Supplementary Tables S1-S7. This is a multi-"tabbed" Excel file containing the supplementary data of the manuscript and includes a "Summary" tab with descriptions/captions for the enclosed data sheets. They are as follows: Supplementary Table S1: 800-gene Ovarian Cancer Biomarker Nanostring Panel content Supplementary Table S2: Fourteen differentially expressed genes between Plat-R primary vs Plat-S primary tumors (discovery dataset) Supplementary Table S3: Sixty five differentially expressed genes between Plat-R recurrent vs Plat-R primary tumors (discovery dataset) Supplementary Table S4: TP53 mutation status in 32 Plat-R and 26 Plat-S primary tumors (discovery dataset) Supplementary Table S5: CNV analysis on 35 cancer genes in 32 Plat-R and 26 Plat-S primary tumors (discovery dataset) Supplementary Table S6: Demographics summary of ICON7 chemo-treatment arm (biomarker population vs. ITT) Supplementary Table S7: Ten differentially expressed genes between Plat-R primary vs Plat-S primary tumors (ICON7 dataset)
ARTICLE ABSTRACT
Purpose: Up to one third of ovarian cancer patients are intrinsically resistant to platinum-based treatment. However, predictive and therapeutic strategies are lacking due to a poor understanding of the underlying molecular mechanisms. This study aimed to identify key molecular characteristics that are associated with primary chemoresistance in epithelial ovarian cancers.Experimental Design: Gene expression profiling was performed on a discovery set of 85 ovarian tumors with clinically well-defined response to chemotherapies as well as on an independent validation dataset containing 138 ovarian patients from the chemotreatment arm of the ICON7 trial.Results: We identified a distinct “reactive stroma” gene signature that is specifically associated with primary chemoresistant tumors and was further upregulated in posttreatment recurrent tumors. Immunohistochemistry (IHC) and RNA in situ hybridization (RNA ISH) analyses on three of the highest-ranked signature genes (POSTN, LOX, and FAP) confirmed that modulation of the reactive stroma signature genes within the peritumoral stromal compartments was specifically associated with the clinical chemoresistance. Consistent with these findings, chemosensitive ovarian cells grown in the presence of recombinant POSTN promoted resistance to carboplatin and paclitaxel treatment in vitro. Finally, we validated the reactive stroma signature in an independent dataset and demonstrated that a high POSTN expression level predicts shorter progression-free survival following first-line chemotherapy.Conclusions: Our findings highlight the important interplay between cancer and the tumor microenvironment in ovarian cancer biology and treatment. The identified reactive stromal components in this study provide a molecular basis to the further development of novel diagnostic and therapeutic strategies for overcoming chemoresistance in ovarian cancer. Clin Cancer Res; 21(13); 2941–51. ©2015 AACR.
