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

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). 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). 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