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Publications

Journal Article Clinical Trial, Phase III Multicenter Study Randomized Controlled Trial Ppublish

PubMed: 40513287 DOI: 10.1016/j.ejca.2025.115534

Predictive value of BRCA1/RAD51C methylation in HGSOC - An ancillary study of the PAOLA-1/ENGOT-ov25 phase 3 trial.

Eur J Cancer 225:115534

Authors: H Blons, J Abdelli, S Landman, V Taly, C Mulot, P Laurent-Puig, B You, P Harter, D Lorusso, Y García-García, S Polterauer, S Hietanen, N Colombo, I Vergote, H Kobayashi, T De La Motte Rouge, P Buderath, S C Cecere, G Bataillon, E Pujade-Lauraine, I Ray-Coquard

Affiliations

  • Institut du Cancer Paris Carpem, APHP, Department of Biochemistry, Pharmacogenetics and Molecular Oncology, Hopital Européen Georges Pompidou, Paris, France; Centre de Recherche des Cordeliers, Sorbonne Université, France; Université Paris Cité, Inserm Paris, France; Institut du Cancer Paris Carpem, APHP, Department of Genomics medicine of tumors and cancers, Hopital Européen Georges Pompidou, Paris, France.
  • Centre de Recherche des Cordeliers, Sorbonne Université, France; Université Paris Cité, Inserm Paris, France.
  • Institut du Cancer Paris Carpem, APHP, Department of Biochemistry, Pharmacogenetics and Molecular Oncology, Hopital Européen Georges Pompidou, Paris, France.
  • Centre de Recherche des Cordeliers, Sorbonne Université, France; Université Paris Cité, Inserm Paris, France; Institut du Cancer Paris Carpem, APHP, Department of Genomics medicine of tumors and cancers, Hopital Européen Georges Pompidou, Paris, France.
  • Medical oncology, Hospices Civils de lyon (HCL), CITOHL, EPSILYON, EA 3738, CICLY, Lyon, France.
  • Department of Gynecology & Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany; AGO, Germany.
  • Humanitas San Pio X and Humanitas University (Pieve Emanuele), Milan Italy; MITO, Italy.
  • Department of Oncology. Parc Taulí Hospital Universitari. Institut d'Investigació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, Sabadell, Spain.
  • Department of Obstetrics and Gynecology, Medical University Vienna, Austria; AGO Austria, Austria.
  • Department of Gynecologic Oncology, Turku University Hospital, Turku, Finland; NSGO, Denmark.
  • Gynecologic Oncology Program, European Institute of Oncology IRCCS, Milan, Italy; Department of Medicine and Surgery, University of Milan-Bicocca, Italy.
  • University Hospital Leuven, Leuven Cancer Institute, Leuven, Belgium, European Union; BGOG, Belgium, European Union.
  • Dept. of Obstetrics and Gynecology, Faculty of Medicine, Kagoshima University, Kagoshima, Japan; GOTIC, Japan.
  • Centre Eugène Marquis, Rennes, France; GINECO, France.
  • AGO, Germany; Universitätsklinikum Essen, Frauenklinik, Essen, Germany.
  • MITO, Italy; Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy.
  • GINECO, France; Department of Pathology, Oncopole University Hospital Toulouse, Toulouse, France.
  • GINECO, France; Medical Oncology Department, ARCAGY Research, Paris.
  • GINECO, France; Department of Medical Oncology, Centre Léon Berard, Lyon.

Abstract

IMPORTANCE AND BACKGROUND

In high-grade serous ovarian cancer (HGSOC) bevacizumab (bev)/olaparib (ola) maintenance was approved for patients with homologous recombination DNA repair deficiency (HRD+) tumors. Although different methods exist to score genomic instability, DNA quality, tumor cell content, and costs may impair our ability to identify patients that will benefit from treatment.

PATIENTS AND METHOD

We analyzed BRCA1 and RAD51C methylation as an HRD determination tool in patients newly diagnosed of HGSOC (n = 519) based on data from the PAOLA-1/ENGOT-ov25 trial phase III prospective trial. Methylation was analyzed using quantitative methylation specific PCR, correlated to HRD scores, PFS and OS.

RESULTS

67 (12.9 %) were BRCA1 and 25 (4.8 %) were RAD51C methylated. Of the 81 samples with a failed HRD score, 13 were methylated. Methylated samples were HRD+ (mean score [95 % CI]; 65.9 [62.7-69.1] and 53.3 [48.0-58.6]) and almost mutually exclusive of BRCA1&2 mutations. A significant PFS1 benefit independently of methylation ratios was observed in patients with methylated tumors with bev-ola maintenance compared to bev alone (HR=0.49, 95 % CI 0.29-0.83, P = 0.008). An OS benefit was shown for patients defined as "all-HRD" (including methylation) (HR=0.59, 95 % CI 0.41-0.86, P = 0.007).

CONCLUSIONS

This study confirms the feasibility and clinical value of BRCA1/RAD51C methylation for predicting response to ola-bev maintenance in newly diagnosed HGSOC. Assessment of methylation in parallel to mutation testing allowed the identification of nearly 85 % of HRD+ samples at low costs. This study suggests that methylation testing could be easily implemented to optimize the selection of patients that benefit from olaparib+bevacizumab maintenance.

MeSH

Research Design, Neoplasms, Bevacizumab, Predictive Value Of Tests, Maintenance, Genes, Brca1, Mutation