Landscape of homologous recombination reversion mutations in gynecologic malignancies.

Abstract

5576 Background: Homologous recombination (HR) reversion mutations (REV) are biomarkers for predicting resistance to platinum and PARP inhibitor therapies. The biologic diversity of REV represents a diagnostic challenge. An automated computational approach was used to detect REV for analysis of genomic features of REV-positive ovarian epithelial, fallopian tube, and peritoneal cancers. Methods: Retrospective study of tissue (n = 23,612) and liquid biopsy (n = 869) samples from patients undergoing hybrid-capture comprehensive genomic profiling during routine clinical care 11/2012-03/2021. A proprietary algorithm tested for seven distinct REV mechanisms in BRCA1, BRCA2, PALB2, RAD51C, or RAD51D. For subjects with multiple samples, the earliest REV-positive sample was used for downstream analyses. Results: Among 23,866 ovarian epithelial, fallopian tube, and peritoneal cancers, 16.4% (n = 3,920) had at least one pathogenic variant (PV) in BRCA1 (10%, n = 2,383), BRCA2 (5.5%, n = 1,320), PALB2 (0.67%, n = 160), RAD51C (0.64%, n = 152), or RAD51D (0.47%, n = 113). 3.9% (154/3,920) of patients with one or more PV had REV. REV were found in tumors with PV in BRCA2 at twice the frequency of BRCA1 (6.0%, [79/1,320] vs 3.0% [71/2,383]; p < 0.001). REV involving RAD51D (1.8%, 2/113), RAD51C (0.7%, 1/152), or PALB2 (0.6%, 1/160) were rarer. A total of 193 REV pairs were identified. The most frequent REV mechanism was an exonic non-frameshift deletion completely encompassing a PV (45%, 87/193). Other recurrent mechanisms included restoration of the reading frame of a frameshift PV (21%, 42/193), replacement of a PV with a benign missense substitution at the same codon (16%, 32/193), and deletion with intronic breakpoints encompassing a PV (15%, 29/193). REV were significantly more prevalent in liquid biopsies than in tissue samples with PV (16% [20/124] vs. 3.5% [134/3,796]; p < 0.001). A range of 1-6 REV pairs were found per sample (liquid: 1-6, tissue: 1-3). Multiple REV per sample was more common in liquid biopsies (35% [7/20] vs. 11% [15/134]; p = 0.011). These differences likely reflect stage of disease and sampling of multiple subclones. Conclusions: BRCA2 PV are most frequently reverted in gynecologic tumors. REV are also common in tumors with BRCA1 PV and can more rarely occur in other HR genes. Liquid biopsy is enriched for detection of polyclonal resistance. Diverse REV mechanisms highlight a need for robust detection to incorporate REV in identifying treatment resistance and guiding downstream therapy selection.