Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Pujade-Lauraine, E; Brown, J; Barnicle, A; Wessen, J; Lao-Sirieix, P; Criscione, SW; du, Bois, A; Lorusso, D; Romero, I; Petru, E; Yoshida, H; Vergote, I; Colombo, N; Hietanen, S; Provansal, M; Schmalfeldt, B; Pignata, S; Martín, Lorente, C; Berton, D; Runnebaum, IB; Ray-Coquard, I.
Homologous Recombination Repair Gene Mutations to Predict Olaparib Plus Bevacizumab Efficacy in the First-Line Ovarian Cancer PAOLA-1/ENGOT-ov25 Trial.
JCO Precis Oncol. 2023; 7:e2200258
Doi: 10.1200/PO.22.00258
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- Co-authors Med Uni Graz
- Petru Edgar
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- Abstract:
- PURPOSE: The PAOLA-1/ENGOT-ov25 trial of maintenance olaparib plus bevacizumab for newly diagnosed advanced high-grade ovarian cancer demonstrated a significant progression-free survival (PFS) benefit over placebo plus bevacizumab, particularly in patients with homologous recombination deficiency (HRD)-positive tumors. We explored whether mutations in non-BRCA1 or BRCA2 homologous recombination repair (non-BRCA HRRm) genes predicted benefit from olaparib plus bevacizumab in PAOLA-1. METHODS: Eight hundred and six patients were randomly assigned (2:1). Tumors were analyzed using the Myriad MyChoice HRD Plus assay to assess non-BRCA HRRm and HRD status; HRD was based on a genomic instability score (GIS) of ≥ 42. In this exploratory analysis, PFS was assessed in patients harboring deleterious mutations using six non-BRCA HRR gene panels, three devised for this analysis and three previously published. RESULTS: The non-BRCA HRRm prevalence ranged from 30 of 806 (3.7%) to 79 of 806 (9.8%) depending on the gene panel used, whereas 152 of 806 (18.9%) had non-BRCA1 or BRCA2 mutation HRD-positive tumors. The majority of tumors harboring non-BRCA HRRm had a low median GIS; however, a GIS of > 42 was observed for tumors with mutations in five HRR genes (BLM, BRIP1, RAD51C, PALB2, and RAD51D). Rates of gene-specific biallelic loss were variable (0% to 100%) in non-BRCA HRRm tumors relative to BRCA1-mutated (99%) or BRCA2-mutated (86%) tumors. Across all gene panels tested, hazard ratios for PFS (95% CI) ranged from 0.92 (0.51 to 1.73) to 1.83 (0.76 to 5.43). CONCLUSION: Acknowledging limitations of small subgroup sizes, non-BRCA HRRm gene panels were not predictive of PFS benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in PAOLA-1, irrespective of the gene panel tested. Current gene panels exploring HRRm should not be considered a substitute for HRD determined by BRCA mutation status and genomic instability testing in first-line high-grade ovarian cancer.
- Find related publications in this database (using NLM MeSH Indexing)
- Humans - administration & dosage
- Female - administration & dosage
- Bevacizumab - therapeutic use
- Recombinational DNA Repair - genetics
- Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use
- Ovarian Neoplasms - drug therapy, genetics
- Mutation - administration & dosage
- Genomic Instability - administration & dosage