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

PURPOSE: 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.

PATIENTS AND

METHODS

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.

RESULTS

The median GIS was 26 (IQR, 19-37). Samples with pathogenic variants in BRCA1, BRCA2, or PALB2 (BRCA complex) had a significantly higher median GIS (38 v 26, P < .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 v 28, P = .0003) and PlCh (41 v 26, P = .0113). Similarly, patients with a partial response by RECIST1.1 had higher GIS than those with progressive disease (PARPi: 39 v 26, P = .0356; PlCh: 44 v 25, P = .0046). Adding GIS to BRCA-complex status improved PSA response prediction in logistic models (AUC PARPi: 0.849 v 0.781, P = .0308; PlCh: 0.731 v 0.658, P = .1888).

CONCLUSION

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.