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. 2013 Nov 15;19(22):6261-71.
doi: 10.1158/1078-0432.CCR-13-0596. Epub 2013 Sep 18.

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

Ignacio I Wistuba  1 , 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
Affiliations

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

Ignacio I Wistuba et al. Clin Cancer Res. .

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 may be a valuable tool in selecting patients for adjuvant treatment.

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Conflict of interest statement

Conflicts of Interest: AG, EH, JSL, JR, RR, ZS and SW are employees of Myriad Genetics.

Figures

Figure 1
Figure 1
Association between CCP scores and lung cancer death in several cohorts: Director’s consortium (A), GSE31210 (B) and MDACC/IEO (C). Each patient set was separated into three equally sized groups based on CCP scores. The lowest tercile of CCP scores defines a subpopulation with higher survival. (D) Forest plot of hazard ratios for the interquartile CCP range observed in the three study sets.
Figure 2
Figure 2
(A) Five year predicted risk of lung cancer related death as a function of CCP score analyzed by quantitative PCR in FFPE samples (top panel) and distribution of CCP scores within stage IA, IB and II patient samples (bottom panel). (B) Absolute benefit from adjuvant treatment depending on CCP score. Association of the expression score with treatment benefit was derived from the difference in survival ratios between the treated and untreated patients in the MDACC cohort.
See this image and copyright information in PMC

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