Combining Homologous Recombination-Deficient Testing and Functional RAD51 Analysis Enhances the Prediction of Poly(ADP-Ribose) Polymerase Inhibitor Sensitivity

Abstract

PURPOSE: To meet the urgent need for accessible homologous recombination-deficient (HRD) test options, we validated a laboratory-developed test (LDT) and a functional RAD51 assay to assess patients with ovarian cancer and predict the clinical benefit of poly(ADP-ribose) polymerase inhibitor therapy.

METHODS: Optimization of the LDT cutoff and validation on the basis of samples from 91 patients enrolled in the ENGOT-ov24/NSGO-AVANOVA1&2 trial (ClinicalTrials.gov identifier: NCT02354131), previously subjected to commercial CDx HRD testing (CDx). RAD51 foci analysis was performed and tumors with ≥five foci/nucleus were classified as RAD51-positive (homologous recombination-proficient).

RESULTS: The optimal LDT cutoff is 54. Comparing CDx genome instability score and LDT HRD scores show a Spearman's correlation of rho = 0.764 (P < .0001). Cross-tabulation analysis shows that the sensitivity of the LDT HRD score is 86% and of the LDT HRD status is 91.8% (Fisher's exact test P < .001). Survival analysis on progression-free survival (PFS) of LDT-assessed patients show a Cox regression P < .05. RAD51 assays show a correlation between low RAD51 foci detection (<20% RAD51+ cells) and significantly prolonged PFS (P < .001).

CONCLUSION: The robust concordance between the open standard LDT and the CDx, especially the correlation with PFS, warrants future validation and implementation of the open standard LDT for HRD testing in diagnostic settings.

Original languageEnglish
Article numbere2300483
JournalJCO Precision Oncology
Volume8
ISSN2473-4284
DOIs
Publication statusPublished - Feb 2024

Keywords

  • Humans
  • Female
  • Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
  • Antineoplastic Agents
  • Homologous Recombination/genetics
  • Ovarian Neoplasms/diagnosis
  • Progression-Free Survival
  • Rad51 Recombinase/genetics

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