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Impact of mutations in homologous recombination repair genes on treatment outcomes for metastatic castration resistant prostate cancer.

ABSTRACT: INTRODUCTION:A significant proportion of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor mutations in homologous recombination (HR) repair genes, with some of these mutations associating with increased tumor susceptibility to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy. While mutations in some HR repair genes (e.g., BRCA1/2) have been associated with a more aggressive clinical course, prior studies correlating HR mutational status with treatment response to androgen receptor (AR) signaling inhibitors (ARSIs) or taxane-based chemotherapy have yielded conflicting results. METHODS:We conducted a single-center retrospective analysis to assess clinical outcomes to conventional, regulatory-approved therapies in mCRPC patients with somatic (monoallelic and biallelic) and/or germline HR repair mutations compared to patients without alterations as determined by clinical-grade next-generation sequencing assays. The primary endpoint was PSA30/PSA50 response, defined as ?30%/?50% prostate-specific antigen (PSA) reduction from baseline. Secondary endpoints of PSA progression-free survival (pPFS) and clinical/radiographic progression-free survival (crPFS) were estimated using Kaplan-Meier methods. RESULTS:A total of 90 consecutively selected patients were included in this analysis, of which 33 (37%) were identified to have HR repair gene mutations. Age, race, Gleason score, prior surgery, and receipt of prior radiation therapy were comparable between carriers and non-carriers. There was no evidence that PSA30/PSA50 differed by HR gene mutational status. Median pPFS and crPFS ranged 3-14 months across treatment modalities, but there was no evidence either differed by HR gene mutational status (all p>0.05). There was also no difference in outcomes between those with BRCA2 or PALB2 mutations (n = 17) compared to those without HR repair mutations. CONCLUSION:HR gene mutational status was associated with comparable clinical outcomes following treatment with ARSIs or taxane-based chemotherapy. Additional prospective studies are needed to confirm these findings.

SUBMITTER: Carlson AS

PROVIDER: S-EPMC7526881 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Impact of mutations in homologous recombination repair genes on treatment outcomes for metastatic castration resistant prostate cancer.

Carlson Alexander S AS Acevedo Rigo I RI Lim Daniel M DM Gulati Roman R Gawne Agnes A Sokolova Alexandra O AO Cheng Heather H HH Nelson Peter S PS Montgomery R Bruce RB Yu Evan Y EY Schweizer Michael T MT

PloS one 20200930 9

<h4>Introduction</h4>A significant proportion of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor mutations in homologous recombination (HR) repair genes, with some of these mutations associating with increased tumor susceptibility to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy. While mutations in some HR repair genes (e.g., BRCA1/2) have been associated with a more aggressive clinical course, prior studies correlating HR mutational s ...[more]

PMID: 32997692

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Project description:BackgroundPathogenic mutations in genes mediating homologous recombination (HR) DNA repair are present in 20-30% of men with metastatic castrate-resistant prostate cancer (mCRPC). Radium-223 is a bone-seeking α-emitter that induces double-strand DNA breaks, thereby killing cancer cells in the bone microenvironment.ObjectiveTo evaluate the potential impact of germline or somatic HR-deficiency (HRD) mutations on radium-223 efficacy in mCRPC with bone metastasis.Design, setting, and participantsThis is a retrospective single-institution study. Medical records of 190 mCRPC patients for whom germline and/or somatic DNA sequencing data were available were reviewed. Of these patients, 28 had received standard-of-care radium-223 at Johns Hopkins between February 2013 and February 2018.Outcome measurements and statistical analysisAlkaline phosphatase (ALP) responses and time-to-ALP-progression were the coprimary endpoints. Prostate-specific antigen (PSA) responses, overall survival (OS), and time to next systemic therapy were also evaluated.Results and limitationsOf the 28 patients included, 10 men (35.7%) had a germline/somatic HRD mutation (three in BRCA2, and one each in ATM, ATR, CHEK2, FANCG, FANCI, FANCL, and PALB2) and 18 (64.3%) did not. Men with HRD mutations (HRD+) had numerically lower ages (66 vs 73yr, p=0.25), more soft-tissue metastases (50% vs 38%, p=0.43), and higher baseline ALP levels (130 vs 108 U/l, p=0.84). Compared with HRD(-) men, HRD(+) patients showed greater ALP responses (80% vs 39%, p=0.04), longer time to ALP progression (median10.4 vs 5.8mo, hazard ratio [HR] 6.4, p=0.005), and a trend toward longer OS (median 36.9 vs 19.0mo, HR 3.3, p=0.11). PSA responses (0% vs 0%, p>0.99) and time to next systemic therapy (HR 1.5, p=0.39) were similar between the two groups. Results are limited by the retrospective nature of the analysis and the small sample size.ConclusionsIn this exploratory study, bone-metastatic CRPC patients with inactivating HRD mutations demonstrated significantly improved ALP responses and time to ALP progression. These results should motivate prospective validation of the "synthetic lethality" hypothesis between HRD mutations and radium-223 activity.Patient summaryIn this report, we retrospectively examined outcomes to metastatic prostate cancer in patients with and without DNA repair mutations who received radium-223, a therapy that kills cancer cells by causing direct DNA damage. Our study suggested that patients who have inherited or acquired DNA repair gene mutations derived greater benefit from radium-223 when compared with patients without these mutations. We concluded that radium-223 might have an important role in this setting; however, prospective studies are needed to confirm whether DNA repair mutations truly make radium-223 work better or not.

Project description:BackgroundInherited DNA-repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully understood.ObjectiveTo 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 participantsWe 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 analysisWe 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 limitationsAmong 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.ConclusionsOutcomes 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 summaryPatients with metastatic castration-resistant prostate cancer and harboring germline mutations in BRCA1/2 and ATM benefit from treatment with abiraterone and enzalutamide.

Dataset Information

Impact of mutations in homologous recombination repair genes on treatment outcomes for metastatic castration resistant prostate cancer.

Publications

Impact of mutations in homologous recombination repair genes on treatment outcomes for metastatic castration resistant prostate cancer.

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