Abstract A35: Elucidating mechanisms involved in long-term response to platinum-based chemotherapy in high-grade serous ovarian cancer.
Authors: Stephanie Lheureux, Cindy Yang, Patricia Shaw, Blaise Clarke, Julissa Tsao, Katherine Karakasis, Marcus Butler, Noor Salman, Mark Dowar, Jing Xu, Laurent Poulain, Pamela S. Ohashi, Trevor Pugh, Amit Oza
Journal: Clinical Cancer Research (2016)

Abstract Introduction: Approximately eighty percent of women with stage III high-grade serous ovarian cancer (HGSOC) develop recurrent disease despite initial surgery and platinum-based combination chemotherapy. Clinico-pathological factors do not allow precise prediction of outcome and hence initial treatment is not stratified. Potential genomic and immunologic predictive factors of response/resistance to platinum-based chemotherapy could be identified by comparing and contrasting long-term with short-term survivors. Methods: Patients with stage III HGSOC and upfront debulking surgery followed by platinum-based chemotherapy were selected from the Princess Margaret Cancer Centre registry. Retrospectively, 25 patients were identified as long-term responders (alive 10 years or more from the time of diagnosis) and 24 patients as short-term responders (dead within 2 years of diagnosis and primary platinum resistant). Available archival snap frozen or formalin-fixed paraffin-embedded tumor and matched normal tissue sections from identified patients were obtained through the University Health Network (UHN) Biobank. Pathology was confirmed by an expert gynecological pathologist. Each archival specimen was characterized by histological, molecular, genomic and immunologic patterns at presentation of disease. We performed whole exome sequencing (WES) and transcriptome sequencing (RNAseq) from total DNA and RNA extracted from archival tumor tissues to characterize genetic alterations and gene expression profiles. We profiled the tumor tissue protein expression of p53, Ki67, p16, Rb1, cyclin E, cyclin D1, CD3, CD8, CD68, PDL-1, FoxP3, and the Bcl-2 family proteins (Bcl-xL, Bcl-2, MCL-1, Bax, Bak, Bim, Noxa, Puma) through immunohistochemistry (IHC) analyses. Results: Preliminary genomic data were analyzed from the initial set of 3 long-term survivors and 7 short-term survivors. 8/10 tumors were characterized by TP53 mutations. All long-term survivors harbor germline mutations in BRCA1 or 2. Somatic mutations in ADAMTS family genes associated with chemo-sensitivity occur at a higher frequency in long-term survivors. One patient with a long-term response had a hyper-mutated phenotype. Preliminary IHC analyses on 21 patients (10 long- and 11 short-term survivors) examined to date showed that apoptosis-regulating genes—such as p53, Bcl-2, Bcl-xL, Bax, which regulate cancer cell sensitivity/resistance—do not have a significant difference in protein expression at baseline. Purity estimates generated from WES shows that tumors from long survivors have reduced purity as compared to short-term survivors. Overall levels of immune and stromal infiltration for each tumor by applying the ESTIMATE algorithm to the quantile-normalized gene expression profiles suggest higher immune and stromal scores in long surviving compared to short surviving HGSOC. Conclusions: The initial results indicate a potential predictive signature for long-term response in HGSOC. Citation Format: Stephanie Lheureux, Cindy Yang, Patricia Shaw, Blaise Clarke, Julissa Tsao, Katherine Karakasis, Marcus Butler, Noor Salman, Mark Dowar, Jing Xu, Laurent Poulain, Pamela S. Ohashi, Trevor Pugh, Amit Oza. Elucidating mechanisms involved in long-term response to platinum-based chemotherapy in high-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A35.