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Ref Type Journal Article
PMID (42133897)
Authors Swisher EM, Konecny G, Cohen J, Colon-Otero G, Danziger N, Lin DI, Li G, Quintanilha JCF, Decker B, Ross JS, Gearing M, Baker K, Scott T, Poyser L, Vallejos P, Elvin JA, Graf RP
Title Homozygous Loss of Recombination Repair Genes and Poly ADP-Ribose Polymerase Inhibitor Benefit for Patients With Ovarian Cancer.
Journal Vol Issue Date Pages Journal Short Title
JCO precision oncology 10 5 2026 May e2500763 JCO Precis Oncol
URL
Abstract Text We sought to characterize outcome associations of poly ADP-ribose polymerase inhibitors (PARPi) in patients with ovarian cancer (OVCA) whose cancers contain homozygous loss (deletions) of homologous recombination repair (HRR) pathway genes, an alteration class not uniformly reported on clinical testing and not susceptible to acquired resistance via secondary reversion mutations.This study used US-based deidentified Flatiron Health-Foundation Medicine OVCA Clinico-Genomic Database. Patients with advanced OVCA and genomic profiling by Foundation Medicine were assembled into cohorts evaluating PARPi monotherapy use, and separately, PARPi maintenance therapy use, with outcomes associated with HRR gene alterations: BRCA1/2, PALB2, RAD51B/C/D, BARD1, and BRIP1.1.5% (82/5,404) had HRR gene homozygous loss, with BRCA1 and BRCA2 loss being most common. Among all OVCAs with BRCA1/2 alterations, 7.5% (63/836) were homozygous losses. Most BRCA1 (34/38, 89%) and BRCA2 (18/25, 72%) homozygous losses were intragenic, with breakpoints not spanning entire gene. Maintenance cohort: 22 patients had HRR gene homozygous loss, with strongly improved progression-free survival (PFS) for PARPi versus no PARPi use (HR, 0.06, 95% CI, 0.01 to 0.37). Monotherapy cohort: patients without HRR alterations (n = 198), HRR mutations or rearrangements (n = 93), and HRR homozygous loss (n = 8) had median PFS of 4.9, 10.6, and 25.4 months, and median overall survival of 18.5, 22.5, and 51.8 months, respectively.We observe durable PARPi effectiveness for patients with OVCA and HRR gene homozygous loss in routine practice. We demonstrate the importance of detecting and reporting homozygous loss in HRR genes, an aspect not standard to all sequencing assays.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RAD51B del ovarian cancer predicted - sensitive unspecified PARP inhibitor Case Reports/Case Series Actionable In a clinical study, PARP inhibitor monotherapy (niraparib (n=1), olaparib (n=5) or rucaparib), resulted in a median progression-free survival (PFS) of 25.4 mo and an overall survival (OS) of 51.8 mo in ovariant patients with homozygous deletion of homologous recombination repair (HRR) genes (n=8), including RAD51B (n=1), compared to a median PFS of 4.9 mo and OS of 18.5 mo in patients without HRR gene alterations (n=198) (PMID: 42133897). 42133897
RAD51D del ovarian cancer predicted - sensitive unspecified PARP inhibitor Case Reports/Case Series Actionable In a clinical study, PARP inhibitor monotherapy (niraparib (n=1), olaparib (n=5) or rucaparib (n=2)), resulted in a median progression-free survival (PFS) of 25.4 mo and an overall survival (OS) of 51.8 mo in ovarian cancer patients with homozygous deletion of homologous recombination repair (HRR) genes (n=8) including RAD51D (n=1), compared to a median PFS of 4.9 mo and OS of 18.5 mo in patients without HRR gene alterations (n=198) (PMID: 42133897). 42133897
RAD51C del ovarian cancer predicted - sensitive unspecified PARP inhibitor Case Reports/Case Series Actionable In a clinical study, PARP inhibitor monotherapy (niraparib (n=1), olaparib (n=5) or rucaparib (n=2)), resulted in a median progression-free survival (PFS) of 25.4 mo and an overall survival (OS) of 51.8 mo in ovarian cancer patients with homozygous deletion of homologous recombination repair (HRR) genes (n=8) including RAD51C (n=1), compared to a median PFS of 4.9 mo and OS of 18.5 mo in patients without HRR gene alterations (n=198) (PMID: 42133897). 42133897