Germline DNA-repair Gene Mutations and Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Receiving First-line Abiraterone and Enzalutamide

Emmanuel S. Antonarakis, Changxue Lu, Brandon Luber, Chao Liang, Hao Wang, Yan Chen, John L. Silberstein, Danilo Piana, Zhao Lai, Yidong Chen, William B. Isaacs, Jun Luo

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Background: Inherited DNA-repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully understood. Objective: To investigate the clinical significance of germline DNA-repair gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving next-generation hormonal therapy (NHT), with a particular emphasis on BRCA/ATM mutations. Design, setting, and participants: We interrogated 50 genes for pathogenic or likely pathogenic germline mutations using leukocyte DNA from 172 mCRPC patients beginning treatment with first-line NHT with abiraterone or enzalutamide. Outcome measurements and statistical analysis: We assessed the impact of germline DNA-repair gene mutation status on ≥50% and ≥90% PSA responses, PSA progression-free survival (PSA-PFS), clinical/radiologic progression-free survival (PFS), and overall survival (OS). Survival outcomes were adjusted using propensity score-weighted multivariable Cox regression analyses. Results and limitations: Among 172 mCRPC patients included, germline mutations (in any DNA-repair gene) were found in 12% (22/172) of men, and germline BRCA/ATM mutations specifically in 5% (9/172) of men. In unadjusted analyses, outcomes to first-line NHT were better in men with germline BRCA/ATM mutations (vs no mutations) with respect to PSA-PFS (hazard ratio [HR] 0.47; p = 0.061), PFS (HR 0.50; p = 0.090), and OS (HR 0.28; p = 0.059). In propensity score-weighted multivariable analyses, outcomes were superior in men with germline BRCA/ATM mutations with respect to PSA-PFS (HR 0.48, 95% confidence interval [CI] 0.25–0.92; p = 0.027), PFS (HR 0.52, 95% CI 0.28–0.98; p = 0.044), and OS (HR 0.34, 95% CI 0.12–0.99; p = 0.048), but not in men with non-BRCA/ATM germline mutations (all p > 0.10). These results require prospective validation, and our conclusions are limited by the small number of patients (n = 9) with BRCA/ATM mutations. Conclusions: Outcomes to first-line NHT appear better in mCRPC patients harboring germline BRCA/ATM mutations (vs no mutations), but not for patients with other non-BRCA/ATM germline mutations. Patient summary: Patients with metastatic castration-resistant prostate cancer and harboring germline mutations in BRCA1/2 and ATM benefit from treatment with abiraterone and enzalutamide. To determine whether and how germline DNA-repair gene mutations influence clinical outcomes to abiraterone or enzalutamide in patients with castration-resistant prostate cancer (CRPC), we performed germline genotyping for 50 DNA-repair genes using blood samples from 172 patients with CRPC beginning first-line systemic therapy with abiraterone or enzalutamide. We discovered that the presence of germline DNA-repair gene defects (particularly mutations in the BRCA1/2 and ATM genes) were associated with better outcomes to abiraterone and enzalutamide.

Original languageEnglish (US)
JournalEuropean Urology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Castration
DNA Repair
Prostatic Neoplasms
Mutation
Germ-Line Mutation
Genes
Disease-Free Survival
Propensity Score
Survival
Confidence Intervals
Therapeutics
abiraterone
MDV 3100
Leukocytes
Regression Analysis

Keywords

  • Abiraterone
  • DNA repair
  • Enzalutamide
  • Germline
  • Mutation

ASJC Scopus subject areas

  • Urology

Cite this

Germline DNA-repair Gene Mutations and Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Receiving First-line Abiraterone and Enzalutamide. / Antonarakis, Emmanuel S.; Lu, Changxue; Luber, Brandon; Liang, Chao; Wang, Hao; Chen, Yan; Silberstein, John L.; Piana, Danilo; Lai, Zhao; Chen, Yidong; Isaacs, William B.; Luo, Jun.

In: European Urology, 01.01.2018.

Research output: Contribution to journalArticle

Antonarakis, Emmanuel S. ; Lu, Changxue ; Luber, Brandon ; Liang, Chao ; Wang, Hao ; Chen, Yan ; Silberstein, John L. ; Piana, Danilo ; Lai, Zhao ; Chen, Yidong ; Isaacs, William B. ; Luo, Jun. / Germline DNA-repair Gene Mutations and Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Receiving First-line Abiraterone and Enzalutamide. In: European Urology. 2018.
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title = "Germline DNA-repair Gene Mutations and Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Receiving First-line Abiraterone and Enzalutamide",
abstract = "Background: Inherited DNA-repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully understood. Objective: To investigate the clinical significance of germline DNA-repair gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving next-generation hormonal therapy (NHT), with a particular emphasis on BRCA/ATM mutations. Design, setting, and participants: We interrogated 50 genes for pathogenic or likely pathogenic germline mutations using leukocyte DNA from 172 mCRPC patients beginning treatment with first-line NHT with abiraterone or enzalutamide. Outcome measurements and statistical analysis: We assessed the impact of germline DNA-repair gene mutation status on ≥50{\%} and ≥90{\%} PSA responses, PSA progression-free survival (PSA-PFS), clinical/radiologic progression-free survival (PFS), and overall survival (OS). Survival outcomes were adjusted using propensity score-weighted multivariable Cox regression analyses. Results and limitations: Among 172 mCRPC patients included, germline mutations (in any DNA-repair gene) were found in 12{\%} (22/172) of men, and germline BRCA/ATM mutations specifically in 5{\%} (9/172) of men. In unadjusted analyses, outcomes to first-line NHT were better in men with germline BRCA/ATM mutations (vs no mutations) with respect to PSA-PFS (hazard ratio [HR] 0.47; p = 0.061), PFS (HR 0.50; p = 0.090), and OS (HR 0.28; p = 0.059). In propensity score-weighted multivariable analyses, outcomes were superior in men with germline BRCA/ATM mutations with respect to PSA-PFS (HR 0.48, 95{\%} confidence interval [CI] 0.25–0.92; p = 0.027), PFS (HR 0.52, 95{\%} CI 0.28–0.98; p = 0.044), and OS (HR 0.34, 95{\%} CI 0.12–0.99; p = 0.048), but not in men with non-BRCA/ATM germline mutations (all p > 0.10). These results require prospective validation, and our conclusions are limited by the small number of patients (n = 9) with BRCA/ATM mutations. Conclusions: Outcomes to first-line NHT appear better in mCRPC patients harboring germline BRCA/ATM mutations (vs no mutations), but not for patients with other non-BRCA/ATM germline mutations. Patient summary: Patients with metastatic castration-resistant prostate cancer and harboring germline mutations in BRCA1/2 and ATM benefit from treatment with abiraterone and enzalutamide. To determine whether and how germline DNA-repair gene mutations influence clinical outcomes to abiraterone or enzalutamide in patients with castration-resistant prostate cancer (CRPC), we performed germline genotyping for 50 DNA-repair genes using blood samples from 172 patients with CRPC beginning first-line systemic therapy with abiraterone or enzalutamide. We discovered that the presence of germline DNA-repair gene defects (particularly mutations in the BRCA1/2 and ATM genes) were associated with better outcomes to abiraterone and enzalutamide.",
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author = "Antonarakis, {Emmanuel S.} and Changxue Lu and Brandon Luber and Chao Liang and Hao Wang and Yan Chen and Silberstein, {John L.} and Danilo Piana and Zhao Lai and Yidong Chen and Isaacs, {William B.} and Jun Luo",
year = "2018",
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TY - JOUR

T1 - Germline DNA-repair Gene Mutations and Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Receiving First-line Abiraterone and Enzalutamide

AU - Antonarakis, Emmanuel S.

AU - Lu, Changxue

AU - Luber, Brandon

AU - Liang, Chao

AU - Wang, Hao

AU - Chen, Yan

AU - Silberstein, John L.

AU - Piana, Danilo

AU - Lai, Zhao

AU - Chen, Yidong

AU - Isaacs, William B.

AU - Luo, Jun

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background: Inherited DNA-repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully understood. Objective: To investigate the clinical significance of germline DNA-repair gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving next-generation hormonal therapy (NHT), with a particular emphasis on BRCA/ATM mutations. Design, setting, and participants: We interrogated 50 genes for pathogenic or likely pathogenic germline mutations using leukocyte DNA from 172 mCRPC patients beginning treatment with first-line NHT with abiraterone or enzalutamide. Outcome measurements and statistical analysis: We assessed the impact of germline DNA-repair gene mutation status on ≥50% and ≥90% PSA responses, PSA progression-free survival (PSA-PFS), clinical/radiologic progression-free survival (PFS), and overall survival (OS). Survival outcomes were adjusted using propensity score-weighted multivariable Cox regression analyses. Results and limitations: Among 172 mCRPC patients included, germline mutations (in any DNA-repair gene) were found in 12% (22/172) of men, and germline BRCA/ATM mutations specifically in 5% (9/172) of men. In unadjusted analyses, outcomes to first-line NHT were better in men with germline BRCA/ATM mutations (vs no mutations) with respect to PSA-PFS (hazard ratio [HR] 0.47; p = 0.061), PFS (HR 0.50; p = 0.090), and OS (HR 0.28; p = 0.059). In propensity score-weighted multivariable analyses, outcomes were superior in men with germline BRCA/ATM mutations with respect to PSA-PFS (HR 0.48, 95% confidence interval [CI] 0.25–0.92; p = 0.027), PFS (HR 0.52, 95% CI 0.28–0.98; p = 0.044), and OS (HR 0.34, 95% CI 0.12–0.99; p = 0.048), but not in men with non-BRCA/ATM germline mutations (all p > 0.10). These results require prospective validation, and our conclusions are limited by the small number of patients (n = 9) with BRCA/ATM mutations. Conclusions: Outcomes to first-line NHT appear better in mCRPC patients harboring germline BRCA/ATM mutations (vs no mutations), but not for patients with other non-BRCA/ATM germline mutations. Patient summary: Patients with metastatic castration-resistant prostate cancer and harboring germline mutations in BRCA1/2 and ATM benefit from treatment with abiraterone and enzalutamide. To determine whether and how germline DNA-repair gene mutations influence clinical outcomes to abiraterone or enzalutamide in patients with castration-resistant prostate cancer (CRPC), we performed germline genotyping for 50 DNA-repair genes using blood samples from 172 patients with CRPC beginning first-line systemic therapy with abiraterone or enzalutamide. We discovered that the presence of germline DNA-repair gene defects (particularly mutations in the BRCA1/2 and ATM genes) were associated with better outcomes to abiraterone and enzalutamide.

AB - Background: Inherited DNA-repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully understood. Objective: To investigate the clinical significance of germline DNA-repair gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving next-generation hormonal therapy (NHT), with a particular emphasis on BRCA/ATM mutations. Design, setting, and participants: We interrogated 50 genes for pathogenic or likely pathogenic germline mutations using leukocyte DNA from 172 mCRPC patients beginning treatment with first-line NHT with abiraterone or enzalutamide. Outcome measurements and statistical analysis: We assessed the impact of germline DNA-repair gene mutation status on ≥50% and ≥90% PSA responses, PSA progression-free survival (PSA-PFS), clinical/radiologic progression-free survival (PFS), and overall survival (OS). Survival outcomes were adjusted using propensity score-weighted multivariable Cox regression analyses. Results and limitations: Among 172 mCRPC patients included, germline mutations (in any DNA-repair gene) were found in 12% (22/172) of men, and germline BRCA/ATM mutations specifically in 5% (9/172) of men. In unadjusted analyses, outcomes to first-line NHT were better in men with germline BRCA/ATM mutations (vs no mutations) with respect to PSA-PFS (hazard ratio [HR] 0.47; p = 0.061), PFS (HR 0.50; p = 0.090), and OS (HR 0.28; p = 0.059). In propensity score-weighted multivariable analyses, outcomes were superior in men with germline BRCA/ATM mutations with respect to PSA-PFS (HR 0.48, 95% confidence interval [CI] 0.25–0.92; p = 0.027), PFS (HR 0.52, 95% CI 0.28–0.98; p = 0.044), and OS (HR 0.34, 95% CI 0.12–0.99; p = 0.048), but not in men with non-BRCA/ATM germline mutations (all p > 0.10). These results require prospective validation, and our conclusions are limited by the small number of patients (n = 9) with BRCA/ATM mutations. Conclusions: Outcomes to first-line NHT appear better in mCRPC patients harboring germline BRCA/ATM mutations (vs no mutations), but not for patients with other non-BRCA/ATM germline mutations. Patient summary: Patients with metastatic castration-resistant prostate cancer and harboring germline mutations in BRCA1/2 and ATM benefit from treatment with abiraterone and enzalutamide. To determine whether and how germline DNA-repair gene mutations influence clinical outcomes to abiraterone or enzalutamide in patients with castration-resistant prostate cancer (CRPC), we performed germline genotyping for 50 DNA-repair genes using blood samples from 172 patients with CRPC beginning first-line systemic therapy with abiraterone or enzalutamide. We discovered that the presence of germline DNA-repair gene defects (particularly mutations in the BRCA1/2 and ATM genes) were associated with better outcomes to abiraterone and enzalutamide.

KW - Abiraterone

KW - DNA repair

KW - Enzalutamide

KW - Germline

KW - Mutation

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