Suboptimal cytoreduction in ovarian carcinoma is associated with molecular pathways characteristic of increased stromal activation

Abstract

ObjectiveSuboptimal cytoreductive surgery in advanced epithelial ovarian cancer (EOC) is associated with poor survival but it is unknown if poor outcome is due to the intrinsic biology of unresectable tumors or insufficient surgical effort resulting in residual tumor-sustaining clones. Our objective was to identify the potential molecular pathway(s) and cell type(s) that may be responsible for suboptimal surgical resection. MethodsBy comparing gene expression in optimally and suboptimally cytoreduced patients, we identified a gene network associated with suboptimal cytoreduction and explored the biological processes and cell types associated with this gene network. ResultsWe show that primary tumors from suboptimally cytoreduced patients express molecular signatures that are typically present in a distinct molecular subtype of EOC characterized by increased stromal activation and lymphovascular invasion. Similar molecular pathways are present in EOC metastases, suggesting that primary tumors in suboptimally cytoreduced patients are biologically similar to metastatic tumors. We demonstrate that the suboptimal cytoreduction network genes are enriched in reactive tumor stroma cells rather than malignant tumor cells. ConclusionOur data suggest that the success of cytoreductive surgery is dictated by tumor biology, such as extensive stromal reaction and increased invasiveness, which may hinder surgical resection and ultimately lead to poor survival.