Validation of a proliferation-based expression signature as prognostic marker in early stage lung adenocarcinoma

Ignacio I. Wistuba, Carmen Behrens, Francesca Lombardi, Susanne Wagner, Junya Fujimoto, M. Gabriela Raso, Lorenzo Spaggiari, Domenico Galetta, Robyn Riley, Elisha Hughes, Julia Reid, Zaina Sangale, Steven G. Swisher, Neda Kalhor, Cesar A. Moran, Alexander Gutin, Jerry S. Lanchbury, Massimo Barberis, Edward S. Kim

Research output: Contribution to journalArticle

Abstract

Purpose: New prognostic markers to guide treatment decisions in early stage non-small cell lung cancer are necessary to improve patient outcomes. In this report, we assess the utility of a predefined mRNA expression signature of cell-cycle progression genes (CCP score) to define 5-year risk of lung cancer-related death in patients with early stage lung adenocarcinoma. Experimental Design: A CCP score was calculated from the mRNA expression levels of 31 proliferation genes in stage I and stage II tumor samples from two public microarray datasets [Director's Consortium (DC) and GSE31210]. The same gene set was tested by quantitative PCR in 381 formalin-fixed paraffin-embedded (FFPE) primary tumors. Association of the CCP score with outcome was assessed by Cox proportional hazards analysis. Results: In univariate analysis, the CCP score was a strong predictor of cancer-specific survival in both the Director's Consortium cohort (P = 0.00014; HR = 2.08;95% CI, 1.43-3.02) and GSE31210 (P = 0.0010; HR = 2.25;95% CI, 1.42-3.56). In multivariate analysis, the CCP score remained the dominant prognostic marker in the presence of clinical variables (P = 0.0022; HR = 2.02;95% CI, 1.29-3.17 in Director's Consortium, P= 0.0026; HR = 2.16;95%CI, 1.32-3.53 in GSE31210). On a quantitative PCR platform, the CCP score maintained highly significant prognostic value in FFPE-derived mRNA from clinical samples in both univariate (P = 0.00033; HR = 2.10;95% CI, 1.39-3.17) and multivariate analyses (P= 0.0071; HR = 1.92;95% CI, 1.18-3.10). Conclusions: The CCP score is a significant predictor of lung cancer death in early stage lung adenocarcinoma treated with surgery and maybe a valuable tool in selecting patients for adjuvant treatment.

Original languageEnglish
Pages (from-to)6261-6271
Number of pages11
JournalClinical Cancer Research
Volume19
Issue number22
DOIs
Publication statusPublished - Nov 15 2013

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Wistuba, I. I., Behrens, C., Lombardi, F., Wagner, S., Fujimoto, J., Raso, M. G., Spaggiari, L., Galetta, D., Riley, R., Hughes, E., Reid, J., Sangale, Z., Swisher, S. G., Kalhor, N., Moran, C. A., Gutin, A., Lanchbury, J. S., Barberis, M., & Kim, E. S. (2013). Validation of a proliferation-based expression signature as prognostic marker in early stage lung adenocarcinoma. Clinical Cancer Research, 19(22), 6261-6271. https://doi.org/10.1158/1078-0432.CCR-13-0596