Excision Repair Cross Complementing 1 (ERCC1) and Ribonucleotide Reductase Regulatory Subunit M1 (RRM1) as Predictors of Survival and Response in Pancreatic Ductal Adenocarcinoma Treated with Gemcitabine-Based Chemotherapy.
Thomas Holdbrook, Kathleen D Danenberg, Suneeta Satti, Jessica Kline, Charles J Yeo, Jonathan R Brody, Peter McCue, Agnieszka K Witkiewicz. Thomas Jefferson University Hospital, Philadelphia, PA
Background: Gemcitabine-based chemotherapy is a standard treatment for pancreatic ductal adenocarcinoma (PDA). Several biomarkers are currently being evaluated as predictors of survival and response in gemcitabine treated PDA. Two such markers, excision repair cross-complementation group 1 (ERCC1) and ribonucleotide reductase regulatory subunit M1 (RRM1), play a pivotal role in DNA damage repair. The purpose of our study was to correlate ERCC1 and RRM1 expression with survival in gemcitabine treated PDA patients.
Design: We investigated the mRNA and protein expression of ERCC1 and RRM1 by RT-PCR and immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded PDA tissues from patients treated with gemcitabine-based chemotherapy. Relative gene expression quantification was calculated according to the comparative cycle threshold (Ct) method using ß-actin as an endogenous control and commercial RNA controls (Stratagene, La Jolla, CA) as calibrators. IHC was performed using purified RRM1 antibodies (1:150 dilution; Abcam, Cambridge, MA) and ERCC1 antibodies (1:50 dilution; Abcam, Cambridge, MA). RRM1 and ERCC1 immunoreactivity was evaluated semi-quantitatively based on staining intensity and proportion of staining in the area of most intense staining. The stained tumor tissues were scored blindly with respect to clinical patient data.
Results: RRM1 RT-PCR results were available for 26 patients and ERCC1 for 60 patients. IHC stains were performed on all cases. Low RMM1 expression by RT-PCR was associated with a two-fold decrease in risk of mortality compared to high expression; however, due to the small sample size, this difference was not statistically significant. Low ERCC1 expression by RT-PCR was associated with 2.5 times higher risk of mortality than high expression (p=0.031). High expression of RRM1 by IHC was associated with shorter survival (p=0.02). There was no association between ERCC1 expression by IHC and survival. Agreement between mRNA and protein expression was modest for RRM1 (kappa = 0.57) and poor for ERCC1 (kappa=0.14).
Conclusions: PDA patients with low expression of RRM1 derive benefit from gemcitabine chemotherapy. The ERCC1 levels measured by RT-PCR but not by IHC predict survival in these patients.
Category: Liver & Pancreas
Tuesday, March 1, 2011 1:00 PM
Poster Session IV # 205, Tuesday Afternoon