prostate cancer</topic><topic>Prostatic Neoplasms, Castration-Resistant - drug therapy</topic><topic>Prostatic Neoplasms, Castration-Resistant - genetics</topic><topic>Prostatic Neoplasms, Castration-Resistant - mortality</topic><topic>Prostatic Neoplasms, Castration-Resistant - pathology</topic><topic>Retrospective Studies</topic><topic>Risk Assessment</topic><topic>Survival Analysis</topic><topic>Treatment Outcome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mateo, Joaquin</creatorcontrib><creatorcontrib>Cheng, Heather H.</creatorcontrib><creatorcontrib>Beltran, Himisha</creatorcontrib><creatorcontrib>Dolling, David</creatorcontrib><creatorcontrib>Xu, Wen</creatorcontrib><creatorcontrib>Pritchard, Colin C.</creatorcontrib><creatorcontrib>Mossop, Helen</creatorcontrib><creatorcontrib>Rescigno, Pasquale</creatorcontrib><creatorcontrib>Perez-Lopez, Raquel</creatorcontrib><creatorcontrib>Sailer, Verena</creatorcontrib><creatorcontrib>Kolinsky, Michael</creatorcontrib><creatorcontrib>Balasopoulou, Ada</creatorcontrib><creatorcontrib>Bertan, Claudia</creatorcontrib><creatorcontrib>Nanus, David M.</creatorcontrib><creatorcontrib>Tagawa, Scott T.</creatorcontrib><creatorcontrib>Thorne, Heather</creatorcontrib><creatorcontrib>Montgomery, Bruce</creatorcontrib><creatorcontrib>Carreira, Suzanne</creatorcontrib><creatorcontrib>Sandhu, Shahneen</creatorcontrib><creatorcontrib>Rubin, Mark A.</creatorcontrib><creatorcontrib>Nelson, Peter S.</creatorcontrib><creatorcontrib>de Bono, Johann S.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>European urology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mateo, Joaquin</au><au>Cheng, Heather H.</au><au>Beltran, Himisha</au><au>Dolling, David</au><au>Xu, Wen</au><au>Pritchard, Colin C.</au><au>Mossop, Helen</au><au>Rescigno, Pasquale</au><au>Perez-Lopez, Raquel</au><au>Sailer, Verena</au><au>Kolinsky, Michael</au><au>Balasopoulou, Ada</au><au>Bertan, Claudia</au><au>Nanus, David M.</au><au>Tagawa, Scott T.</au><au>Thorne, Heather</au><au>Montgomery, Bruce</au><au>Carreira, Suzanne</au><au>Sandhu, Shahneen</au><au>Rubin, Mark A.</au><au>Nelson, Peter S.</au><au>de Bono, Johann S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Clinical Outcome of Prostate Cancer Patients with Germline DNA Repair Mutations: Retrospective Analysis from an International Study</atitle><jtitle>European urology</jtitle><addtitle>Eur Urol</addtitle><date>2018-05-01</date><risdate>2018</risdate><volume>73</volume><issue>5</issue><spage>687</spage><epage>693</epage><pages>687-693</pages><issn>0302-2838</issn><issn>1873-7560</issn><eissn>1873-7560</eissn><abstract>Germline DNA damage repair gene mutation (gDDRm) is found in &gt;10% of metastatic prostate cancer (mPC). Their prognostic and predictive impact relating to standard therapies is unclear. To determine whether gDDRm status impacts benefit from established therapies in mPC. This is a retrospective, international, observational study. Medical records were reviewed for 390 mPC patients with known gDDRm status. All 372 patients from Royal Marsden (UK), Weill-Cornell (NY), and University of Washington (WA) were previously included in a prevalence study (Pritchard, NEJM 2016); the remaining 18 were gBRCA1/2m carriers, from the kConFab consortium, Australia. Response rate (RR), progression-free survival (PFS), and overall survival (OS) data were collected. To account for potential differences between cohorts, a mixed-effect model (Weibull distribution) with random intercept per cohort was used. The gDDRm status was known for all 390 patients (60 carriers of gDDRm [gDDRm+], including 37 gBRCA2m, and 330 cases not found to carry gDDRm [gDDRm–]); 74% and 69% were treated with docetaxel and abiraterone/enzalutamide, respectively, and 36% received PARP inhibitors (PARPi) and/or platinum. Median OS from castration resistance was similar among groups (3.2 vs 3.0 yr, p=0.73). Median docetaxel PFS for gDDRm+ (6.8 mo) was not significantly different from that for gDDRm– (5.1 mo), and RRs were similar (gDDRm+=61%; gDDRm–=54%). There were no significant differences in median PFS and RR on first-line abiraterone/enzalutamide (gDDRm+=8.3 mo, gDDRm–=8.3 mo; gDDRm+=46%, gDDRm–=56%). Interaction test for PARPi/platinum and gDDRm+ resulted in an OS adjusted hazard ratio of 0.59 (95% confidence interval 0.28–1.25; p=0.17). Results are limited by the retrospective nature of the analysis. mPC patients with gDDRm appeared to benefit from standard therapies similarly to the overall population; prospective studies are ongoing to investigate the impact of PARPi/platinum. Patients with inherited DNA repair mutations benefit from standard therapies similarly to other metastatic prostate cancer patients. Metastatic prostate cancer patients carrying germline mutations in DNA damage repair genes derive similar benefit from standard of care taxanes and androgen receptor signalling inhibitors to the overall population. Moreover, this exploratory analysis supports further investigation of the impact of PARP inhibitors and platinum chemotherapy in this subset of patients.</abstract><cop>Switzerland</cop><pub>Elsevier B.V</pub><pmid>29429804</pmid><doi>10.1016/j.eururo.2018.01.010</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0002-2034-595X</orcidid><oa>free_for_read</oa></addata></record>
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source MEDLINE; Elsevier ScienceDirect Journals
subjects Aged
Androgen Antagonists - therapeutic use
Antineoplastic Agents - therapeutic use
Biomarkers
Biopsy, Needle
BRCA
Cohort Studies
Disease-Free Survival
DNA repair
DNA Repair - drug effects
DNA Repair - genetics
Genomics
Germ-Line Mutation - genetics
Germline
Humans
Immunohistochemistry
Internationality
Kaplan-Meier Estimate
Male
Middle Aged
Neoplasm Grading
Precision medicine
Prognosis
Proportional Hazards Models
Prostate cancer
Prostatic Neoplasms, Castration-Resistant - drug therapy
Prostatic Neoplasms, Castration-Resistant - genetics
Prostatic Neoplasms, Castration-Resistant - mortality
Prostatic Neoplasms, Castration-Resistant - pathology
Retrospective Studies
Risk Assessment
Survival Analysis
Treatment Outcome
title Clinical Outcome of Prostate Cancer Patients with Germline DNA Repair Mutations: Retrospective Analysis from an International Study
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