Dataset Information

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.

SUBMITTER: Korsholm LM

PROVIDER: S-EPMC10919475 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Korsholm Lea M LM Kjeldsen Maj M Perino Lorenzo L Mariani Luca L Nyvang Gitte-Bettina GB Kristensen Elisabeth E Bagger Frederik O FO Mirza Mansoor Raza MR Rossing Maria M

JCO precision oncology 20240201

<h4>Purpose</h4>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.<h4>Methods</h4>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: NCT023541 ...[more]

PMID: 38427930

Similar Datasets

Project description:BackgroundClinical success of poly(ADP-ribose) polymerase inhibitors (PARP i ) has been limited to repair-deficient cancers and by resistance. Oncolytic herpes simplex viruses (oHSVs) selectively kill cancer cells, irrespective of mutation, and manipulate DNA damage responses (DDR). Here, we explore potential synthetic lethal-like interactions between oHSV and PARP i .MethodsThe efficacy of combining PARP i , oHSV MG18L, and G47Δ in killing patient-derived glioblastoma stem cells (GSCs) was assessed using cell viability assays and Chou-Talalay synergy analysis. Effects on DDR pathways, apoptosis, and cell cycle after manipulation with pharmacological inhibitors and lentivirus-mediated knockdown or overexpression were examined by immunoblotting and FACS. In vivo efficacy was evaluated in two GSC-derived orthotopic xenograft models (n = 7-8 per group). All statistical tests were two-sided.ResultsGSCs are differentially sensitive to PARP i despite uniform inhibition of PARP activity. oHSV sensitized GSCs to PARP i , irrespective of their PARP i sensitivity through selective proteasomal degradation of key DDR proteins; Rad51, mediating the combination effects; and Chk1. Rad51 degradation required HSV DNA replication. This synthetic lethal-like interaction increased DNA damage, apoptosis, and cell death in vitro and in vivo. Combined treatment of mice bearing PARP i -sensitive or -resistant GSC-derived brain tumors greatly extended median survival compared to either agent alone (vs olaparib: P ≤.001; vs MG18L: P = .005; median survival for sensitive of 83 [95% CI = 77 to 86], 94 [95% CI = 75 to 107], 102 [95% CI = 85 to 110], and 131 [95% CI = 108 to 170] days and for resistant of 54 [95% CI = 52 to 58], 56 [95% CI = 52 to 61], 62 [95% CI = 56 to 72], and 75 [95% CI = 64 to 90] days for mock, PARPi, oHSV, and combination, respectively).ConclusionsThe unique oHSV property to target multiple components of DDR generates cancer selective sensitivity to PARP i . This combination of oHSV with PARP i is a new anticancer strategy that overcomes the clinical barriers of PARP i resistance and DNA repair proficiency and is applicable not only to glioblastoma, an invariably lethal tumor, but also to other tumor types.

Dataset Information

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

Purpose

Methods

Results

Conclusion

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets