title: ERCC1 and RRM1 in the international adjuvant lung trial by automated quantitative in situ analysis.
abstract: The excision repair cross completing group 1 gene product (ERCC1) and the regulatory subunit of ribonucleotide reductase (RRM1) have been reported as being prognostic of outcome and predictive of therapeutic efficacy in patients with non-small cell lung cancer. Routinely processed surgical specimens from 784 patients from the International Adjuvant Lung Trial were arrayed as tissue microarrays. In situ protein levels were scored with an automated, quantitative analysis system, dichotomized into high and low marker categories, and analyzed for associations with patients' characteristics, survival, and benefit from adjuvant chemotherapy. Scores for both markers were significantly associated with contributing center (P < 0.001) and skewed, with the bulk of scores being low. High scores were more frequent in women for ERCC1 and RRM1 and in older patients and those with adenocarcinoma for RRM1. Low ERCC1 scores indicated significant benefit from adjuvant chemotherapy [hazard ratio (HR) = 0.73 for chemotherapy versus control, P = 0.02]. Although all other survival associations were not statistically significant, low RRM1 scores trended to indicate benefit from adjuvant chemotherapy (HR = 0.84, P = 0.25), and ERCC1 scores were marginally prognostic of survival (HR = 0.77 for high versus low scores, P = 0.10). We conclude that contributing center and specimen quality substantially affect the levels of both markers. Future trials should incorporate the collection and processing of tumor specimens prospectively on standardized protocols to better reveal the impact of biomarkers on clinically relevant outcomes.
authors.affiliation: Karmanos Cancer Institute, Detroit, Michigan 48201, USA. beplerg@karmanos.org
authors.forename: Gerold
authors.initials: G
authors.lastname: Bepler
authors.forename: Ken André
authors.initials: KA
authors.lastname: Olaussen
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Vataire
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zheng
authors.forename: Ariane
authors.initials: A
authors.lastname: Dunant
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pignon
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schell
authors.forename: Pierre
authors.initials: P
authors.lastname: Fouret
authors.forename: Robert
authors.initials: R
authors.lastname: Pirker
authors.forename: Martin
authors.initials: M
authors.lastname: Filipits
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brambilla
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D017024:Chemotherapy, Adjuvant; D004268:DNA-Binding Proteins / Q000032:analysis*; D004720:Endonucleases / Q000032:analysis*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D040081:Protein Array Analysis / Q000379:methods; D012262:Ribonucleoside Diphosphate Reductase; D046888:Tissue Array Analysis / Q000379:methods; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000032:analysis*
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; C071447:ERCC1 protein, human; D004720:Endonucleases