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

Background

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.

Methods

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.

Results

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.

Conclusions

Altogether, these results highlight the importance of the immune component in HGSC primary tumors in the context of intrinsic resistance to NACT.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

DECIDER project.

Funding

European Union’s Horizon 2020 research and innovation programme (grant agreement No 965193).

Disclosure

All authors have declared no conflicts of interest.