Is there a role for the quantification of RRM1 and ERCC1 expression in pancreatic ductal adenocarcinoma?

Matias Emanuel Valsecchi,Charles Yeo,Benjamin Leiby,Agnieszka Witkiewicz,Edith P Mitchell,Thomas Holdbrook,Jonathan Robert Brody,Susan Joy Littman

doi:10.1200/jco.2012.30.4_suppl.246

Abstract

246 Background: RRM1 and ERCC1 overexpression has been extensively investigated as potential predictive markers of tumor sensitivity to conventional chemotherapy agents, most thoroughly in lung cancer. However, data in pancreatic cancer are scarce. Methods: We investigated the mRNA and protein expression of ERCC1 and RRM1 by RT-PCR and immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded pancreatic ductal carcinoma (PDA) tissues. The primary outcome investigated was the association between RRM1 and ERCC1 expression and overall survival (OS) or disease-free survival (DFS). Results: A total of 94 patients with resected PDA were included in this study. Most of them (87%) received gemcitabine based chemotherapy. Data for OS analysis was available in all cases but only 68% had enough information to estimate DFS. IHC analysis revealed information for 99% (93/94) and 100% of the cases for RRM1 and ERCC1 expression respectively. However, PCR data interpretation was possible in only 49 (52%) and 79 (84%) cases respectively. There was no significant association between high or low expression of either RRM1 or ERCC1, either in univariate or multivariate analyses, detected by IHC and OS (14.4 vs. 19.9 months; P = 0.5 and 17.1 vs. 19.9; P = 0.83 respectively) or PCR and OS (48.0 vs. 24.1 months; P = 0.21 and 22.0 vs. 16.0 months; P = 0.39 respectively) (Table 1). Similar results were obtained for DFS. Conclusions: RRM1 and ERCC1 expression does not seem to have a clear predictive or prognostic value in pancreatic cancer. Our data raise some questions regarding the real clinical and practical significance of analyzing these molecules as predictors of outcomes. [Table: see text]

Highlights

ribonucleotide reductase subunit M1 (RRM1) and excision repair cross complementary 1 (ERCC1) overexpression has been extensively investigated as potential predictive markers of tumor sensitivity to conventional chemotherapy agents, most thoroughly in lung cancer
RRM1 inhibition translates into reduced activity of the ribonucleotide reductase complex resulting in decreased production of deoxyribonucleotides needed for the DNA synthesis [8]
Patient selection and data collection We studied 94 patients with confirmed Pancreatic ductal adenocarcinoma (PDA) who underwent surgical resection at The Thomas Jefferson University Hospital between 2002 and 2010, and for whom sufficient material was available for immunohistochemical (IHC) and polymerase chain reaction (PCR) analysis

Summary

Introduction

RRM1 and ERCC1 overexpression has been extensively investigated as potential predictive markers of tumor sensitivity to conventional chemotherapy agents, most thoroughly in lung cancer. The ribonucleotide reductase subunit M1 (RRM1) and the excision repair cross complementary 1 (ERCC1) enzymes are two of the many proteins that physiologically participate in the synthesis and damage repair of human DNA Both molecules have been extensively investigated as potential predictive markers of tumor sensitivity to conventional chemotherapy agents. Over-expression of ERCC1 and other enzymes able to remove those DNA adducts can translate into tumoral resistance to platinum analogues [12,13] These two phenomenon have been consistently found to be true especially in non-small cell lung cancer (NSCLC) [14,15,16,17,18,19]; it is unclear whether the same concept can be applied to other cancer types, such as PDA. At least one previous study showed a better overall survival associated with high levels of RRM1 and ERCC1 in resected

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