Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer Part 2: Medical Perspectives

SIMPLE SUMMARY: High-grade serous ovarian cancer (HGSOC—the most frequent and aggressive form of ovarian cancer) represents an important challenge for clinicians. Half of HGSOC cases exhibit homologous recombination deficiency (HRD), mainly through alterations in BRCA1 and BRCA2. This leads to sensitivity to PARP inhibitors, a novel class of breakthrough molecules that improved HGSOC prognoses. To date, three companion diagnostic assays have received FDA approval for the evaluation of HRD status, but their use remains controversial. In this companion review (Part 1: Technical considerations; Part 2: Medical perspectives), we develop an integrative perspective, from translational research to clinical application, that could help physicians and researchers manage HGSOC. ABSTRACT: High-grade serous ovarian cancer (HGSOC) is the most frequent and aggressive form of ovarian cancer, representing an important challenge for clinicians. Half of HGSOC cases have homologous recombination deficiency (HRD), which has specific causes (mainly alterations in BRCA1/2, but also other alterations encompassed by the BRCAness concept) and consequences, both at molecular (e.g., genomic instability) and clinical (e.g., sensitivity to PARP inhibitor) levels. Based on its prevalence and clinical impact, HRD status merits investigation. To date, three PARP inhibitors have received FDA/EMA approval. For some approvals, the presence of specific molecular alterations is required. Three companion diagnostic (CDx) assays based on distinct technical and medical considerations have received FDA approval to date. However, their use remains controversial due to their technical and medical limitations. In this companion and integrated review, we take a “bench-to-bedside” perspective on HRD definition and evaluation in the context of HGSOC. Part 1 of the review adopts a molecular perspective regarding technical considerations and the development of CDx. Part 2 focuses on the clinical impact of HRD evaluation, primarily through currently validated CDx and prescription of PARP inhibitors, outlining achievements, limitations and medical perspectives.