Abstract 809: Selecting ovarian cancer patients for clinical trials using a broad panel of molecular markers
Authors: Zajchowski Deborah A. , Gross Jenny , Karlan Beth Y. , Bloom Ken , Loesch David , Thompson Eric , Alarcon Arlet , Shawver Laura K. 
Published: February 2011

Abstract
Our understanding of the molecular biology of ovarian cancer is rapidly expanding, in part through efforts such as The Cancer Genome Atlas (TCGA) project, which is comprehensively cataloguing the genomic aberrations of 500 advanced serous ovarian carcinomas. These and other studies have shown that ovarian cancers are molecularly complex and highly heterogeneous. Importantly, the prevalence of over-expression or alteration of any one drug target is very low in ovarian cancer (with the exception of p53 mutations, which occur in 70-90% of advanced stage serous carcinomas). Therefore, the identification of patients for clinical trials of targeted drug therapies by measuring expression of a single target or pathway has limited usefulness. To improve the efficiency of trial enrollment and also the likelihood of successful therapeutic outcomes, we propose to evaluate every patient using a broad tumor marker panel. In feasibility studies, we have analyzed ovarian tumors for a panel of markers that includes molecular targets such as EGFR, HER2, VEGF, PDGFR, IGF1R, c-met, c-kit, ER, and AR, as well as signaling pathway proteins (e.g., HIF1alpha, COX2, PTEN). Because targeted agents are frequently combined with chemotherapy in ovarian cancer clinical trials, we also included proteins associated with response to representative agents (e.g., platinums, taxanes, anthracyclines), such as drug transporters (BCRP, MRP1, PGP) and proteins involved in DNA repair/modification (ERCC1, MGMT) or synthesis (TS, RRM1, TOPO1/2A). Formalin-fixed, paraffin-embedded tumor blocks were obtained following patient consent and protein expression was measured by immunohistochemical analyses at CLIA-certified laboratories. Expression data were recorded as histoscores (% tumor cells stained x intensity). To date, 44 tumor specimens (histology: 28 serous, 6 clear cell, 1 endometrioid, 1 MMMT, and 2 granulosa cell; 3 stage I, 3 stage II, 31 stage III, 2 stage IV, 5 unknown) have been profiled. Approximately half of the specimens were derived from the ovary; the others were recurrent lesions or metastases (peritoneum, pelvis, omentum, liver, and colon) discovered at diagnosis. Two were pleural effusion or lung nodule biopsies. The markedly heterogeneous nature of ovarian tumors is apparent from the results of this analysis. One exception is the expression of the angiogenic factor VEGF, which is highly expressed in &gt;80% of these tumors. PDGFR alpha and beta were highly co-expressed in multiple tumors. IGF1R was highly expressed in ∼25%, ER alpha in ∼40%, and AR in ∼20% of ovarian tumors. No tumor over-expressed HER2 and EGFR was highly detected in only 10% of the cases. Importantly, hierarchical clustering analyses based upon drug target expression revealed the existence of several sub-groups of ovarian cancer patients and provide clues to select from treatment options.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 809.