Abstract 3394: CGP identifies largely non-overlapping high tumor mutational burden and HRD genomic alterations in 721 clinically advanced prostate acinar adenocarcinoma cases
Authors: Dewal Ninad , He Yuting , Lee Richard J. , Schrock Alexa B. , Chung Jon , Hoimes Christopher , Chalmers Zachary R. , Frampton Garrett M. , Sun James X. , Lara Primo N. , Agrawal Neeraj , Matthew Paul , Stephens Philip J. , Miller Vincent A. , Ross Jeffrey S. , Ali Siraj M. 
Published: July 2017

Abstract
Background: Effective therapies for the management of castrate resistant prostate cancer are lacking. We performed comprehensive genomic profiling (CGP) on advanced prostate carcinomas (PC) in the course of clinical care to identify genomic alterations that could suggest benefit from targeted, immune- and PARP inhibitor therapeutic strategies.
Methods: DNA was extracted from 40 microns of FFPE specimen from 721 clinically advanced PC cases. CGP was performed using a hybrid-capture, adaptor ligation based next generation sequencing assay to a mean coverage depth of over 500X. All four classes of genomic alterations (GA) - base substitutions, insertions and deletions, gene fusions, and copy number alterations (amplifications and losses) - were identified.
Results: Of the 721 PC patients - men with median age of 65 (range 34 - 88) - CGP was performed on 335 (46.5%) prostate specimens and 386 (53.5%) specimens from metastatic sites. The most common genes altered were TP53 (N=336, 46.6%), PTEN (N=254, 35.2%), TMPRSS2-ERG (N=214, all fusions, 29.7%), AR (N=173, 24%), and MYC (N=105, 14.6%). Median tumor mutational burden (TMB) for this series was 3.6 mut/Mb (range 0 - 305). AR and MYC amplifications were enriched in metastatic tumors compared to primary tumors (p &lt; 0.001 for both). Alterations characteristic of homologous recombination deficiency (HRD) were found in &gt;15% of cases, including homozygous deletions and truncating mutations in BRCA2 in 79 (11%) samples, as well as truncating mutations in ATM in 41 (5.7%) samples, with only 3 samples possessing alterations in both genes. Cases with these HRD-relevant alterations possessed overall higher genomic loss of heterozygosity (LOH) content than did those without (p = 0.02). HRD and non-HRD cases had median TMB of 4.8 versus 2.7 mut/Mb, respectively, and mean TMB of 10.4 versus 4.0 mut/Mb (p &lt; 0.01). Only 2.6% of non-HRD cases were TMB-high (20 mut/Mb or more), versus 8.4% of HRD cases, a small but significant enrichment in the latter.
Conclusions: CGP for advanced PC cases identifies largely non-overlapping TMB-high and HRD positive cases, suggesting benefit from immunotherapeutics and PARP inhibitors respectively. Further investigation will assess whether HRD pathway alterations result in genomic LOH in the context of a hypermutated tumor, and enrichment or exclusivity with other GA in prostate carcinoma.
Citation Format: Ninad Dewal, Yuting He, Richard J. Lee, Alexa B. Schrock, Jon Chung, Christopher Hoimes, Zachary R. Chalmers, Garrett M. Frampton, James X. Sun, Primo N. Lara, Neeraj Agrawal, Paul Matthew, Philip J. Stephens, Vincent A. Miller, Jeffrey S. Ross, Siraj M. Ali. CGP identifies largely non-overlapping high tumor mutational burden and HRD genomic alterations in 721 clinically advanced prostate acinar adenocarcinoma cases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3394. doi:10.1158/1538-7445.AM2017-3394