Biological Features Associated with Poor Response to Neoadjuvant Chemotherapy in High-Grade Serous Ovarian Carcinoma

Objective To characterize the biological features associated with poor response to neoadjuvant chemotherapy in high-grade serous ovarian carcinoma and evaluate the predictive value of the radiological neoadjuvant chemotherapy response on patient outcome. Methods We included 180 patients treated with neoadjuvant chemotherapy from the DECIDER cohort. The poor responders (n=40) had either progressive or stable disease according to the RECIST 1.1 Criteria after neoadjuvant chemotherapy. They were compared to good responders (n=47) who achieved partial response and had successful interval cytoreductive surgery and at least 80% CA-125 reduction after neoadjuvant chemotherapy. Samples for whole-genome and RNA sequencing, ctDNA and CT-scans were analyzed before and after neoadjuvant chemotherapy. Results Patients were diagnosed with advanced stage high-grade serous ovarian carcinoma (FIGO Stage III 62%, Stage IV 38%). Median age was 67 years (range; 38-83). The poor responders demonstrated a significantly higher residual tumor burden following neoadjuvant chemotherapy, reflected by greater tumor proportion in surgical specimens, higher ctDNA levels, and larger residual omental volume on CT imaging. At diagnosis, the poor responders were more often homologous recombination proficient (HRP) and transcriptomic proliferation and interferon pathways were downregulated. The combination of these independent factors was predictive of the neoadjuvant chemotherapy response (AUC 0.85). After neoadjuvant chemotherapy, proliferation pathways diminished significantly in good responders but showed little change in poor responders. The predictive value of the radiological neoadjuvant chemotherapy response for overall survival was modest, whereas the homologous recombination deficiency (HRD) status showed a stronger association. Notably, platinum rechallenge was attempted to 40% of poor responders and nine survived over three years. Conclusions The failure to respond to neoadjuvant chemotherapy is associated with HRP and the downregulation of proliferation and interferon pathways. Whilst the radiological neoadjuvant chemotherapy response remains an imperfect predictive marker for overall survival, radiological poor responders with HRD merit maximal therapeutic effort.