Introduction/Background Neoadjuvant chemotherapy (NACT) is the preferred treatment strategy for high-grade serous (ovarian) cancer (HGSC) patients, if optimal cytoreduction is estimated unachievable at the time of the diagnosis. In such cases, intrinsic sensitivity to standard-of-care (platinum and taxane combination therapy) is a major determinant of the disease progression. With data from 159 NACT-treated patients, diagnosed during years 2009–2022 and enrolled in the prospective DECIDER study, we sought to define the cellular and molecular features associated with intrinsic resistance to chemotherapy.

Methodology Herein, we tested for association between patient survival and genomic summary statistics for mutation signatures, sub-clonal heterogeneity, and driver aberrations. Furthermore, we used mRNA sequencing data for agnostic, hypothesis-generating, analyses to infer differential pathway activity the between chemo-refractory and responsive cancers. The groups were defined according to outcome from the primary therapy (progressive/stable disease vs. partial/complete response) and progression-free interval (<45 days vs. >6 months). The novel hypotheses were further explored with whole-genome sequencing, methylation sequencing, and imaging data.

Results Homologous recombination (HR) deficiency and loss-of-function mutations in HR genes were associated with longer patient survival in a multivariable Cox regression model. In terms of other genomic or clinical features, the chemo-refractory cancers resembled the responsive cancers. A Progeny analysis of differential pathway activity suggested that the JAK-STAT pathway activity was lower in the carcinoma cells of the chemo-refractory cancers. A gene set enrichment analysis of Reactome pathways supported this finding, indicating lower expression of Interferon alpha/beta and gamma pathway transcriptional target genes and interleukins CXCL10 and CXCL11.

Conclusion Our analyses support a model where the primary response to neoadjuvant chemotherapy of HGSC is mediated by the immune system. Immunologically cold tumours have a poor response to the treatment, which is manifested in a chemo-refractory disease.

Disclosures The authors declare no conflicts of interest.