Shallow Whole-Genome Sequencing to Assess Genomic Instability and Predict Treatment Response in Metastatic Castration-Resistant Prostate Cancer.

Abstract

Patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination deficiency (HRD) benefit from poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) or platinum-based chemotherapy (PlCh). Pathogenic variants in homologous recombination repair genes are used as a proxy for the phenotype. Genomic Instability Score (GIS) is a metric for the effect of HRD. This study used shallow whole-genome sequencing (sWGS), a cost-effective alternative to full-depth WGS, to calculate GIS and evaluate its predictive value for PARPi or PlCh response. We analyzed 288 tumor samples from 266 patients with mCRPC, consisting of 120 whole-genome samples from formalin-fixed paraffin-embedded material newly profiled at a sequencing depth of 2× and 168 from fresh frozen material downsampled in silico from 106× to 2×. The GIS was defined as the sum of large-scale transitions, telomeric-allelic imbalances, and genomic loss of heterozygosity. The median GIS was 26 (IQR, 19-37). Samples with pathogenic variants in <i>BRCA1</i>, <i>BRCA2</i>, or <i>PALB2</i> (BRCA complex) had a significantly higher median GIS (38 <i>v</i> 26, <i>P</i> < .0005). The median GIS increased significantly with tumor ploidy. Patients showing ≥50% prostate-specific antigen (PSA) declines had higher GIS on both PARPi (median 40 <i>v</i> 28, <i>P</i> = .0003) and PlCh (41 <i>v</i> 26, <i>P</i> = .0113). Similarly, patients with a partial response by RECIST1.1 had higher GIS than those with progressive disease (PARPi: 39 <i>v</i> 26, <i>P</i> = .0356; PlCh: 44 <i>v</i> 25, <i>P</i> = .0046). Adding GIS to BRCA-complex status improved PSA response prediction in logistic models (AUC PARPi: 0.849 <i>v</i> 0.781, <i>P</i> = .0308; PlCh: 0.731 <i>v</i> 0.658, <i>P</i> = .1888). GIS assessment by sWGS is feasible and associated with response to PARPis and PlCh. The combination of BRCA-complex status and GIS is superior to BRCA-complex status alone in predicting PSA response to PARPis but not to PlCh.