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 patients with poor response (n = 40) had either progressive or stable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1 after neoadjuvant chemotherapy. They were compared with patients with good response (n = 47) who achieved partial response and had successful interval cytoreductive surgery and at least 80% cancer antigen 125 reduction after neoadjuvant chemotherapy. Samples for whole-genome and RNA sequencing, circulating tumor DNA, as well as computed tomography scans, were analyzed before and after neoadjuvant chemotherapy.

RESULTS

Patients were diagnosed with advanced-stage high-grade serous ovarian carcinoma (International Federation of Gynecology and Obstetrics stage III, 62%; stage IV, 38%). Median age was 67 years (range; 38-83). The patients with poor response demonstrated a significantly higher residual tumor burden following neoadjuvant chemotherapy, reflected by greater tumor proportion in surgical specimens, higher circulating tumor DNA levels, and larger residual omental volume on computed tomography imaging. At diagnosis, the patients with poor response were more often had homologous recombination-proficient status, and transcriptomic proliferation and interferon pathways were downregulated. The combination of these independent factors was predictive of the neoadjuvant chemotherapy response (area under the curve 0.85). After neoadjuvant chemotherapy, proliferation pathways diminished significantly in patients with good response but showed little change in patients with poor response. The predictive value of the radiological neoadjuvant chemotherapy response for overall survival was modest, whereas the homologous recombination deficiency status showed a stronger association. Notably, platinum re-challenge was attempted in 40% of patients with poor response, and 9 survived over 3 years.

CONCLUSIONS

The failure to respond to neoadjuvant chemotherapy is associated with homologous recombination proficient and the downregulation of proliferation and interferon pathways. While the radiological neoadjuvant chemotherapy response remains an imperfect predictive marker for overall survival, patients with radiological poor response and homologous recombination deficiency merit maximal therapeutic effort.