Validating the Impact of a Molecular Subtype in Ovarian Cancer on Outcomes - A Study of the OVCAD Consortium
Pils, Dietmar × Hager, Gudrun Tong, Dan Aust, Stefanie Heinze, Georg Kohl, Maria Schuster, Eva Wolf, Andrea Sehouli, Jalid Braicu, Ioana Vergote, Ignace Cadron, Isabelle Mahner, Sven Hofstetter, Gerda Speiser, Paul Zeillinger, Robert #
Wiley-Blackwell Publishing Japan
Cancer Science vol:103 issue:7 pages:1334-41
The majority of patients with epithelial ovarian cancer (EOC) is diagnosed at advanced stage and has a poor prognosis. A small proportion of these patients though will survive while others die very quickly. Clinicopathological factors do not allow precise identification of these subgroups. Thus we have validated a molecular subclassification as new prognostic factor in EOC. One hundred ninety-four patients with stage II to IV EOC were characterized by whole-genome expression profiling of tumor tissues and classified using a published 112 gene-set, derived from a FIGO stage directed supervised classification approach. The 194 tumor samples were classified into two subclasses of 95 (subclass 1) and 99 (subclass 2) tumors, grouping all 9 FIGO II tumors in subclass 1 (p=0.001). Subclass 2 (54% of advanced stage tumors) correlated significantly with peritoneal carcinomatosis and non-optimal debulking. Patients with subclass 2 tumors had a worse overall survival in both histological subtypes both, univariate (HRs 3.17 (serous) and 17.11 (non-serous), p≤0.001) and in models corrected for relevant clinicopathologic parameters (HRs 2.87 (serous) and 12.42 (non-serous), p≤0.023). Significance analysis of microarrays revealed 2,082 genes differentially expressed in advanced grade serous tumors of both subclasses and the focal adhesion pathway as the most deregulated pathway. In this validation study we showed that in advanced-stage serous ovarian cancer two approximately equally large molecular subtypes exist, independent from classical clinocopathological parameters presenting with highly different whole genome expression profiles and an impressively different overall survival. Similar results were obtained in a small cohort of patients with non-serous tumors.