Validation of a Proliferation-Based Expression Signature as Prognostic Marker in Early Stage Lung Adenocarcinoma

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 pre-defined 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 II tumor samples from two public microarray data sets (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 DC 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 DC, 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.

Cost-Utility of a Prognostic Test Guiding Adjuvant Chemotherapy Decisions in Early-Stage Non-Small Cell Lung Cancer

“…Myriad Genetics, Inc. provided patient-level data, which were pooled to determine the distribution of CCP scores by stage from published studies on myPlan [21,22]. Each patient in the model was assigned a CCP score based on these distributions.…”

“…Because of this, each patient in the model had the same mortality risk and received the same benefit from ACT in the myPlan or SoC arms. The estimated treatment benefit of ACT on NSCLC-related mortality by CCP score was determined from the subset of patients who received ACT [21]. Higher CCP scores indicate cancer cells may be dividing more rapidly, and chemotherapytraditionally is moreeffective in rapidly dividing cells, so it may be that ACT would be more effective in patients with higher CCP scores.This was seen in the small subset of patients who received ACT [21].…”

“…The estimated treatment benefit of ACT on NSCLC-related mortality by CCP score was determined from the subset of patients who received ACT [21]. Higher CCP scores indicate cancer cells may be dividing more rapidly, and chemotherapytraditionally is moreeffective in rapidly dividing cells, so it may be that ACT would be more effective in patients with higher CCP scores.This was seen in the small subset of patients who received ACT [21]. However, because of a limited number of patients receiving ACT in that study, this assumption was explored in sensitivity analyses by using data from other studies [8,40].…”

“…Recently, the expression levels of cell cycle progression (CCP) genes, reflecting the inherent aggressiveness of the tumor, have shown to be prognostic in patients with early-stage adenocarcinoma of the lung [14]. The CCP score has been shown to predict patients at high risk of cancer recurrence and cancer-related death [15][16][17][18][19][20].…”

“…The CCP score has been shown to predict patients at high risk of cancer recurrence and cancer-related death [15][16][17][18][19][20]. A proprietary prognostic test, myPlan Lung Cancer (myPlan), which is based on CCP score and pathologic tumor stage, has been developed by Myriad Genetics, Inc. (Salt Lake City, UT; http://www.myriad.com/products-services/lung-cancer/myplanlung-cancer/) and validated as a prognostic marker of cancerrelated death in patients with NSCLC [21,22]. Specifically, in an independent validation cohort of 650 patients with stage I or II lung adenocarcinoma, the prognostic score was a more significant indicatoroflungcancermortalityriskthanpathologicstage[hazard ratio (HR), 2.01; p , .001] and efficiently stratified patients into low-and high-risk groups with a significant difference (p , .001) in 5-year lung cancer-specific survival [22].…”