Elsevier

The Lancet

Volume 379, Issue 9818, 3–9 March 2012, Pages 823-832
The Lancet

Articles
A practical molecular assay to predict survival in resected non-squamous, non-small-cell lung cancer: development and international validation studies

https://doi.org/10.1016/S0140-6736(11)61941-7Get rights and content

Summary

Background

The frequent recurrence of early-stage non-small-cell lung cancer (NSCLC) is generally attributable to metastatic disease undetected at complete resection. Management of such patients depends on prognostic staging to identify the individuals most likely to have occult disease. We aimed to develop and validate a practical, reliable assay that improves risk stratification compared with conventional staging.

Methods

A 14-gene expression assay that uses quantitative PCR, runs on formalin-fixed paraffin-embedded tissue samples, and differentiates patients with heterogeneous statistical prognoses was developed in a cohort of 361 patients with non-squamous NSCLC resected at the University of California, San Francisco. The assay was then independently validated by the Kaiser Permanente Division of Research in a masked cohort of 433 patients with stage I non-squamous NSCLC resected at Kaiser Permanente Northern California hospitals, and on a cohort of 1006 patients with stage I–III non-squamous NSCLC resected in several leading Chinese cancer centres that are part of the China Clinical Trials Consortium (CCTC).

Findings

Kaplan-Meier analysis of the Kaiser validation cohort showed 5 year overall survival of 71·4% (95% CI 60·5–80·0) in low-risk, 58·3% (48·9–66·6) in intermediate-risk, and 49·2% (42·2–55·8) in high-risk patients (ptrend=0·0003). Similar analysis of the CCTC cohort indicated 5 year overall survivals of 74·1% (66·0–80·6) in low-risk, 57·4% (48·3–65·5) in intermediate-risk, and 44·6% (40·2–48·9) in high-risk patients (ptrend<0·0001). Multivariate analysis in both cohorts indicated that no standard clinical risk factors could account for, or provide, the prognostic information derived from tumour gene expression. The assay improved prognostic accuracy beyond National Comprehensive Cancer Network criteria for stage I high-risk tumours (p<0·0001), and differentiated low-risk, intermediate-risk, and high-risk patients within all disease stages.

Interpretation

Our practical, quantitative-PCR-based assay reliably identified patients with early-stage non-squamous NSCLC at high risk for mortality after surgical resection.

Funding

UCSF Thoracic Oncology Laboratory and Pinpoint Genomics.

Section snippets

Background

By contrast with other common solid tumours such as breast and colon cancer, outcomes after resection of early-stage non-small-cell lung cancer (NSCLC) are poor, with 35–50% recurrence rates.1 Little progress has been made in the past 30 years in the reduction of distant recurrence and subsequent mortality,1 which remain unacceptably high, even for patients with stage I disease in whom no nodal or other metastatic involvement can be detected at the time of surgery.2 Despite the high rate of

Study design and participants

A 14-gene assay that uses quantitative PCR analysis of formalin-fixed, paraffin-embedded tissues was developed with a cohort of 361 patients with non-squamous NSCLC resected at the University of California, San Francisco (UCSF), USA. This assay, developed and run at an independent laboratory certified by Clinical Laboratory Improvement Amendments (CLIA), was then validated by the Kaiser Permanente Division of Research (KPDOR) with a blinded study design in a cohort of 433 patients with stage I

Results

A total of 399 patients were identified who had undergone resection of non-squamous NSCLC at UCSF during the study period; of these, 361 met criteria for inclusion in the training cohort. 460 patients at Kaiser Northern California had undergone resections of stage I non-squamous NSCLC, of whom 433 met criteria for inclusion in the independent validation cohort. 1006 patients were identified in the CCTC institutions that met criteria for inclusion in that validation study. Relevant clinical and

Discussion

Our practical, quantitative-PCR-based assay reliably identified patients with early-stage non-squamous NSCLC at high risk for mortality after surgical resection, discriminating such patients with greater accuracy than use of NCCN criteria alone.

Outcomes after the diagnosis of stage I NSCLC are poor compared with other solid tumours, despite advances in the molecular understanding of lung cancer. Several randomised controlled trials32, 33, 34, 35, 36 have shown improved survival with

References (45)

  • L Guo et al.

    Constructing molecular classifiers for the accurate prognosis of lung adenocarcinoma

    Clin Cancer Res

    (2006)
  • JE Larsen et al.

    Expression profiling defines a recurrence signature in lung squamous cell carcinoma

    Carcinogenesis

    (2007)
  • JE Larsen et al.

    Gene expression signature predicts recurrence in lung adenocarcinoma

    Clin Cancer Res

    (2007)
  • SK Lau et al.

    Three-gene prognostic classifier for early-stage non small-cell lung cancer

    J Clin Oncol

    (2007)
  • Y Lu et al.

    A gene expression signature predicts survival of patients with stage I non-small cell lung cancer

    PLoS Med

    (2006)
  • M Raponi et al.

    Gene expression signatures for predicting prognosis of squamous cell and adenocarcinomas of the lung

    Cancer Res

    (2006)
  • DJ Raz et al.

    A multigene assay is prognostic of survival in patients with early-stage lung adenocarcinoma

    Clin Cancer Res

    (2008)
  • P Roepman et al.

    An immune response enriched 72-gene prognostic profile for early-stage non-small-cell lung cancer

    Clin Cancer Res

    (2009)
  • K Shedden et al.

    Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study

    Nat Med

    (2008)
  • M Skrzypski et al.

    Three-gene expression signature predicts survival in early-stage squamous cell carcinoma of the lung

    Clin Cancer Res

    (2008)
  • Z Sun et al.

    Non-overlapping and non-cell-type-specific gene expression signatures predict lung cancer survival

    J Clin Oncol

    (2008)
  • S Tomida et al.

    Gene expression-based, individualized outcome prediction for surgically treated lung cancer patients

    Oncogene

    (2004)
  • Cited by (282)

    View all citing articles on Scopus

    These authors share first authorship

    View full text