ERCC1 and RRM1 in the international adjuvant lung trial by automated quantitative in situ analysis

Abstract

The excision repair cross completing group 1 gene product (ERCC1) and the regulatory subunit of ribonucleotide reductase (RRM1) have been reported as being prognostic of outcome and predictive of therapeutic efficacy in patients with non-small cell lung cancer. Routinely processed surgical specimens from 784 patients from the International Adjuvant Lung Trial were arrayed as tissue microarrays. In situ protein levels were scored with an automated, quantitative analysis system, dichotomized into high and low marker categories, and analyzed for associations with patients' characteristics, survival, and benefit from adjuvant chemotherapy. Scores for both markers were significantly associated with contributing center (P < 0.001) and skewed, with the bulk of scores being low. High scores were more frequent in women for ERCC1 and RRM1 and in older patients and those with adenocarcinoma for RRM1. Low ERCC1 scores indicated significant benefit from adjuvant chemotherapy [hazard ratio (HR) = 0.73 for chemotherapy versus control, P = 0.02]. Although all other survival associations were not statistically significant, low RRM1 scores trended to indicate benefit from adjuvant chemotherapy (HR = 0.84, P = 0.25), and ERCC1 scores were marginally prognostic of survival (HR = 0.77 for high versus low scores, P = 0.10). We conclude that contributing center and specimen quality substantially affect the levels of both markers. Future trials should incorporate the collection and processing of tumor specimens prospectively on standardized protocols to better reveal the impact of biomarkers on clinically relevant outcomes.

Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Distribution of ERCC1 and RRM1 in situ protein expression scores. Lines indicate scores of 10. ERCC1 and RRM1 expression levels were modestly correlated (N = 730, correlation between log expressions: r = 0.22, 95% confidence interval, 0.15-0.29).

Figure 2

Distribution of ERCC1 AQUA scores by H-score categories. The box width is proportional to the number of patients in each category, the cross is the mean, and the horizontal bar is the median value. The correlation coefficient between log AQUA scores and raw H-score was 0.27 (95% confidence interval, 0.20 to 0.33).

Figure 3

Overall (A and C) and disease-free (B and D) survival by high and low ERCC1 (A and B) and RRM1 (C and D) expression categories and treatment arm.

Figure 4

Overall survival by high and low ERCC1 and RRM1 expression categories and treatment arm (A, control group; B, chemotherapy group).