Association between gene expression profiles and clinical outcome of pemetrexed-based treatment in patients with advanced non-squamous non-small cell lung cancer: exploratory results from a phase II study..pdf (368.37 kB)
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Association between gene expression profiles and clinical outcome of pemetrexed-based treatment in patients with advanced non-squamous non-small cell lung cancer: exploratory results from a phase II study

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posted on 27.07.2016, 14:51 by Dean A. Fennell, Scott P. Myrand, Tuan S. Nguyen, David Ferry, Keith M. Kerr, Perry Maxwell, Stephen D. Moore, Carla Visseren-Grul, Mayukh Das, Marianne C. Nicolson
INTRODUCTION: We report exploratory gene-expression profiling data from a single-arm Phase-II-study in patients with non-squamous (ns)NSCLC treated with pemetrexed and cisplatin. Previously disclosed results indicated a significant association of low thymidylate-synthase (TS)-expression with longer progression-free and overall survival (PFS/OS). METHODS: Treatment-naïve nsNSCLC patients (IIIB/IV) received 4 cycles of pemetrexed/cisplatin; non-progressing patients continued on pemetrexed-maintenance. Diagnostic tissue-samples were used to assess TS-expression by immunohistochemistry (IHC) and mRNA-expression array-profiling (1,030 lung cancer-specific genes). Cox proportional-hazard models were applied to explore the association between each gene and PFS/OS. Genes significantly correlated with PFS/OS were further correlated with TS-protein expression (Spearman-rank). Unsupervised clustering was applied to all evaluable samples (n = 51) for all 1,030 genes and an overlapping 870-gene subset associated with adenocarcinoma (ADC, n = 47). RESULTS: 51/70 tissue-samples (72.9%) were evaluable; 9 of 1,030 genes were significantly associated with PFS/OS (unadjusted p < 0.01, genes: Chromosome 16 open reading frame 89, napsin A, surfactant protein B, aquaporin 4, TRAF2- and Nck-interacting kinase, Lysophosphatidylcholine acyltransferase 1, Interleukin 1 receptor type II, NK2 homeobox 1, ABO glycosyl-transferase); expression for all except IL1R2 correlated negatively with nuclear TS-expression (statistically significant for 5/8 genes, unadjusted p<0.01). Cluster-analysis based on 1,030 genes revealed no clear trend regarding PFS/OS; the ADC-based cluster analysis identified 3 groups (n = 21/11/15) with median (95%CI) PFS of 8.1(6.9,NE)/2.4(1.2,NE)/4.4(1.2,NE) months and OS of 20.3(17.5,NE)/4.3(1.4,NE)/8.3(3.9,NE) months, respectively. CONCLUSIONS: These exploratory gene-expression profiling results describe genes potentially linked to low TS-expression. Nine genes were significantly associated with PFS/OS but could not be differentiated as prognostic or predictive as this was a single-arm study. Although these hypotheses-generating results are interesting, they provide no evidence to change the current histology-based treatment approach with pemetrexed.

History

Citation

PLoS One, 2014, 9 (9), e107455

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cancer Studies and Molecular Medicine

Version

VoR (Version of Record)

Published in

PLoS One

Publisher

Public Library of Science

issn

1932-6203

Acceptance date

28/06/2014

Copyright date

2016

Available date

27/07/2016

Publisher version

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0107455

Language

en