Ribonucleotide reductase subunit-2 (RRM2) and thymidylate synthase (TS) to predict shorter survival in patients (pts) with resected stage I-III non-small cell lung cancer (NSCLC).

Abstract

11063 Background: Tumor biomarkers can help to identify pts with early-stage NSCLC with high risk of relapse and poor prognosis. The aim of this study was to investigate the prognostic value of 7 biomarkers involved in DNA synthesis and repair. Methods: Tumour tissues from 82 radically resected, stage I-III NSCLC pts were consecutively collected to investigate the following biomarkers: excision repair cross-complementation group 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunit 1 (RRM1), ribonucleotide reductase subunit 2 (RRM2), subunit p53R2, thymidylate synthase (TS) and class III beta-tubulin (TUBB3) using immunohistochemistry (IHC) and quantitative real time-polymerase chain reaction (qRT-PCR). Expression levels of these genes were also investigated in a large publicly available NSCLC microarray dataset (Director Challenge Consortium, DCC). Results: RRM2 expression (p=0.031), TS expression (p=0.023), and pathologic stage (p<0.001) were found as independent prognostic factors for shorter survival. The expression of ERCC1, RRM1, p53R2, TUBB3, BRCA1, as well as other clinical characteristics, failed to show any statistically significant association with the survival. Despite the lack of statistical significance, patients with lower RRM2 expression (i.e., ≤ 140) survived longer than pts with higher RRM2 levels (p=0.069). There was a trend towards longer survival for BRCA1-, ERCC1-, RRM1- and TS-negative pts and for p53R2- and TUBB3-positive pts. For all of the biomarkers except TUBB3, the OS trends relative to the protein expression levels were in agreement with those relative to the respective gene expression levels, although the differences were not statistically significant. In the larger DCC dataset, TS (p=0.005), and BRCA1 (p=0.021) were identified as prognostic markers for OS, independent of tumour stage. Conclusions: This study has shown that high RRM2 and TS protein levels are negative prognostic factors for resected, stage I-III NSCLC pts. The data obtained by qRT-PCR confirmed these results. Analysis of the DCC microarray dataset detected TS and BRCA1 as independent prognostic markers of OS.