Abstract 5077: Molecular profiling in recurrent ovarian cancer patients: Considerations for the design of clinical studies to validate profiling for therapy selection
Authors: Deborah A. Zajchowski, Cory Bentley, Jenny Gross, Beth Y. Karlan, Laura K. Shawver
Journal: Cancer Research (2011)

Abstract Therapies for recurrent, advanced stage ovarian cancer are often empirically selected and associated with similarly poor response rates and short progression-free survivals. Our ultimate goal is to improve patient outcomes by enabling a more rational selection of chemotherapies based upon individual tumor molecular profiles. To identify molecular markers to include in such profiling, we performed a literature search for evidence supporting the association between chemotherapy response markers and in vivo responses to drugs currently employed in ovarian cancer treatment. We found multiple reports that demonstrated a correlation between expression levels of RRM1, TOPO1, TOPO2, ERCC1, TS, MGMT, SPARC, MRP1, MDR1, or BCRP and clinical responses to gemcitabine, topoisomerase 1 and 2 inhibitors, platinum, fluoropyrimidines, temozolamide, nab-paclitaxel, taxanes, and other drugs. However, few studies addressed the correlation between these biomarkers and therapy responses for ovarian cancer patients. We therefore measured expression of these markers in formalin-fixed, paraffin-embedded tumor blocks (obtained following informed patient consent) by immunohistochemical analyses at CLIA-certified laboratories to establish expression characteristics of these proteins in epithelial ovarian carcinomas. Protein expression data were recorded as histoscores (% tumor cells stained x intensity). We profiled fifty-nine advanced stage ovarian, peritoneal, or fallopian tube cancers of which 42 were of either serous papillary histology or adenocarcinomas (25 primary and 17 recurrent serous ovarian tumor specimens). The first-line response to platinum-taxane therapy for most of these patients (23 sensitive, 7 resistant, 2 refractory) and BRCA1 and 2 mutation status (7 BRCA1 mutation carriers) were also known. Most of the marker proteins were heterogeneously expressed both within the tumor sample and across the cohort of patient tumors. The exceptions were TOPO2 and MDR1, which were poorly detected in most tumors. Interestingly, primary specimens had significantly lower expression levels of MDR1 and higher expression of RRM1 and TOPO1 than recurrent lesions underscoring the potential importance of determining the molecular profile of recurrent specimens. Six of the seven BRCA1 mutation carriers were sensitive to platinum-taxane treatment, but no significant association with platinum responsiveness was observed for expression of any of the measured proteins. These data provide a basis for establishing expression cutoff points for each marker to test hypotheses that correlate individual or combined marker expression profiles with responses to chemotherapy in prospective analyses. Profiling of recurrent specimens is recommended for future clinical trials to evaluate this approach to individualize cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5077. doi:10.1158/1538-7445.AM2011-5077