Molecular Prognostic Index Improves Risk Stratification of Early-Stage NSCLC


Key Points

  • A nine-gene molecular prognostic index distinguished survival risk groups in patients with stage I non–small cell lung cancer.
  • Greater prognostic power was observed with integration of the molecular prognostic index and clinical variables into a composite risk model.

In a study reported in the Journal of the National Cancer Institute, Gentles et al identified a nine-gene molecular prognostic index that improved the overall survival prognostic power of clinical factors in patients with stage I non–small cell lung cancer (NSCLC).

Study Details

In the study, tumor and stroma gene-expression profiles from 1,106 nonsquamous NSCLCs were used to generate and validate a nine-gene molecular prognostic index. A quantitative polymerase chain reaction assay was developed and validated in an independent cohort of formalin-fixed paraffin-embedded tissues (n = 98). A prognostic score using clinical variables was generated using Surveillance, Epidemiology, and End Results data and was combined with the molecular prognostic index in a composite risk model.

The genes included in the molecular prognostic index were expressed in distinct tumor cell subpopulations. Those implicated in proliferation and stem cells were associated with poor outcomes, and those involved in normal lung differentiation and immune infiltration were associated with better outcomes. The genes included four with expression associated with poorer outcome (MAD2L1, GINS1, SLC2A1, and KRT6A) and five associated with favorable outcome (TNIK, BCAM, KDM6A, FCGRT, and FAIM3).

Molecular Prognostic Index

The molecular prognostic index stratified stage I patients into overall survival prognostic categories in three microarray cohorts and the formalin-fixed paraffin-embedded polymerase chain reaction cohort. Hazard ratios were 2.99 (P < .001) in stage IA patients in the largest microarray validation cohort (n = 543) and 3.95 (P = .01) in stage IA patients in the polymerase chain reaction cohort.

Integration of the molecular prognostic index with clinical variables was associated with the greatest prognostic power, with hazard ratios of 3.43 (P < .001) in stage I patients in the largest microarray cohort and 3.99 (P < .001) in stage I patients of the polymerase chain reaction cohort. The molecular prognostic index was prognostic irrespective of somatic alterations in EGFR, KRAS, TP53, and ALK.

The authors concluded: “[W]e envision that the molecular prognostic index and [composite risk model] will be useful for assessing recurrence risk for patients with nonsquamous NSCLC.”

The study was supported in part by the National Institutes of Health.

Maximilian Diehn, MD, PhD, and Ash A. Alizadeh, MD, PhD, of Stanford University School of Medicine, and Sylvia K. Plevritis, PhD, of the Center for Cancer Systems Biology, Stanford University, are the corresponding authors of the Journal of the National Cancer Institute article.

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