Unraveling the complexity of HRD assessment in ovarian cancer by combining genomic and functional approaches: translational analyses of MITO16-MaNGO-OV-2 trial

B Pellegrino; E D Capoluongo; M Bagnoli; L Arenare; D Califano; G Scambia; S C Cecere; E M Silini; G L Scaglione; A Spina; G Tognon; N Campanini; C Pisano; D Russo; A Pettinato; P Scollo; R Iemmolo; L De Cecco; A Musolino; S Marchini; L Beltrame; L Paracchini; F Perrone; D Mezzanzanica; S Pignata

doi:10.1016/j.esmoop.2024.104091

Unraveling the complexity of HRD assessment in ovarian cancer by combining genomic and functional approaches: translational analyses of MITO16-MaNGO-OV-2 trial

ESMO Open. 2025 Jan 3;10(1):104091. doi: 10.1016/j.esmoop.2024.104091. Online ahead of print.

Authors

B Pellegrino¹, E D Capoluongo², M Bagnoli³, L Arenare⁴, D Califano⁵, G Scambia⁶, S C Cecere⁷, E M Silini⁸, G L Scaglione⁹, A Spina⁵, G Tognon¹⁰, N Campanini⁸, C Pisano⁷, D Russo⁵, A Pettinato¹¹, P Scollo¹², R Iemmolo¹³, L De Cecco³, A Musolino¹⁴, S Marchini¹⁵, L Beltrame¹⁵, L Paracchini¹⁵, F Perrone⁴, D Mezzanzanica³, S Pignata¹⁶

Affiliations

¹ Medical Oncology Unit, University Hospital of Parma, Parma, Italy; Breast Unit, University Hospital of Parma, Parma, Italy.
² Department of Molecular Medicine and Medical Biotechnology, Università degli Studi di Napoli Federico II, Naples, Italy; Department of Clinical Pathology, Azienda Ospedaliera San Giovanni Addolorata, Rome, Italy.
³ Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
⁴ Clinical Trial Unit, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Naples, Italy.
⁵ Microenvironment Molecular Targets Unit, Istituto Nazionale Tumori IRCCS e Fondazione G. Pascale, Naples, Italy.
⁶ Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy; Catholic University of Sacred Heart, Rome, Italy.
⁷ Uro-Gynecologic Oncology Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy.
⁸ Unit of Pathological Anatomy, Department of Medicine and Surgery, University Hospital of Parma, Parma, Italy.
⁹ Laboratory of Molecular Oncology, IDI-IRCCS, Rome, Italy.
¹⁰ Division of Obstetrics and Gynecology, ASST Spedali Civili di Brescia, Brescia, Italy.
¹¹ Department of Pathological Anatomy, A.O.E. Cannizzaro, Catania, Italy.
¹² Division of Gynecology and Obstetrics, Maternal and Child Department, Cannizzaro Hospital, Kore University of Enna, Enna, Italy.
¹³ Laboratory of Genomics, L.C. Laboratori Campisi, Avola, Italy.
¹⁴ Medical Oncology Unit, University Hospital of Parma, Parma, Italy; Breast Unit, University Hospital of Parma, Parma, Italy; Department of Medicine and Surgery, University of Parma, Parma, Italy.
¹⁵ Cancer Pharmacology Lab, IRCCS Humanitas Research Hospital, Milan, Italy.
¹⁶ Uro-Gynecologic Oncology Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy. Electronic address: s.pignata@istitutotumori.na.it.

PMID: 39754985
DOI: 10.1016/j.esmoop.2024.104091

Abstract

Background: Ovarian cancer (OvC) constitutes significant management challenges primarily due to its late-stage diagnosis and the development of resistance to chemotherapy. The standard treatment regimen typically includes carboplatin and paclitaxel, with the addition of poly (ADP-ribose) polymerase inhibitors for patients with high-grade serous ovarian cancer (HGSOC) harboring BRCA1/2 mutations. However, the variability in treatment responses suggests the need to investigate factors beyond BRCA1/2 mutations, such as DNA repair mechanisms and epigenetic alterations. Notably, homologous recombination repair deficiency (HRD) is observed in an additional 20% of HGSOC cases, indicating a broader spectrum of DNA repair defects. Existing commercial HRD assays have certain limitations, prompting a global effort to develop new genomic and functional tests through academic research.

Materials and methods: This study investigates, in the 187 high-grade serous and endometrioid tumors from the MITO16/MaNGO-OV-2 trial, academic HRD genomic tests in conjunction with a RAD51 immunofluorescence assay to assess functional activation of HRD. Additionally, the study incorporates analysis of microRNA-506 (miR-506) expression as a putative epigenetic effector.

Results: The RAD51 test identified HRD in 73% of the samples and genomic HRD testing in 57%, with HRD identified in 45% of samples by both tests. The significant discrepancy between the two assays emphasizes the need to refine tumor classification for HRD. A three-group genomic classification unveiled superior progression-free survival (PFS) in high- and mild-HRD tumors compared with negative-HRD tumors. High concordance between RAD51 and genomic testing in high-HRD tumors suggests a subset of 'super-HRD' tumors exhibiting superior PFS. High expression of miR-506 may be used to further refine HRD status.

Conclusions: The study underscores the complexities of HRD assessment and advocates for a combined genomic and functional approach to enhance predictive accuracy in OvC treatment responses.

Keywords: HRD; RAD51; miR-506; ovarian cancer.