Whole-exome sequencing provides assessment of homologous recombination deficiency for identification of PARPi-responsive ovarian tumors

Abstract

Background/objectives

Homologous recombination repair deficiency (HRD) is frequently detected in gynecological cancers and is associated with sensitivity to poly-ADP ribose polymerase inhibition (PARPi). BRCA1/2 mutations have been approved as biomarkers for PARPi therapy, along with genomic patterns such as genomic loss of heterozygosity (gLOH) and large-scale transitions (LSTs). Clinical applications of various HRD assays are still under investigation. Here we validate the performance of a novel HRD assay based on whole-exome sequencing (WES).

Methods

WES was used to evaluate gLOH, LST, and BRCA mutations and this data was compared to standard assays. An optimized genomic scar score (GSS) was based on combined gLOH and LST. A comprehensive HRD score was then developed, combining GSS and BRCA status. Survival data from 1661 PARPi-treated ovarian cancer patients was queried to optimize GSS and HRD scores associated with PARPi response.

Results

A comparison of WES results to the OncoScan CNV assay and Myriad MyChoice assay showed high concordance for LOH values and GSS values, respectively. Median overall survival in PARPi-treated patients was 50.8 months for GSS-high, BRCA1/2-mut, 42.7 months for GSS-high, BRCA1/2-WT, and 36.6 months for GSS-low, BRCA1/2-WT patients with significant differences between each group. Combining the BRCA1/2-mut and WT GSS-high groups resulted in a median OS value of 47.8 months, significantly higher than the GSS-low BRCA1/2-WT group.

Conclusions

The use of a WES assay to assess BRCA results, along with a GSS method incorporating gLOH and LST, produced a HRD test that is predictive for PARPi therapy.