Journal of Thoracic Oncology. 2015 Jan;10(1): 67-73.

Validation of a Molecular and Pathological Model for Five-Year Mortality Risk in Patients with Early Stage Lung Adenocarcinoma


Raphael Bueno, MD1; Elisha Hughes, PhD2; Susanne Wagner, PhD2; Alexander S. Gutin, PhD2; Jerry S. Lanchbury, PhD2; Yifan Zheng, MD1; Michael A. Archer, DO1; Corinne Gustafson; PhD1; Joshua T. Jones, PhD3; Kristen Rushton, MBA3; Jennifer Saam, MS, LCGC, PhD3; Edward Kim, MD4; Massimo Barberis, MD5; Ignacio Wistuba, MD6; Richard J. Wenstrup, MD3; William A. Wallace, PhD, FRCPE, FRCPath7; Anne-Renee Hartman, MD3*, and David J. Harrison8*

*Both authors contributed equally to this work.

  1. Division of Thoracic Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
  2. Myriad Genetics, Inc., Salt Lake City, UT
  3. Myriad Genetic Laboratories, Inc., Salt Lake City, UT
  4. Levine Cancer Institute, Charlotte, NC
  5. Istituto Europeo di Oncologia, Milan, Italy
  6. The University of Texas MD Anderson Cancer Center, Houston, TX
  7. Royal Infirmary of Edinburgh, Edinburgh, Scotland
  8. University of St. Andrews, St. Andrews, Scotland



Introduction: The aim of this study was to validate a molecular expression signature [cell cycle progression (CCP) score] that identifies patients with a higher risk of cancer-related death after surgical resection of early stage (I-II) lung adenocarcinoma in a large patient cohort and evaluate the effectiveness of combining CCP score and pathological stage for predicting lung cancer mortality.

Methods: Formalin-fixed paraffin-embedded surgical tumor samples from 650 patients diagnosed with stage I and II adenocarcinoma who underwent definitive surgical treatment without adjuvant chemotherapy were analyzed for 31 proliferation genes by quantitative real-time polymerase chain reaction. The prognostic discrimination of the expression score was assessed by Cox proportional hazards analysis using 5-year lung cancer-specific death as primary outcome.

Results: The CCP score was a significant predictor of lung cancer-specific mortality above clinical covariates [hazard ratio (HR) = 1.46 per interquartile range (95% confidence interval = 1.12–1.90; p = 0.0050)]. The prognostic score, a combination of CCP score and pathological stage, was a more significant indicator of lung cancer mortality risk than pathological stage in the full cohort (HR = 2.01; p = 2.8 × 10−11) and in stage I patients (HR = 1.67; p = 0.00027). Using the 85th percentile of the prognostic score as a threshold, there was a significant difference in lung cancer survival between low-risk and high-risk patient groups (p = 3.8 × 10−7).

Conclusions: This study validates the CCP score and the prognostic score as independent predictors of lung cancer death in patients with early stage lung adenocarcinoma treated with surgery alone. Patients with resected stage I lung adenocarcinoma and a high prognostic score may be candidates for adjuvant therapy to reduce cancer-related mortality.

PMID: 25396679



Additional Information:

Lung cancer is one of the most common cancers in the US and Europe, with approximately 85% of cases being non-small cell lung cancer (NSCLC). The current standard of care for early stage NSCLC is surgical resection; however, 5-year survival rates remain relatively low (73% in stage IA, 58% in stage IB disease and 46-36% in stage II). Although recent studies have demonstrated that patients with stage II and III disease benefit from the addition of adjuvant chemotherapy, the benefit to patients with stage I disease is far less clear.

The literature suggests that some patients with stage I disease may benefit from adjuvant therapy, with tumor size (≥ 4 cm) being a possible indicator in stage IB patients. The ability to identify those patients with a high rate of recurrence, for whom adjuvant chemotherapy might provide benefit, is crucial to reducing the mortality from NSCLC. The fundamental role of this strategy is to identify which patients with early stage lung adenocarcinoma are at significantly higher or lower mortality risk so the potential risk and cost versus benefit of adjuvant chemotherapy can be assessed more accurately.

A 46-gene signature measuring cell cycle progression (CCP) gene expression has been developed and validated to predict cancer specific mortality in stage I and II NSCLC adenocarcinomas.  Unlike traditional clinicopathological features which are often subjective and difficult to standardize, cell cycle progression and prognostic scores are robust, objective, and independent measures of patient mortality risk.

Our study further validates the association of CCP with 5-year lung cancer mortality after adjusting for clinical parameters. This was done in a large cohort of 650 surgically treated, chemotherapy and radiation naïve patients with stage I-II lung adenocarcinoma. The CCP score was a highly significant predictor of mortality in the overall cohort as well as when the analysis was restricted to only stage I patients.

When combined with pathologic stage, this CCP score provides a molecular Prognostic Score (PS). We observed that the predictive value of the PS is two orders of magnitude more significant than pathologic stage alone.

A threshold value for the PS was designed to capture within the high risk group the 15% of stage IA patients who recur within 5 years of treatment. This threshold serves as a cut-point to classify patients into low and high risk groups, independent of clinical features. Using this PS threshold value to stratify the high- and low-risk patients, the high prognostic score group had an average mortality risk that was nearly two-fold higher than the low prognostic score group. This suggests that the PS can classify patients into low and high risk categories to allow for improved clinical management by utilizing stage and CCP. For example, in this cohort and by stage alone, patients with stage IB disease had a 29% risk of 5-year mortality. However, when cell cycle progression is assessed, the risk can be seen to range from a low of 17% to a high of 43% and irrespective of tumor size (Figure 1).



Figure 1: Prognostic Score effectively stratifies patient risk within pathological staging risk groups.


Notably, tumor size (≥ 4 cm) was not a significant prognostic factor in stage IB patients in this cohort. This highlights the value of a molecular test to identify the high-risk early stage NSCLC patients, independent of clinical features, who may benefit from adjuvant therapy.

Overall, this study shows independent validation of a previously described CCP signature and prognostic score to predict death from early stage adenocarcinoma. With the expected increase in diagnosis of early stage lung cancer due to adoption of screening modalities, the prognostic score can be used to identify a subset of early stage patients who have a high risk for recurrence and for whom adjuvant chemotherapy may be more effective.



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