Peritoneal tumor spread in serous ovarian cancer-epithelial mesenchymal status and outcome

// Katharina Auer 1 , Anna Bachmayr-Heyda 1 , Stefanie Aust 1 , Nyamdelger Sukhbaatar 1 , Agnes Teresa Reiner 1 , Christoph Grimm 1 , Reinhard Horvat 2 , Robert Zeillinger 1 , Dietmar Pils 1 1 Department of Obstetrics and Gynecology, Comprehensive Cancer Center (CCC), Medical University of Vienna and Ludwig Boltzmann Cluster Translational Oncology, Vienna, Austria 2 Department of Pathology, Medical University of Vienna, Vienna, Austria Correspondence to: Dietmar Pils, e-mail: dietmar.pils@univie.ac.at Keywords: epithelial ovarian cancer, peritoneal tumor spread, flow cytometric analysis, RNA-sequencing, next generation sequencing Received: February 10, 2015 Accepted: April 28, 2015 Published: May 11, 2015 ABSTRACT In this study we aimed to analyze the biological mechanisms underlying apparently different modes of peritoneal tumor spread in serous ovarian cancer: miliary (widespread, millet-like lesions) versus non-miliary (bigger, exophytically growing implants). Tumor tissues and ascites from 23 chemotherapy naive patients were analyzed by RNA-sequencing and flow cytometry. On the basis of differential gene expression between miliary and non-miliary, gene signatures were developed. A calculated tumor spread factor revealed a significant independent negative impact of miliary spread on overall survival (HR 3.77; CI 95 1.14–12.39; p = 0.029) in an independent cohort of 165 serous ovarian cancer patients. Comparing previously published epithelial-mesenchymal transition (EMT) gene signatures, non-miliary spread correlated significantly with a reduced epithelial status. We conclude that serous ovarian cancer is a heterogeneous disease with distinct modes of peritoneal tumor spread, differing not only in clinical appearance, but also in molecular characteristics and outcome. EMT, peritoneal inflammation status, and therapeutic options are discussed. Significance: More than half of serous epithelial ovarian cancer patients present with a newly described type of intraperitoneal tumor spread, associated with differences in the inflammation status, activated oncogenic pathways, lack of EMT, and thus reduced overall survival. Both, the diminished immune reaction and the enhanced epithelial and malignant characteristics of the tumor cells open new avenues for therapeutic options and strategies, like Catumaxomab, already in clinical use.