Combination of gene set signatures correlates with response to nivolumab in platinum-resistant ovarian cancer

Abstract

Background Based on our previous phase II clinical trial of anti-programmed death-1 (PD-1) antibody nivolumab for platinum-resistant ovarian cancer (n=19, UMIN000005714), we aimed to identify the therapeutic response biomarkers to nivolumab in ovarian cancer. Methods Tumor gene expressions were evaluated by proliferative, mesenchymal, differentiated, and immunoreactive gene signatures derived from high-grade serous carcinomas in The Cancer Genome Atlas and a signature established prior to ovarian clear cell carcinoma. Gene sets were scored using the single-sample gene set enrichment analysis, and resulting scores were used to assess the correlation between each gene set and the clinical response to nivolumab therapy. Statistical analyses were performed to identify pathways differentially expressed by either the complete response (CR) or progressive disease (PD) groups. Results The clear cell gene signature significantly had higher score in the CR group, and the proliferative gene signature had significantly higher score in the PD group where nivolumab was not effective (respective p-values 0.005 and 0.026). Combinations of gene signatures improved correlation with response, where a projection of immunoreactive, proliferative, and clear cell signatures differentiated clinical response. Conclusion Ovarian cancer-specific gene signature and related pathway scores provide a preliminary indicator for ovarian cancer prior to receiving anti-PD-1 antibody therapy.