title: Histology-related associations of ERCC1, RRM1, and TS biomarkers in patients with non-small-cell lung cancer: implications for therapy.
abstract: BACKGROUND
  On the basis of the results of recent clinical trials, histology-based decision-making for therapy of non-small-cell lung cancer has been advocated. We hypothesized associations of the biomarkers excision repair cross-complementing 1 (ERCC1), ribonucleotide reductase M1 (RRM1), and thymidylate synthase (TS) with histology as a contributing factor to reported differences in chemotherapy outcomes between squamous cell carcinoma (SCCA) and adenocarcinoma (AC) subtypes. Here, we report analysis of the Response Genetics Inc., database and implications for histology-based therapy.
  
  
  METHODS
  RNA from microdissected formalin-fixed paraffin-embedded tumors was extracted and analyzed as previously described. Specimens from 2540 individual non-small-cell lung cancer patients were analyzed for one or more biomarkers, of which 1457 were categorized as AC or SCCA.
  
  
  RESULTS
  For each biomarker, gene expression was lower in AC compared with SCCA (<0.001), although there was a wide range between individual patients. Gene expression was higher in men versus women: ERCC1: 2.51 versus 2.22 (p = 0.005); RRM1: 1.41 versus 1.24 (p = 0.004); TS: 3.23 versus 2.83 (p < 0.001). However, SCCA was more frequent in men versus women (30%/19%; p < 0.001). When AC and SCCA were assessed separately, the statistical significance between gene expression and sex was lost (in SCCA: ERCC1, p = 0.14; RRM1, p = 0.26; TS, p = 0.11).
  
  
  CONCLUSIONS
  This analysis represents the largest data set for gene expression of these biomarkers reported so far. Significant histology-related associations for ERCC1, RRM1, and TS are seen. However, marked heterogeneity exists in individual patient tumor expression levels. Randomized phase III trials assessing the predictive value of these chemotherapy-related biomarkers are warranted.
authors.affiliation: Department of General, Visceral and Tumor Surgery, University of Cologne, Germany. mausman@gmx.at
authors.forename: Martin K H
authors.initials: MK
authors.lastname: Maus
authors.forename: Philip C
authors.initials: PC
authors.lastname: Mack
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Astrow
authors.forename: Craig L
authors.initials: CL
authors.lastname: Stephens
authors.forename: Gary D
authors.initials: GD
authors.lastname: Zeger
authors.forename: Peter P
authors.initials: PP
authors.lastname: Grimminger
authors.forename: Jack H
authors.initials: JH
authors.lastname: Hsiang
authors.forename: Eric
authors.initials: E
authors.lastname: Huang
authors.forename: Tianhong
authors.initials: T
authors.lastname: Li
authors.forename: Primo N
authors.initials: PN
authors.lastname: Lara
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Danenberg
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D004720:Endonucleases / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D012262:Ribonucleoside Diphosphate Reductase; D012737:Sex Factors; D013940:Thymidylate Synthase / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D013940:Thymidylate Synthase; C071447:ERCC1 protein, human; D004720:Endonucleases