Homologous Recombination Proficiency in High-Grade Serous Epithelial Ovarian Cancer Tumors: The Dark Side of the Moon.

Extensive research on homologous-recombination-deficient (HRD) tumors has led to advancements in targeted therapies, such as PARP inhibitors (PARPis). Around 50% of high-grade serous ovarian cancer (HGSOC) cases exhibit HR deficiency, but understanding the remaining half, referred to as homologous-recombination-proficient (HRP) tumors, is limited. This review explores existing knowledge regarding HGSOC patients with HRP tumors and offers insights into potential targets for innovative treatments. Patients with HRP tumors do not experience the same benefits from PARPi and have poorer survival outcomes compared to those with HRD tumors. CCNE1 amplification is a common, well-established molecular feature in HGSOC HRP tumors, occurring in about 20% of cases. Targeting CCNE1 amplification and/or overexpression shows promise with emerging therapies like CDK2 or Wee1 inhibitors. Additionally, approaches using immunotherapy and antibody-drug conjugates could represent promising targets for HRP patients. This review also covers lesser-known molecular features in HRP tumors, such as fold-back inversions and CARM1 amplification and/or overexpression, as well as HRD tumors that acquire HR proficiency (BRCA1/2 reversion mutations, demethylation of BRCA1 and RAD51C). We also discuss controversial topics regarding HRP tumors and limitations of HRD detection. Addressing this need is critical to reduce toxicity and improve disease management.