Molecular determinants of response in laparoscopically triaged advanced ovarian cancer

BACKGROUND: High-grade serous ovarian cancer (HGSC) is the most lethal gynecologic malignancy, marked by genomic instability, extensive peritoneal spread, and frequent recurrence despite initial chemosensitivity. Complete gross resection (CGR) at primary surgery is the strongest predictor of survival, yet it is not always achievable. Conventional imaging often underestimates disease burden and reliable molecular predictors of surgical and chemotherapeutic response are lacking. To address this, we performed a multi-omic analysis of tumors obtained during laparoscopic scoring procedures that triaged patients to primary tumor reductive surgery (pTRS) or neoadjuvant chemotherapy (NACT) followed by interval tumor reductive surgery (iTRS). METHODS: Pre-treatment fresh-frozen tumor samples were collected from 40 patients across four groups: pTRS-CGR, pTRS-R1 (gross residual disease), iTRS-CGR, and iTRS-R1. Bulk RNA sequencing and multiplexed quantitative proteomics were performed to characterize transcriptomic and proteomic profiles. Integrative proteogenomic analyses identified concordant molecular signatures associated with treatment outcomes. Findings were validated in an independent multi-omic cohort of 30 HGSC patients treated with identical protocols. RESULTS: Patients achieving pTRS-CGR had the most favorable overall survival (OS) (87.5 months, median OS), whereas iTRS-R1 had the poorest outcome (22.9 months, median OS). Multi-omic integration revealed distinct expression signatures across response groups. A total of 73 proteins and 229 transcripts were significantly upregulated in iTRS-R1 tumors compared to others, with strong proteomic-transcriptomic concordance (Spearman Rho=0.837, P<1E-4). Pathway analysis showed enrichment for primary cilium formation and cell anchoring in pTRS-CGR tumors, while iTRS-R1 tumors exhibited activation of oxidative phosphorylation, mitochondrial metabolism, and stress-adaptive signaling. Notably, EEF2K (Eukaryotic elongation factor 2 kinase), a key regulator of energy conservation and stress response, was markedly overexpressed in iTRS-R1 tumors. Validation confirmed elevated EEF2K in poor NACT responders with higher residual disease burden. CONCLUSION: Laparoscopic triage effectively stratifies advanced HGSC for optimal surgical management, with pTRS-CGR achieving the best survival outcome. Multi-omic analyses highlight metabolic reprogramming as a hallmark of poor responders and identify EEF2K as a potential prognostic biomarker and therapeutic target. These data support biomarker-driven approaches to improve outcomes in advanced ovarian cancer.