title: A practical molecular assay to predict survival in resected non-squamous, non-small-cell lung cancer: development and international validation studies.
abstract: 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).
  
  
  RESULTS
  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 (p(trend)=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 (p(trend)<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.
  
  
  CONCLUSIONS
  Our practical, quantitative-PCR-based assay reliably identified patients with early-stage non-squamous NSCLC at high risk for mortality after surgical resection.
  
  
  BACKGROUND
  UCSF Thoracic Oncology Laboratory and Pinpoint Genomics.
authors.affiliation: University of California, San Francisco, CA 94143-1724, USA.
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Kratz
authors.forename: Jianxing
authors.initials: J
authors.lastname: He
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Van Den Eeden
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Zhu
authors.forename: Wen
authors.initials: W
authors.lastname: Gao
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Pham
authors.forename: Michael S
authors.initials: MS
authors.lastname: Mulvihill
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Ziaei
authors.forename: Huanrong
authors.initials: H
authors.lastname: Zhang
authors.forename: Bo
authors.initials: B
authors.lastname: Su
authors.forename: Xiuyi
authors.initials: X
authors.lastname: Zhi
authors.forename: Charles P
authors.initials: CP
authors.lastname: Quesenberry
authors.forename: Laurel A
authors.initials: LA
authors.lastname: Habel
authors.forename: Qiuhua
authors.initials: Q
authors.lastname: Deng
authors.forename: Zongfei
authors.initials: Z
authors.lastname: Wang
authors.forename: Jiangfen
authors.initials: J
authors.lastname: Zhou
authors.forename: Huiling
authors.initials: H
authors.lastname: Li
authors.forename: Mei-Chun
authors.initials: MC
authors.lastname: Huang
authors.forename: Che-Chung
authors.initials: CC
authors.lastname: Yeh
authors.forename: Mark R
authors.initials: MR
authors.lastname: Segal
authors.forename: M Roshni
authors.initials: MR
authors.lastname: Ray
authors.forename: Kirk D
authors.initials: KD
authors.lastname: Jones
authors.forename: Dan J
authors.initials: DJ
authors.lastname: Raz
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Xu
authors.forename: Thierry M
authors.initials: TM
authors.lastname: Jahan
authors.forename: David
authors.initials: D
authors.lastname: Berryman
authors.forename: Biao
authors.initials: B
authors.lastname: He
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mann
authors.forename: David M
authors.initials: DM
authors.lastname: Jablons
mesh_terms: D000328:Adult; D000368:Aged; D002140:California / Q000453:epidemiology; D002289:Carcinoma, Non-Small-Cell Lung / Q000401:mortality* / Q000473:pathology / Q000601:surgery; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007391:International Cooperation; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000401:mortality* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D018570:Risk Assessment