CtDNA pathogenic variants (PVs) in homologous recombination repair (HRR) genes in patients with metastatic CRPC.

Abstract

138 Background: HRR PVs can serve as predictive biomarkers and two PARP inhibitors are approved for metastasic CRPC (mCRPC) pts. Published data are predominantly focused on tissue-based assays, but obtaining tissue from mCRPC pts is problematic. In a large tissue based series (PROfound), 4047 mCRPC pts had tumor samples submitted for genomic testing but only 69% had interpretable results. No data were published from PROfound enumerating pts without available tissue to submit. Herein we assess frequency of PVs from selected HRR genes using a ctDNA assay. Methods: 292 mCRPC pts at Tulane Cancer Center were assessed for detectable HRR ctDNA changes using the Guardant 360 assay (which assesses the HRR genes BRCA1, BRCA2, and ATM). Results: 20/292 (6.8%) pts had a PV in ATM. However only 4/292 (1.4%) had > 1% mutant allelic fraction. Germline testing occurred in 18/20 of the ctDNA ATM PV pts and 0/18 had a germline PV. The PROfound series had 6.3% somatic PVs in ATM. 18/292 pts (6.2%) had a PV in BRCA2 and 12/292 (4.1%) had a mutant allelic fraction of > 1%. Germline testing was performed in 17/18 with BRCA2 ctDNA PVs and 9/17 had germline PVs. The PROfound series had 9.7% somatic BRCA2 PVs. BRCA1 PVs were detected in 6/292 (2.1%) pts and 3/292 (1%) had a mutant allelic fraction > 1%. 6/6 of the ctDNA PVs has germline testing and 1/6 had a BRCA1 PV. The PROfound series had 1.3% somatic PVs in BRCA1. Conclusions: Using ctDNA essay, it is feasible to measure PVs in only a small subset of HRR genes in mCRPC pts. These assays fail to detect deep deletions, a known and important mechanism of HRR gene loss. The ctDNA mutant allelic fractions are often low. The ability of ctDNA PVs using this assay to predict treatment effects are unknown.