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

Abstract

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 biomarkers predictive of response. Tumor gene expression was evaluated by proliferative, mesenchymal, differentiated, and immunoreactive gene signatures derived from high-grade serous carcinomas and a signature established prior for ovarian clear cell carcinoma. Resulting signature scores were statistically assessed with both univariate and multivariate approaches for correlation to clinical response. Analyses were performed to identify pathways differentially expressed by either the complete response (CR) or progressive disease (PD) patient groups. The clear cell gene signature was scored significantly higher in the CR group, and the proliferative gene signature had significantly higher scores 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 visual projection of immunoreactive, proliferative, and clear cell signatures differentiated clinical response. An applicable clinical response prediction formula was derived. Ovarian cancer-specific gene signatures and related pathway scores provide a robust preliminary indicator for ovarian cancer patients prior to anti-PD-1 therapy decisions.

Treatment of ovarian clear cell carcinoma with immune checkpoint blockade: a case series

“…Although the conclusions that can be drawn are limited by the small cohort, our data support other clinical and pre-clinical studies that have shown the potential role of ARID1A and HER2 alterations, as well as a clear cell carcinoma-specific gene signature, as biomarkers of response to immune checkpoint blockade. [17][18][19][20][21][22] Interestingly, the patient with a germline monoallelic PMS2 mutation had preserved PMS2 immunohistochemistry and low tumor mutation burden, suggesting the tumor was not driven by mismatch repair alteration.…”