Abstract 4340: DNA repair genes aberrations in germline DNA in metastatic castration-resistant prostate cancer patients
Authors: MATEO JOAQUIN , Carreira Suzanne , Mossop Helen , Rescigno Pasquale , Kolinsky Michael , Castro Elena , Balasopoulou Ada , Hunt Jo , Roda Desamparados , Bertan Claudia , Goodall Jane , Miranda Susana , Flohr Penny , Porta Nuria , Kote-Jarai Zsofia , Olmos David , Lord Christopher J. , Hall Emma , Eeles Ros , de Bono Johann S. 
Published: July 2016

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.