title: 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.
abstract: BACKGROUND
  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.
authors.affiliation: Leicester University Hospital, Leicester, United Kingdom.
authors.forename: Dean A
authors.initials: DA
authors.lastname: Fennell
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, United States of America.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Myrand
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, United States of America.
authors.forename: Tuan S
authors.initials: TS
authors.lastname: Nguyen
authors.affiliation: New Cross Hospital, Wolverhampton, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Ferry
authors.affiliation: Aberdeen Royal Infirmary, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Kerr
authors.affiliation: Queens University, Belfast, United Kingdom.
authors.forename: Perry
authors.initials: P
authors.lastname: Maxwell
authors.affiliation: Almac Diagnostics, Craigavon, United Kingdom.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Moore
authors.affiliation: Eli Lilly and Company, Houten, Netherlands.
authors.forename: Carla
authors.initials: C
authors.lastname: Visseren-Grul
authors.affiliation: Eli Lilly and Company, Basingstoke, United Kingdom.
authors.forename: Mayukh
authors.initials: M
authors.lastname: Das
authors.affiliation: Aberdeen Royal Infirmary, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Marianne C
authors.initials: MC
authors.lastname: Nicolson
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D002945:Cisplatin / Q000008:administration & dosage; D016000:Cluster Analysis; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D000068437:Pemetrexed; D011379:Prognosis; D016016:Proportional Hazards Models; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects*
chemical_list: D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D013940:Thymidylate Synthase; D002945:Cisplatin