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Original Investigation
July 6, 2017

Development and Validation of an Individualized Immune Prognostic Signature in Early-Stage Nonsquamous Non–Small Cell Lung Cancer

Author Affiliations
  • 1Department of Radiation Oncology, Stanford University School of Medicine, Palo Alto, California
  • 2Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo, Japan
  • 3Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Palo Alto, California
  • 4Stanford Cancer Institute, Stanford University School of Medicine, Palo Alto, California
JAMA Oncol. Published online July 6, 2017. doi:10.1001/jamaoncol.2017.1609
Key Points

Question  Can molecular profiling of immune-related genes be used to estimate prognosis in early-stage nonsquamous non–small cell lung cancer?

Findings  In this multiple-cohort study that analyzed frozen tumor tissue samples from 2414 patients, an immune signature of 25 gene pairs significantly stratified patients into low- vs high-risk groups for overall survival across and within subpopulations at various tumor stages (I, IA, IB, or II).

Meaning  Dysregulated immune contexture may contribute to the survival differences among patients with nonsquamous non–small cell lung cancer.


Importance  The prevalence of early-stage non–small cell lung cancer (NSCLC) is expected to increase with recent implementation of annual screening programs. Reliable prognostic biomarkers are needed to identify patients at a high risk for recurrence to guide adjuvant therapy.

Objective  To develop a robust, individualized immune signature that can estimate prognosis in patients with early-stage nonsquamous NSCLC.

Design, Setting, and Participants  This retrospective study analyzed the gene expression profiles of frozen tumor tissue samples from 19 public NSCLC cohorts, including 18 microarray data sets and 1 RNA-Seq data set for The Cancer Genome Atlas (TCGA) lung adenocarcinoma cohort. Only patients with nonsquamous NSCLC with clinical annotation were included. Samples were from 2414 patients with nonsquamous NSCLC, divided into a meta-training cohort (729 patients), meta-testing cohort (716 patients), and 3 independent validation cohorts (439, 323, and 207 patients). All patients underwent surgery with a negative surgical margin, received no adjuvant or neoadjuvant therapy, and had publicly available gene expression data and survival information. Data were collected from July 22 through September 8, 2016.

Main Outcomes and Measures  Overall survival.

Results  Of 2414 patients (1205 men [50%], 1111 women [46%], and 98 of unknown sex [4%]; median age [range], 64 [15-90] years), a prognostic immune signature of 25 gene pairs consisting of 40 unique genes was constructed using the meta-training data set. In the meta-testing and validation cohorts, the immune signature significantly stratified patients into high- vs low-risk groups in terms of overall survival across and within subpopulations with stage I, IA, IB, or II disease and remained as an independent prognostic factor in multivariate analyses (hazard ratio range, 1.72 [95% CI, 1.26-2.33; P < .001] to 2.36 [95% CI, 1.47-3.79; P < .001]) after adjusting for clinical and pathologic factors. Several biological processes, including chemotaxis, were enriched among genes in the immune signature. The percentage of neutrophil infiltration (5.6% vs 1.8%) and necrosis (4.6% vs 1.5%) was significantly higher in the high-risk immune group compared with the low-risk groups in TCGA data set (P < .003). The immune signature achieved a higher accuracy (mean concordance index [C-index], 0.64) than 2 commercialized multigene signatures (mean C-index, 0.53 and 0.61) for estimation of survival in comparable validation cohorts. When integrated with clinical characteristics such as age and stage, the composite clinical and immune signature showed improved prognostic accuracy in all validation data sets relative to molecular signatures alone (mean C-index, 0.70 vs 0.63) and another commercialized clinical-molecular signature (mean C-index, 0.68 vs 0.65).

Conclusions and Relevance  The proposed clinical-immune signature is a promising biomarker for estimating overall survival in nonsquamous NSCLC, including early-stage disease. Prospective studies are needed to test the clinical utility of the biomarker in individualized management of nonsquamous NSCLC.