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

ABSTRACT: BACKGROUND: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. OBJECTIVE:To determine whether gDDRm status impacts benefit from established therapies in mPC. DESIGN, SETTING, AND PARTICIPANTS: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. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: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. RESULTS AND LIMITATIONS: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. CONCLUSIONS: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. PATIENT SUMMARY:Patients with inherited DNA repair mutations benefit from standard therapies similarly to other metastatic prostate cancer patients.

SUBMITTER: Mateo J

PROVIDER: S-EPMC6745088 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Mateo Joaquin J Cheng Heather H HH Beltran Himisha H Dolling David D Xu Wen W Pritchard Colin C CC Mossop Helen H Rescigno Pasquale P Perez-Lopez Raquel R Sailer Verena V Kolinsky Michael M Balasopoulou Ada A Bertan Claudia C Nanus David M DM Tagawa Scott T ST Thorne Heather H Montgomery Bruce B Carreira Suzanne S Sandhu Shahneen S Rubin Mark A MA Nelson Peter S PS de Bono Johann S JS

European urology 20180208 5

<h4>Background</h4>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.<h4>Objective</h4>To determine whether gDDRm status impacts benefit from established therapies in mPC.<h4>Design, setting, and participants</h4>This is a retrospective, international, observational study. Medical records were reviewed for 390 mPC patients with known gDDRm status. All 372 patients ...[more]

PMID: 29429804

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Project description:BACKGROUND:Germline DNA damage repair gene mutations (gDDRm) have been found in approximately 12% of patients with metastatic prostate cancer (mPCa). Previous studies of the clinical impact of gDDRm have mainly been in the setting of metastatic castration-resistant prostate cancer (mCRPC). This study aimed to determine the prognostic value of gDDRm in de novo metastatic and castration-sensitive prostate cancer (mCSPC). MATERIALS AND METHODS:We retrospectively collected the records of 139 consecutive men with de novo mCSPC who initially received systemic therapies following guidelines. This included 128 patients who underwent genetic testing at our center and 11 patients referred to our center after being identified as gDDRm carriers. Time to mCRPC was collected. Kaplan-Meier and log-rank analysis were used to analyze the association between gDDRm and clinical outcomes. Survival outcomes were adjusted using multivariable Cox regression models. RESULTS:Of the 139 patients with de novo mCSPC, 28 gDDRm carriers were identified. Median time progressing to mCRPC was significantly shorter in patients carrying gDDRm than in those without mutations (8.3 vs 13.2 months; hazard ratio [HR], 2.37; p < .001). Moreover, median progression time was almost halved in BRCA2 carriers (6.3 vs. 13.2 months; HR, 3.73; p < .001). Subgroup analysis revealed that the presence of gDDRm indicated poor therapy response regardless of disease volume and prostate-specific antigen nadir within the first 7 months. Presence of gDDRm remained independently associated with increased risk of progression to mCRPC in multivariate analysis (adjusted HR, 1.98; p = .006). CONCLUSION:Our study suggested that positive gDDRm status predicted rapid progression to castration resistance in patients with de novo mCSPC. We propose identifying gDDRm status at the time of diagnosis for mCSPC patients, considering it is the first step of tailoring individualized treatment. In addition, DNA repair genes were a good therapeutic target for poly (ADP-ribose) polymerase inhibitors, and our results call for more frontline targeted therapy trials in gDDRm carriers to prolong the progression time. IMPLICATIONS FOR PRACTICE:Results of this study suggested that positive germline DNA damage repair gene mutation (gDDRm) status predicted earlier progression to castration resistance in patients with de novo metastatic and castration-sensitive prostate cancer (mCSPC). These findings indicated the importance of intense therapy for some subgroups of mCSPC, especially for mCSPC harboring gDDRm with low-volume disease. Moreover, gDDRm was a good therapeutic target for poly (ADP-ribose) polymerase inhibitors, and these findings call for more molecular marker driven trials moving to the mTNPC setting.

Project description:BackgroundGermline mutations in genes mediating DNA repair are common in men with recurrent and advanced prostate cancer, and their presence may alter prognosis and management. We aimed to define pathological and clinical characteristics associated with germline DNA-repair gene mutations, to facilitate selection of patients for germline testing.MethodsWe retrospectively evaluated 150 unselected patients with recurrent or metastatic prostate cancer who were offered germline genetic testing by a single oncologist using a clinical-grade assay (Color Genomics). This platform utilizes next-generation sequencing from saliva to interrogate 30 cancer-susceptibility genes. Presence or absence of a deleterious germline mutation was correlated with histological and clinical characteristics, and with family history of cancer. All patients with DNA-sequence alterations (pathogenic or variants) were offered genetic counseling.ResultsBetween July 2016 and July 2017, 150 consecutive patients underwent germline testing; pathogenic mutations were identified in 21 men (14%). Among those with germline mutations, 9 (43%) were in BRCA2, 3 (14%) were in ATM, 3 (14%) were in CHEK2, and 2 (9%) were in BRCA1. While there were no associations between germline mutations and age, tumor stage, Gleason sum or family history; mutation-positive patients had lower median PSA levels at diagnosis (5.5 vs 8.6 ng/mL, P = 0.01) and unique pathologic features. Namely, men with germline mutations were more likely to harbor intraductal/ductal histology (48% vs 12%, P < 0.01) and lymphovascular invasion (52% vs 14%, P < 0.01). Finally, 44% of patients with a positive germline test would not have been offered genetic screening according to current National Comprehensive Cancer Network (NCCN) guidelines.ConclusionsPresence of intraductal/ductal histology and lymphovascular invasion appear to be associated with pathogenic germline DNA-repair gene mutations in men with prostate cancer, and identification of these features may help to select patients for germline testing. NCCN guidelines may be inadequate in predicting which prostate cancer patients should undergo genetic screening.

Dataset Information

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

Publications

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

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