A RAD51 functional assay as a candidate test for homologous recombination deficiency in ovarian cancer
2023; Elsevier BV; Volume: 171; Linguagem: Inglês
10.1016/j.ygyno.2023.01.026
ISSN1095-6859
AutoresFélix Blanc‐Durand, Elisa Yaniz‐Galende, Alba Llop‐Guevara, Catherine Genestie, Violeta Serra, Andrea Herencia-Ropero, Christophe Klein, Dominique Berton, Alain Lortholary, Nadine Dohollou, Christophe Desauw, Michel Fabbro, Emmanuelle Malaurie, Nathalie Bonichon-Lamaichhane, Coraline Dubot, Jean Emmanuel Kurtz, Gaëtan De Rauglaudre, Nadia Raban, Annick Chevalier-Place, Gwénaël Ferron, Marie‐Christine Kaminsky, Claire J.H. Kramer, Étienne Rouleau, Alexandra Léary,
Tópico(s)DNA Repair Mechanisms
ResumoRationale Homologous recombination deficiency (HRD), defined as BRCA1/2 mutation (BRCAmut) or high genomic instability, is used to identify ovarian cancer (OC) patients most likely to benefit from PARP inhibitors. While these tests are useful, they are imperfect. Another approach is to measure the capacity of tumor cells to form RAD51 foci in the presence of DNA damage using an immunofluorescence assay (IF). We aimed to describe for the first time this assay in OC and correlate it to platinum response and BRCAmut. Methods Tumor samples were prospectively collected from the randomized CHIVA trial of neoadjuvant platinum +/− nintedanib. IF for RAD51, GMN and gH2AX was performed on FFPE blocks. Tumors were considered RAD51-low if ≤10% of GMN-positive tumor cells had ≥5 RAD51 foci. BRCAmut were identified by NGS. Results 155 samples were available. RAD51 assay was contributive for 92% of samples and NGS available for 77%. gH2AX foci confirmed the presence of significant basal DNA damage. 54% of samples were considered HRD by RAD51 and presented higher overall response rates to neoadjuvant platinum (P = 0.04) and longer progression-free survival (P = 0.02). In addition, 67% of BRCAmut were HRD by RAD51. Among BRCAmut, RAD51-high tumors seem to harbor poorer response to chemotherapy (P = 0.02). Conclusions We evaluated a functional assay of HR competency. OC demonstrate high levels of DNA damage, yet 54% fail to form RAD51 foci. These RAD51-low OC tend to be more sensitive to neoadjuvant platinum. The RAD51 assay also identified a subset of RAD51-high BRCAmut tumors with unexpected poor platinum response.
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