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.
Highlights
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 expression of the programmed death-1 ligand 1 (PD-L1) is predictive of the therapeutic response in certain tumor types such as melanoma and non-small cell lung c ancer[11,12,13,14,15], we found that progressive disease (PD)-L1 expression alone was not sufficiently predictive of response in the case of ovarian c ancer[10,16]
We report the development and results of a systematic method to leverage gene expression measured in platinum-resistant ovarian tumors by recasting individual gene transcript levels into functionally related groups that can subsequently be complementarily combined to predict a response to immune checkpoint inhibitor therapy
Summary
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. Combinations of gene signatures improved correlation with response, where a visual projection of immunoreactive, proliferative, and clear cell signatures differentiated clinical response. We have previously shown that the correlation between tumor microenvironment and subtype-specific transcriptome profiles, resulting in the “Classification of Ovarian Cancer” (CLOVAR) gene expression s ignatures[4], could be indicative of antitumor and prognostic response to individual small molecule chemotherapeutic a gents[5]. Tumor expression of the programmed death-1 ligand 1 (PD-L1) is predictive of the therapeutic response in certain tumor types such as melanoma and non-small cell lung c ancer[11,12,13,14,15], we found that PD-L1 expression alone was not sufficiently predictive of response in the case of ovarian c ancer[10,16]
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