RB1 expression and HR proficiency define a poor prognosis subtype of high grade serous ovarian cancer.

High-grade serous ovarian carcinoma (HGSOC) is a molecularly heterogeneous and lethal malignancy, with late-stage diagnosis contributing to high risk of recurrence and poor clinical outcomes. Although homologous recombination (HR) deficiency and retinoblastoma gene (RB1) expression have been implicated in prognosis, their combined role in shaping tumor biology and survival outcomes is not well defined. To investigate the relationship between HR status and RB1 expression and explore their potential as a combined prognostic marker, we analyzed data from two cohorts: (1) 272 HGSOC cases from The Cancer Genome Atlas (TCGA) with RB1 mRNA expression data and HR status previously annotated by Takaya et al. (HR-deficient, HRD; HR-proficient, HRP), and (2) 226 clinical HGSOC cases profiled by comprehensive genomic and immune profiling (CGIP) at OmniSeq, categorized as either HR-intact (HRi) or harboring BRCA1/2 alterations (BRCAa). Cases were additionally stratified according to RB1 mRNA expression level as RB1-high (> 25th percentile; RBH) or RB1-low (≤ 25th percentile; RBL). HRP-RBH tumors (n = 120, 44.1%) were associated with significantly worse overall survival (OS) and progression free survival (PFS) compared to all other subgroups. Survival metrics were evaluated from the TCGA cohort and demonstrated that median OS for HRP-RBH was 35.9 mo, shorter than HRP-RBL (52.0 mo), HRD-RBL (57.1 mo), and HRD-RBH subgroups (53.3 mo; all p < 0.0001). PFS demonstrated a similar trend (15.1 mo vs. 20.6, 20.2 and 20.4 mo, respectively, p = 0.0021). HRP-RBH tumors also showed higher aneuploidy scores (median 18 vs. ≤ 10.5 in other subgroups, all p < 0.01). From the OmniSeq cohort, HRi-RBH tumors exhibited a distinct immune gene signature, including elevated mRNA expression of 213 differentially expressed genes and enrichment of pathways such as EMT, PI3K/AKT signaling, and interleukin signaling. Overall, this study suggests that molecular subtyping of HGSOC based on HR status and RB1 expression may provide valuable prognostic insight. HRP tumors with high RB1 expression represent a high-risk subgroup with a distinct molecular profile and poor clinical outcomes, underscoring the need for novel therapeutic strategies targeting this aggressive subset. These findings provide a foundation for future studies aimed at developing biomarkers and treatments tailored to this challenging subset of HGSOC patients.