Abstract 3541: Biallelic alterations in BRCA2, ATM, or CDK12 in metastatic prostate cancer via circulating tumor DNA
Authors: Warner Evan , Yip Steven , Annala Matti , Murtha Andrew , Herberts Cameron , Chi Kim , Wyatt Alexander 
Published: September 2020

Abstract
Background: Genomic instability is a hallmark of metastatic prostate cancer. Defects in homologous recombination repair genes such BRCA2 are associated with response to platinum-based chemotherapy and poly ADP ribose polymerase (PARP) inhibitors. However, monoallelic DNA damage repair (DDR) mutations are unlikely to result in therapeutic vulnerability. Here, we used clinically-practical liquid biopsies to distinguish between monoallelic and biallelic DDR defects. Our secondary objective was to characterize the downstream genomic alterations enabled by each class of underlying DDR defect.
Methods: We performed targeted sequencing of 1615 cell-free DNA samples from 882 patients with mPCa using a custom prostate cancer panel. Samples with deleterious BRCA2 mutation(s) were subjected to deep sequencing of tumor suppressor introns to identify structural rearrangements. Hypermutated mismatch-repair defective tumors were excluded from analysis.
Results: 101 patients had at least one deleterious germline or somatic mutation in one of 19 assessed DDR genes in the targeted panel. BRCA2, ATM, and CDK12 were most commonly affected, collectively mutated in 16.0% of patients with sufficient circulating tumor DNA (ctDNA) content to be assessed for both germline and somatic mutations (n = 630). In 345 patients with &gt;20% ctDNA content, eight somatic biallellic BRCA2 deletions were identified. In patients with &gt;1 deleterious mutation in BRCA2, ATM, and CDK12, disruption of the second allele (via mutation, deletion, or copy-neutral loss of heterozygosity) was detected in 97%, 85%, and 91% of cases, respectively. Patients with a mutation in these genes had fewer TP53 mutations than DDR-intact controls (p&lt;0.05). However, BRCA2-defective patients instead harbored frequent compound deletions and/or rearrangements that disrupted tumor-suppressor genes (e.g. TP53, PTEN, RB1). In patients with CDK12 mutations, tumor-suppressor loss was rare but copy number gains of MDM2, CCND1, CDK4/6 were common. ATM-loss was not associated with evidence of genomic instability.
Conclusions: In metastatic prostate cancer, deleterious mutations in BRCA2, ATM or CDK12, as detected in ctDNA, are frequently accompanied by alteration to the second allele. This means that detection of one deleterious mutation in these genes may be a surrogate for biallelic loss. In BRCA2 and CDK12-mutant genomes, tumor suppressor genes can be disrupted via structural rearrangements. ATM-mutant genomes show scant evidence for TP53 disruption.
Citation Format: Evan Warner, Steven Yip, Matti Annala, Andrew Murtha, Cameron Herberts, Kim Chi, Alexander Wyatt. Biallelic alterations in BRCA2, ATM, or CDK12 in metastatic prostate cancer via circulating tumor DNA [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3541.