ERCC1 and RRM1 expression in resected pancreatic adenocarcinoma.

Abstract

e14606 Background: Excision repair cross-complementing group 1 (ERCC1) plays a critical role in DNA repair and is associated with resistance to radiation and platinum-based therapy. RRM1 encodes the regulatory subunit of ribonucleotide reductase and is the molecular target of gemcitabine. We hypothesized that ERCC1 and RRM1 expression would predict for outcome and response in pancreatic adenocarcinoma. Methods: We determined ERCC1 and RRM1 expression levels in 89 pancreatic cancer specimens from patients who underwent resection, using automated quantitative analysis (AQUA), a fluorescence-based immunohistochemical method. The relationship between protein expression and patient characteristics was determined using box plots and Pearson’s correlation coefficient. The relationship between protein expression and outcomes was measured using Kaplan-Meier curves, log-rank test and Cox regression. Results: The average expression score of duplicate tissue cores from each patient was used for analysis. Tumor expression scores for ERCC1 and RRM1 ranged from 89 to 1016 (median 323) and 327 to 2,171 (median 1,066) respectively. Median values of ERCC1 and RRM1 expression were used to divide patients into high and low groups. Mean age was 67 years and median overall survival was 20.7 months. There were no significant differences between high and low ERCC1 and RRM1 groups with respect to age, gender, grade, tumor size (T) and lymph node metastases (N) except that T was negatively correlated with ERCC1 expression level (p=0.02). There was no significant correlation between ERCC1 expression and DFS or OS. DFS was significantly better for patients with low RRM1 expression (p=0.026, HR=2.92, 95% CI 1.14 – 7.5) with no significant correlation for OS. For the 21 patients who received gemcitabine at recurrence, low RRM1 expression was associated with improved PFS (p=0.034) and OS (p=0.022). Conclusions: ERCC1 expression did not correlate with outcome in this series. Low RRM1 expression was associated with an improved DFS. Low RRM1 expression also correlated to benefit in patients receiving gemcitabine at disease recurrence. With increasing treatment options for advanced pancreatic cancer, further study of pharmacogenomic-based selection strategies is warranted.