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

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