Abstract
Primary lung adenocarcinoma remains a deadly disease. Gene-expression phenotypes (GEPs) in adenocarcinoma have potential to provide clinically relevant disease stratification for improved prognosis and treatment prediction, given appropriate clinical and methodologic validation. 2,395 transcriptional adenocarcinoma profiles were assembled from 17 public cohorts and classified by a nearest centroid GEP classifier into three subtypes: terminal respiratory unit (TRU), proximal-proliferative, and proximal-inflammatory, and additionally scored by five transcriptional metagenes representing different biologic processes, including proliferation. Prognostic- and chemotherapy-predictive associations of the subtypes were analyzed by univariate and multivariate analysis using overall survival or distant metastasis-free survival as endpoints. Overall, GEPs were associated with patient outcome in both univariate and multivariate analyses, although not in all individual cohorts. The prognostically relevant division was between TRU- and non-TRU-classified cases, with expression of proliferation-associated genes as a key prognostic component. In contrast, GEP classification was not predictive of adjuvant chemotherapy response. GEP classification showed stability to random perturbations of genes or samples and alterations to classification procedures (typically <10% of cases/cohort switching subtype). High classification variability (>20% of cases switching subtype) was observed when removing larger or entire fractions of a single subtype, due to gene-centering shifts not addressable by the classifier. In a large-scale evaluation, we show that GEPs add prognostic value to standard clinicopathologic variables in lung adenocarcinoma. Subject to classifier refinement and confirmation in prospective cohorts, GEPs have potential to affect the prognostication of adenocarcinoma patients through a molecularly driven disease stratification.
Highlights
Non–small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases, with adenocarcinoma as the main histologic subtype [1]
In a large-scale evaluation, we show that Gene-expression phenotypes (GEPs) add prognostic value to standard clinicopathologic variables in lung adenocarcinoma
Subject to classifier refinement and confirmation in prospective cohorts, GEPs have potential to affect the prognostication of adenocarcinoma patients through a molecularly driven disease stratification
Summary
Non–small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases, with adenocarcinoma as the main histologic subtype [1]. Groundbreaking discoveries of treatment predictive alterations in the EGFR and ALK genes [2, 3] primarily made in adenocarcinomas, have led to development of targeted treatments for patients harboring these alterations. Even for NSCLC patients with the best prognosis, resectable stage I disease, the 5-year survival rate after resection is only 58% to 73%, with 3% to 10% additional survival increase if adjuvant chemotherapy is used [5]. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
