Abstract LB-168: A pilot clinical trial of chromodomain-helicase-DNA-binding protein 7 (CHD7) expression as a prognostic and predictive biomarker in patients with early-stage pancreatic adenocarcinoma.

Abstract

Abstract Background/ Objectives Chromodomain helicase DNA Binding protein 7 (CHD7) modulates chromatin remodeling during genome maintenance. Its role in pancreatic cancer (PAC) is unestablished, but preliminary data for Gemcitabine (GEM) sensitivity in pancreatic cell lines and pilot clinical data is promising. This study will evaluate CHD7 as a prognostic and predictive factor in resected PAC using 1) immunohistochemistry (IHC) of patient samples from RTOG 97-04, 2) prospective evaluation of CHD7 over-expression and treatment response in patients receiving FOLFIRINOX and GEM-based chemoradiotherapy (CRT) for locally advanced PAC at our institution and 3) a Phase II molecular-driven randomized trial of personalized therapy based on CHD7 expression. Methodology A loss of function siRNA screen identified genes, including CHD7, that conferred GEM sensitivity when silenced using GEM-treated Mia PaCa-2 cells. CHD7 expression was assessed by IHC scoring in 80 patients who underwent curative intent resection of PAC between 1/2000 and 10/2008. Kaplan-meier survival analysis was performed for recurrence-free survival (RFS) and overall survival (OS). Univariate (UV) and Multivariate (MV) Cox regression analyses using clinically relevant covariates were used to correlate CHD7 expression levels with RFS and OS in patients receiving GEM therapy (n=42). This analysis will be validated in 200 patient samples from RTOG 97-04. CHD7 expression will be correlated with RFS and OS in GEM and 5-Fluorouracil (5-FU) treatment arms. CHD7 expression will also be measured in pre-chemotherapy core biopsies from locally advanced PAC patients treated at our institution. Patients will receive either two cycles of FOLFIRINOX (FOL) followed by GEM-based CRT at a dose of 1000mg/m2 once weekly or two cycles of FOL followed by Capecitabine (CAP)-based CRT. CHD7 expression will again be correlated with survival. These results will be followed by an ECOG- sponsored multi-institutional Phase II randomized trial of FOL and GEM-based CRT or FOL and CAP-based CRT based on CHD7 gene expression. Preliminary Data/ Anticipated Results In patients receiving GEM (n=42), high CHD7 was associated with poor RFS (7 months vs 15 months; p=.025) and poor OS (10 months vs 18 months; p=.015). On MV analysis, high CHD7 expression remained a predictor of poor RFS (HR 8.2 [95% CI 2.4-28]; p=.001) and poor OS (HR 11.6 [95% CI 3.4-40); p<.0001). In the subset of patients receiving adjuvant therapy without GEM (n=17), CHD7 was not associated with RFS (p=0.1) or OS (p=0.4). We expect our RTOG 97-04 validation study to demonstrate stronger correlation of low CHD7 expression with improved RFS and OS in GEM-treated patients. Similarly, we expect our institutional trial to demonstrate improved RFS and OS with low CHD7 in the GEM-treated arm. Citation Format: Lauren E. Colbert, William A. Hall, Claire W. Hardy, Sarah B. Fisher, David S. Yu, Shishir K. Maithel, Bassel El-Rayes, Burcu Saka, N Volkan Adsay, Aleksandra Petrova, Brooke Pantazides, Jeanne Kowalski, Khanjan Gandhi, David Kooby, Charles Staley, Jerome C. Landry. A pilot clinical trial of chromodomain-helicase-DNA-binding protein 7 (CHD7) expression as a prognostic and predictive biomarker in patients with early-stage pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-168. doi:10.1158/1538-7445.AM2013-LB-168