Germline DNA Repair Mutations Research Articles

The effect of germline DNA repair mutations on radiosensitivity in pancreatic ductal adenocarcinoma.

703 Background: The association between homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC) and sensitivity to platinum-based chemotherapy highlights the need to further understand how germline DNA repair mutations influence the efficacy of different therapies. Given the recent ALLIANCE data that chemotherapy alone is an acceptable standard of care to enhance R0 resection, the focus has shifted towards the contribution of radiotherapy. However, the relationship between germline DNA repair mutations in general and radiosensitivity remains less understood. This study explores the relationship between germline mutations and the Radiosensitivity Index (RSI) gene signature. Methods: After obtaining institutional review board approval, a retrospective analysis was performed of patients who had both RSI and germline mutation testing (i.e., BRCA1, BRCA2, BLM, ATM, MLH1, MSH2, MSH6, PMS2, and BARD mutations) between 1999 and 2023 at a single institution. Student T, Chi squared, Kaplan Meier (KM), Cox univariate log regression (UVA), and Mann-Whitney U (MWU) tests were used for statistical analyses. Results: A total of 25 patients were included, 13 with mutations and 12 without. MWU analysis demonstrated a significant difference in RSI values, where patients with mutations exhibited greater radiosensitivity (mean 0.379 vs. 0.464, p=0.040). The median age at diagnosis, max diameter of tumor, and baseline CA 19-9 were 67 years (range 47 – 77), 3.4 cm (range 0.8 – 8.2), and 288 (9.5 – 26,100), respectively. Most of the tumors were resectable (84%), stage IIB (36%), and grade 2 (68%). All patients underwent resection, with the majority without neoadjuvant therapy (96%). Most patients received chemotherapy (n=18; 72%), most commonly gemcitabine monotherapy (n=14/18). A majority also received radiation therapy (n=15; 60%), with 93% receiving chemoradiation (n=14/15). The median follow-up was 20.8 months. KM analysis yielded a median overall survival (OS) of 20.0 months (95% CI: 7.1-33.0) and progression-free survival (PFS) of 15.1 months (95% CI: 12.3-18.0) for the entire cohort. At the time of analysis, 15.4% of patients with mutations were alive (>10 years), compared to none without mutations (p=0.157). There were no statistically significant differences between the two cohorts for clinical outcomes on KM analysis. On UVA, worse OS was correlated with stage III (HR 7.9, 95% CI 1.2 – 50.2) and IV (HR 11.8, 95% CI 1.4 – 102.3). No other variables were associated with OS on UVA or on mutant-only subgroup analysis. Conclusions: Our findings demonstrate an increased radiosensitivity in patients with germline DNA repair mutations, suggesting these cancers might be more susceptible to radiation-induced DNA damage. Since our results are constrained by the small sample size, further studies are needed to understand the relationship between PDAC with DNA repair mutations.

Internet-Based Germline Genetic Testing for Men With Metastatic Prostate Cancer.

Germline mutations in DNA repair genes are present in approximately 10% of men with metastatic prostate cancer (mPC), and guidelines recommend genetic germline testing. Notable barriers exist, including access to genetic counseling, insurance coverage, and out-of-pocket costs. The GENTleMEN study was designed to determine the feasibility of an Internet-based, patient-driven germline genetic testing approach for men with mPC. In this prospective cohort study, men with mPC provided informed consent via an Internet-based platform and completed a questionnaire including demographics and family cancer history. Supporting medical data were also collected. Genetic testing was performed using the Color Genomics 30-gene targeted panel of cancer predisposition genes on a mailed saliva sample. Men whose test results identified a germline pathogenic or likely pathogenic variant received results by phone or telehealth genetic counseling; other participants received results by email with an option for phone-based or telehealth genetic counseling. As of August 18, 2021, 816 eligible men were consented, of whom 68% (551) completed genetic testing, and 8.7% (48 of 551) were found to carry a pathogenic or likely pathogenic variant in a germline DNA repair gene: CHEK2 (17), BRCA2 (15), ATM (6), NBN1 (3), BRCA1 (2), PALB2 (2), PMS2 (2), and MSH6 (1). Participants were more likely to complete the testing process if they were non-Hispanic White, married, highly educated, or from a higher-income bracket. Here, we show the feasibility of delivering germline (inherited) genetic testing by a voluntary, patient-driven, Internet-based platform to men with mPC. Preliminary results show rates of germline DNA repair mutations, consistent with other cohorts. Although feasible for some, reduced steps for participation, more dedicated diverse outreach and participant support, and identification and addressing of additional barriers is needed to ensure equitable access and optimization.

Germline Testing in Prostate Cancer: When and Who to Test.

The results of multiple studies have shown that a substantial proportion of men with advanced prostate cancer carry germline DNA repair mutations. Germline testing in prostate cancer may inform treatment decisions and consideration for clinical trials. There are 2 FDA approved PARP inhibitors (PARPi), olaparib (Lynparza) and rucaparib (Rubraca), for the treatment of advanced prostate cancer with DNA repair deficiency. Increasing demand for germline testing in prostate cancer and a shortage of genetic counselors have created a need for alternative care models and encouraged oncologists to take a more active role in performing germline testing. This article summarizes recommendations for germline testing in prostate cancer and describes care models for providing counseling and testing.

Re: PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair Mutations on the Outcomes of Patients with Metastatic Castration-resistant Prostate Cancer

Re: PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair Mutations on the Outcomes of Patients with Metastatic Castration-resistant Prostate Cancer

PD11-08 A 30-GENE HEREDITARY CANCER MUTATION ANALYSIS PREDICTS TIME TO BIOCHEMICAL RECURRENCE IN CLINICALLY LOCALIZED PROSTATE CANCER

INTRODUCTION AND OBJECTIVES:Pathogenic germline DNA repair mutations are enriched in men with advanced prostate cancer (PC) and are harbingers of an aggressive, lethal course. Though guidelines rec...

Germline DNA repair mutations in men with prostate cancer are less frequent in African Americans as compared with Caucasians.

258 Background: Pathogenic DNA repair defects are well described in Caucasian (C) men with prostate cancer (PCa) but comparative data on African-American (AA) men are sparse. Methods: Germline testing for DNA repair defects were assayed by Invitae (Invitae.com). Pathogenic variants in 14 genes were compared between AA and C men with PCa; these particular genes were also assessed by Pritchard et al NEJM 375:443, 2016. Identical gene panels were not used in all men, thus variations in assay numbers from gene to gene are noted. Chi square was used to compare proportions. Results: In the 14 genes, there were 16/214 (7.5%) AA men and 347/2488 (13.9%) C men with pathogenic findings (p=0.008). As shown in the Table, the most common pathogenic variants in AA men were BRCA2 (6/214, 2.8%), BRCA1 (3/213, 1.4%), PALB2 (2/182, 1.1%), ATM (2/206, 1.0%), RAD51C (1/148, 0.68%), CHEK2 (1/207, 0.48%), and PMS2 (1/212, 0.47%). In contrast to C men in this series, no AA men had pathogenic mutations in BARD1, BRIP1, MLH1, MSH2, MSH6, NBN, or RAD51D. Pathogenic CHEK2 was less commonly detected in AA as compared to C (p=0.03) in this dataset. Comparing our C men revealed no differences in the proportion of men with pathogenic findings compared to Pritchard et al (13.9% here vs 11.8%, P=0.15). Conclusions: AA men with PCa are less likely to have pathogenic DNA repair mutations among these 14 assayed DNA repair genes compared to C men. Limitations regarding lack of stage, Gleason scores, and FH are notable. Details on gene assays and comparison to Pritchard et al NEJM 375:443, 2016 [Table: see text]

PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair Mutations on the Outcomes of Patients With Metastatic Castration-Resistant Prostate Cancer.

Germline mutations in DNA damage repair (DDR) genes are identified in a significant proportion of patients with metastatic prostate cancer, but the clinical implications of these genes remain unclear. This prospective multicenter cohort study evaluated the prevalence and effect of germline DDR (gDDR) mutations on metastatic castration-resistance prostate cancer (mCRPC) outcomes. Unselected patients were enrolled at diagnosis of mCRPC and were screened for gDDR mutations in 107 genes. The primary aim was to assess the impact of ATM/BRCA1/BRCA2/ PALB2 germline mutations on cause-specific survival (CSS) from diagnosis of mCRPC. Secondary aims included the association of gDDR subgroups with response outcomes for mCRPC treatments. Combined progression-free survival from the first systemic therapy (PFS) until progression on the second systemic therapy (PFS2) was also explored. We identified 68 carriers (16.2%) of 419 eligible patients, including 14 with BRCA2, eight with ATM, four with BRCA1, and none with PALB2 mutations. The study did not reach its primary end point, because the difference in CSS between ATM/BRCA1/BRCA2/PALB2 carriers and noncarriers was not statistically significant (23.3 v 33.2 months; P = .264). CSS was halved in germline BRCA2 (g BRCA2) carriers (17.4 v 33.2 months; P = .027), and g BRCA2 mutations were identified as an independent prognostic factor for CCS (hazard ratio [HR], 2.11; P = .033). Significant interactions between g BRCA2 status and treatment type (androgen signaling inhibitor v taxane therapy) were observed (CSS adjusted P = .014; PFS2 adjusted P = .005). CSS (24.0 v 17.0 months) and PFS2 (18.9 v 8.6 months) were greater in g BRCA2 carriers treated in first line with abiraterone or enzalutamide compared with taxanes. Clinical outcomes did not differ by treatment type in noncarriers. g BRCA2 mutations have a deleterious impact on mCRPC outcomes that may be affected by the first line of treatment used. Determination of g BRCA2 status may be of assistance for the selection of the initial treatment in mCRPC. Nonetheless, confirmatory studies are required before these results can support a change in clinical practice.

Recent advances in prostate cancer research: large-scale genomic analyses reveal novel driver mutations and DNA repair defects.

Prostate cancer (PCa) is a disease of mutated and misregulated genes. However, primary prostate tumors have relatively few mutations, and only three genes ( ERG, PTEN, and SPOP) are recurrently mutated in more than 10% of primary tumors. On the other hand, metastatic castration-resistant tumors have more mutations, but, with the exception of the androgen receptor gene ( AR), no single gene is altered in more than half of tumors. Structural genomic rearrangements are common, including ERG fusions, copy gains involving the MYC locus, and copy losses containing PTEN. Overall, instead of being associated with a single dominant driver event, prostate tumors display various combinations of modifications in oncogenes and tumor suppressors. This review takes a broad look at the recent advances in PCa research, including understanding the genetic alterations that drive the disease and how specific mutations can sensitize tumors to potential therapies. We begin with an overview of the genomic landscape of primary and metastatic PCa, enabled by recent large-scale sequencing efforts. Advances in three-dimensional cell culture techniques and mouse models for PCa are also discussed, and particular emphasis is placed on the benefits of patient-derived xenograft models. We also review research into understanding how ETS fusions (in particular, TMPRSS2-ERG) and SPOP mutations contribute to tumor initiation. Next, we examine the recent findings on the prevalence of germline DNA repair mutations in about 12% of patients with metastatic disease and their potential benefit from the use of poly(ADP-ribose) polymerase (PARP) inhibitors and immune modulation. Lastly, we discuss the recent increased prevalence of AR-negative tumors (neuroendocrine and double-negative) and the current state of immunotherapy in PCa. AR remains the primary clinical target for PCa therapies; however, it does not act alone, and better understanding of supporting mutations may help guide the development of novel therapeutic strategies.

Clinical outcome of patients with germline DNA repair mutations: Results from a retrospective international study.

218 Background: CRPC is enriched for germline mutations in DNA damage repair genes (gDDRm). BRCA2 mutations (g BRCA2m) associate with poor prognosis from localized PC, but prognostic and predictive value for standard therapy in CRPC is unclear. We reviewed clinical outcome of 390 patients previously tested for gDDRm. Methods: Patient records were reviewed for 372 patients from 3 institutions (Royal Marsden UK, Weill-Cornell NY, University of Washington, WA) with gDDRm status previously published (Pritchard et al, NEJM 2016) and 18 g BRCA1/2m carriers from KConFab consortium (Australia). Baseline characteristics and survival were annotated. Response (PSA50%/RECIST) and PFS (RECIST/PSA progression or start of a new therapy due to clinical progression) were collected for Abiraterone, Enzalutamide and Docetaxel. To account for potential differences between cohorts, a mixed effect model (Weibull distribution) with random intercept per cohort was pursued. Results: dDDRm status was available for n = 390 (60 gDDRm+, including 37 g BRCA2m, and 330 gDDRm-). Overall, 74% and 69% received Docetaxel and Abiraterone/Enzalutamide respectively; 47% gDDRm+ and 34% gDDRm- received PARPi and/or platinum. Median overall survival from CRPC was 3.0 vs 3.2 years in gDDRm+ vs gDDRm- (p = 0.73; g BRCA2m = 3.0 years, p = 0.72). Age and Gleason score at diagnosis were associated with survival from castration-resistance in multivariate analysis. Median PFS on Docetaxel for gDDRm+ (6.8 months; 6.3 for g BRCA2m) and gDDRm- (5.1 months) were not significantly different (p = 0.2). Similarly, RR to Docetaxel was similar for the two groups (61% vs 54% in gDDRm+ vs gDDRm-; 63% g BRCA2m). Median PFS and RR on first Abiraterone/Enzalutamide were similar across groups (PFS: 8.3 months gDDRm+, 8.3 months for gDDRm-; p = 0.9; RR 46% vs 56% respectively) The Interaction of PARPi/platinum therapy among gDDRm+ patients resulted in an aHR for OS from CRPC of 0.59 (95%CI 0.28-1.25; p = 0.17). Conclusions: In this retrospective analysis, CRPC patients with gDDRm still benefited from standard therapies similarly to non-mutation carriers; interpretation of survival data should consider the high proportion treated with PARPi/platinum.

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

BackgroundGermline 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. ObjectiveTo determine whether gDDRm status impacts benefit from established therapies in mPC. Design, setting, and participantsThis 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 analysisResponse 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 limitationsThe 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. ConclusionsmPC 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 summaryPatients with inherited DNA repair mutations benefit from standard therapies similarly to other metastatic prostate cancer patients.

Prostate Cancer Germline Variations and Implications for Screening and Treatment.

Prostate cancer (PCa) is a highly heritable disease, and rapid evolution of sequencing technologies has enabled marked progression of our understanding of its genetic inheritance. A complex polygenic model that involves common low-penetrance susceptibility alleles causing individually small but cumulatively significant risk and rarer genetic variants causing greater risk represent the current most accepted model. Through genome-wide association studies, more than 100 single-nucleotide polymorphisms (SNPs) associated with PCa risk have been identified. Consistent reports have identified germline mutations in the genes BRCA1, BRCA2, MMR, HOXB13, CHEK2, and NBS1 as conferring moderate risks, with some leading to a more aggressive disease behavior. Considering this knowledge, several research strategies have been developed to determine whether targeted prostate screening using genetic information can overcome the limitations of population-based prostate-specific antigen (PSA) screening. Germline DNA-repair mutations are more frequent in men with metastatic disease than previously thought, and these patients have a more favorable response to therapy with poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors. Genomic information is a practical tool that has the potential to enable the concept of precision medicine to become a reality in all steps of PCa patient care.

Germline DNA repair mutations in metastatic castration-resistant prostate cancer: Therapy response and applicability of circulating tumor DNA.

140 Background: Germline mutations in DNA repair genes were recently reported in 8-12% of patients with metastatic castration-resistant prostate cancer (mCRPC). It is unknown whether these mutations associate with differential response to Androgen Receptor (AR) targeted therapy. The aim of this study was to determine the clinical response of mCRPC patients with germline DNA repair defects to AR-directed therapies, and secondly to establish whether biallelic DNA-repair gene loss is detectable in matched circulating tumor DNA (ctDNA). Methods: We recruited 319 mCRPC patients and performed targeted germline sequencing of 22 DNA repair genes. In affected patients, matched plasma ctDNA was also sequenced. Prostate-specific antigen response and progression were assessed in relation to initial androgen deprivation therapy (ADT) and subsequent therapy for mCRPC using Kaplan-Meier analysis. Results: 24/319 (7.5%) patients had deleterious germline mutations, with BRCA2 (n = 16), PALB2 (n = 2) and CDK12 (n = 2) being the most frequent. Patients (n = 22) with mutations in genes linked to homologous recombination were heterogeneous at initial presentation but after starting ADT progressed to mCRPC with a median time of 12.3 months (95% CI 5.1-18.4). The median time to progression on first and second line AR-targeted therapy in the mCRPC setting was 3.2 months (95% CI 1.9-4.4) and 1.0 month (95% CI 0.8-1.1), respectively. For patients receiving chemotherapy as their initial therapy for mCRPC (n = 8) the median PFS was 7.5 months (95% CI 6.5-8.2). 10/11 evaluable patients with germline BRCA2 mutations had somatic deletion of the intact allele in ctDNA. Conclusions: mCRPC patients with germline DNA repair defects exhibit transient responses to AR-targeted therapy. Biallelic gene loss was robustly detected in ctDNA suggesting that this patient subset could be prioritized for therapies exploiting defective DNA repair using a liquid biopsy.

Abstract CT051: Carboplatin and talazoparib combination therapy results in differential efficacy and hematologic toxicity in BRCA-mutated patients

Abstract Background: Talazoparib is a novel PARP inhibitor (PARPi) in clinical development. Synergistic anti-tumor effects of PARPi and chemotherapy have been observed in preclinical models. This Phase 1 trial evaluates the tolerability, dose limiting toxicities (DLT) and efficacy of talazoparib in combination with carboplatin in patients with or without germ line DNA repair mutations. We hypothesize that talazoparib may overcome carboplatin resistance but induce greater toxicity in patients with DNA repair defects. Methods: Talazoparib and carboplatin pharmacokinetics (PK), safety and anti-tumor activity were evaluated in a 3+3 dose escalation design. Genetic testing, PK, pharmacodynamic effects (PD), biomarkers, and alternate dose modeling were evaluated to better understand the interaction of carboplatin and talazoparib. Results: 24 patients (median age 59y) were enrolled in 4 cohorts and treated with talazoparib 0.75 or 0.1 mg/day and carboplatin AUC 1 or 1.5 for 3/3 or 2/3 weeks. Tumor types included: breast (n = 11), prostate (n = 5), cholangiocarcinoma (n = 2), ovarian (n = 2), bladder (n = 1), adenoid cystic carcinoma (n = 1) and adenocarcinoma of unknown origin (n = 2). Germline mutations were noted in BRCA1 (n = 3), BRCA2 (n = 3), BRIP1 (n = 1), and MSH6 (n = 1) and germ line variants of uncertain significance in BRIP1 (n = 1) and BRCA2 (n = 1). Somatic mutations were found in BRCA2 (n = 1), BAP1 (n = 2) and PALB2 (n = 1). DLTs included fatigue and thrombocytopenia; other non-DLT grade 3/4 toxicities included fatigue (13%), neutropenia (33%), thrombocytopenia (33%), and anemia (58%). Post cycle 1 hematological toxicities required dose delays and reductions in almost all patients. One complete response occurred in a patient with germline BRCA1 (gBRCA1) breast cancer and a partial response (PR) in a gBRCA2 bladder cancer patient; 11 patients (pts) had stable disease (SD) for ?3 months. 5 pts had progressive disease (PD) and 6 pts are not yet evaluable. Of those with PD, 83% had prior platinum therapy, whereas in those with SD or disease response, 46% had prior platinum therapy. Effects of talazoparib/carboplatin on platelet (-11.4% vs. -1.1% P<0.001) and neutrophil counts (-9.1% vs. -3.8% P<0.001) were significantly more profound in gBRCA carriers. Simulations using this model suggest that q4-weekly carboplatin dosing in patients with gBRCA or DNA repair defects and every other week dosing in non-carriers would be more tolerable for the combination. Conclusions: Mutation carriers in BRCA or other DNA repair genes responded better to this combination than non-carriers. Progression with prior platinum or PARPi did not exclude response or clinical benefit. Talazoparib and carboplatin showed significant hematologic toxicity in those with gBRCA or other germ line DNA repair mutations. Lower dosing frequencies of carboplatin when given with PARPi may be required in gBRCA mutation carriers. Citation Format: Mallika S. Dhawan, Rahul Aggarwal, Imke Bartelink, Jim Leng, Scott Thomas, Nela Pawlowska, Laurie Stevenson, Amy Jo Chien, Robin Kate Kelley, Pamela N. Munster. Carboplatin and talazoparib combination therapy results in differential efficacy and hematologic toxicity in BRCA-mutated patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT051.

Abstract 4340: DNA repair genes aberrations in germline DNA in metastatic castration-resistant prostate cancer patients

Abstract INTRODUCTION: DNA repair defects are found in mCRPC and are therapeutically actionable; germline BRCA mutation-associated (gBRCA) prostate cancer has a poor prognosis. We hypothesized that metastatic castration resistant prostate cancer (mCRPC) is enriched for germline DNA repair mutations and that these may be relevant to patient outcome. METHODS: Targeted-sequencing for DNA repair genes was conducted in germline DNA from patients consenting to 3 clinical trials between 2013-2015. Germline DNA was extracted from saliva or buccal swabs using the Oragene kit; libraries were constructed using a customized Qiagen panel and sequenced using the Illumina MiSeq. Family history and clinical data were prospectively collected. For time to event analyses unadjusted Cox regression models were used and comparisons were made using log-rank tests. RESULTS: Germline samples from 154 mCRPC patients were available. Median age at diagnosis was 61years (y), median time to castration-resistance was 14.5 months (m) and median overall survival (OS) from initial diagnosis of prostate cancer was 106.8m; 69% (91/131; 24 N/A) of patients were initially diagnosed with Gleason≥8 tumors. 130/154 (84.4%) and 131/154 (85.0%) received Docetaxel and Abiraterone respectively. Of 154 patients, 4 were previously known to be gBRCA2 mutation carriers and were removed from the prevalence analysis but included in the clinical analyses; 22/150 (14.7%, 95%CI 9.4-21.4%) harboured a truncating or frameshift mutation in a DNA repair gene (9 BRCA2, 6%; 4 ATM, 2.7%; 2 PALB2, 1.3%, 1 each for CHEK2, FANCI, MRE11A, NBN, RAD51C, RAD51D and MSH6). Overall, patients with any germline DNA repair aberrations had a worse median OS (75.8 vs 106.8 m; log-rank p = 0.04). Time to resistance to primary hormonal ablation was shorter specifically for gBRCA2 mutations carriers (11.0 vs 14.8 m; log-rank p = 0.01) but not for non-BRCA2 repair aberrations. Age at diagnosis was similar in patients with or without DNA repair germline mutations (median 61.3 vs 61.7y, Mann-Whitney p = 0.41) as well as frequency of Gleason≥8 tumors (16/21 [76%] vs 75/109 [68%]; Mann-Whitney p = 0.23) Response rates to Docetaxel (14/18 [77.8%] vs 64/94 [68.1%]; Fisher exact p = 0.67) and Abiraterone (10/21 [47.6%] vs 44/94 [46.8%]; Fisher exact p = 0.73) were similar among individuals with and without mutations. Family cancer history was collected in 125/154 cases (81%). While having cases of ovarian/prostate/breast/pancreas cancers in these patients’ families associated with a higher likelihood of finding a germline mutation (Odds Ratio 3.36, p = 0.03), 5 of 68 (7.4%) men with no cases of ovarian/prostate/breast/pancreas cancers registered in their families carried a germline mutation in a DNA repair gene. CONCLUSIONS: mCRPC is enriched for patients with germline mutations in DNA repair genes (15%), with 6% having gBRCA2 mutation. Germline DNA repair aberrations are associated with a worse prognosis from mCRPC. Citation Format: JOAQUIN MATEO, Suzanne Carreira, Helen Mossop, Pasquale Rescigno, Michael Kolinsky, Elena Castro, Ada Balasopoulou, Jo Hunt, Desamparados Roda, Claudia Bertan, Jane Goodall, Susana Miranda, Penny Flohr, Nuria Porta, Zsofia Kote-Jarai, David Olmos, Christopher J. Lord, Emma Hall, Ros Eeles, Johann S. de Bono. DNA repair genes aberrations in germline DNA in metastatic castration-resistant prostate cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4340.

Gene Mutations as a Target in Metastatic Prostate Cancer

The recent report of a high response to PARP1 inhibitors among heavily treated metastatic castration-resistant prostate cancer patients with DNA-repair defects (NEJM JW Oncol Hematol Dec 2015 and N Engl J Med 2015; 373:1697) has led to additional efforts to more fully characterize the potential role of germline DNA-repair mutations, which, although limited in unselected patients with localized prostate cancer, is undefined in advanced disease. To analyze …