Session: PD04: Prostate Cancer: Basic Research & Pathophysiology II
PD04-01: Evaluation of copy number and allelic imbalance of BRCA2 by next-generation sequencing to predict prognosis and drug sensitivity in prostate cancer
Professor Fujita Cancer Center, Fuiita Health University
Introduction: Although pathologic mutations in BRCA1 and BRCA2 are significantly associated with risk of prostate cancer (PC) initiation and metastatic castration-resistant PC (mCRPC), the details of the relationship between BRCA alterations and loss of BRCA function remain unclear. We aimed to establish a method for estimating BRCA function and to elucidate the details and clinical significance of BRCA alterations in PC. We further examined whether estimating BRCA function could be useful to predict PARP inhibitor sensitivity of poly ADP-ribose polymerase (PARP) inhibitors to mCRPC. Methods: DNA was extracted from formalin-fixed paraffin-embedded tissue specimens from 220 clinically localized PC patients who underwent radical prostatectomy and from 18 mCRPC patients with BRCA2 alterations detected by comprehensive genomic profiling panel testing. Mutations and copy number (CN) alterations of 143 cancer genes was analyzed by the in-house PleSSision Rapid test using NGS, and CN changes were also assessed by droplet digital PCR (ddPCR). The allelic imbalance (AI) could be detected by measuring the proportion of one allele relative to the other in cells from individuals that are constitutionally heterozygous at a given locus. Objective response (OR) to a drug was defined as a 50% or greater decrease in serum PSA levels from baseline. Results: NGS analysis revealed that in 220 localized PC patients, BRCA2 CN decreased in 29 (13.2%) and BRCA1 CN in 11 (5.0%). NGS-based CN values were shown to be highly correlated with ddPCR-based CN values. Twelve of the 29 patients with decreased BRCA2 CN were presumed to have somatic heterozygous or homozygous deletions. Pathogenic gene mutations other than deletion of BRCA2 were identified in 5 of 220 patients, while those of BRCA1 in one patient. Five (29.4%) of 17 patients with BRCA2 alterations developed biochemical recurrence within 6 months after surgery. Multivariate analyses revealed that BRCA2 CN and initial PSA levels were independent factors for biochemical recurrence. In the mCRPC study, 8 of 18 patients with BRCA2 alterations have shown to have BRCA2 deletions. Of the 8 patients, 4 patients with BRCA2 CN less than 0.8 had an OR to the PARP inhibitor olaparib, while the other 4 patients with BRCA2 CN greater than 0.8 did not have an OR to olaparib. As for the other 10 patients with frameshift or single nucleotide mutations in BRCA2, 3 of 4 (75.0%) patients without AI in BRCA2 have an OR to olaparib, while only 1 of 6 (16.7%) with AI had an OR to olaparib. Conclusions: Our findings show that estimating CN decrease in BRCA2 using NGS can predict the prognosis of localized PC. Furthermore, our results may provide new insight into the utility of assessing both CN and AI of BRCA2 to accurately predict response to PARP inhibitors in mCRPC patients with BRCA2 alterations. SOURCE OF Funding: None
