776P Multi-omics analysis of chemo-refractory high-grade serous carcinoma patients: Insights from the DECIDER study

Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is a treatment strategy recommended for patients with high-grade serous carcinoma (HGSC), who are ineligible for primary debulking surgery (PDS). The presence of the inherently resistant cancer phenotype in the primary tumor is a key factor determining disease progression in such cases. We collected the data from 159 NACT-treated patients enrolled in the prospective, longitudinal, multi-region DECIDER study which aims to develop effective means to overcome drug resistance in HGSC. 60 patients with platinum-free interval (PFI) above 6 months and partial/complete response as primary therapy outcome according to the RECIST1.1 criteria were considered as responsive, and 31 patients with PFI below 45 days and progressive/stable disease – as refractory. We integrated multiple types of patient data focusing on the pre-NACT samples, explored potential links between genomic features and patient survival, and specifically employed bulk-RNA sequencing data for hypothesis-generating. In terms of many different clinical or genomic features, samples derived from chemo-refractory patients resembled chemo-responsive. Homologous recombination (HR)-related mutation signatures and loss of the core HR genes were less frequent in the chemo-refractory patients than in the NACT-patients with at least partial response to the primary therapy. Using PRISM to retrieve the epithelial ovarian carcinoma (EOC)-specific expression profiles and PROGENy to infer pathways activity scores, we found a significantly lower activity (p value = 0.022) of JAK-STAT pathway in the refractory, as compared to the reference group. Further analysis using GSEA supported this conclusion, revealing lower expression levels of transcriptional target genes affected by the Interferon alpha/beta and gamma pathways. Kassandra deconvolution algorithm detected a significantly lower infiltration (p value = 0.026) of CD4 T-cells in the refractory group. Altogether, these results highlight the importance of the immune component in HGSC primary tumors in the context of intrinsic resistance to NACT.