title: ERCC1 and TS Expression as Prognostic and Predictive Biomarkers in Metastatic Colon Cancer.
abstract: In patients with metastatic colon cancer, response to first line chemotherapy is a strong predictor of overall survival (OS). Currently, oncologists lack diagnostic tests to determine which chemotherapy regimen offers the greatest chance for response in an individual patient. Here we present the results of gene expression analysis for two genes, ERCC1 and TS, measured with the commercially available ResponseDX: Colon assay (Response Genetics, Los Angeles, CA) in 41 patients with de novo metastatic colon cancer diagnosed between July 2008 and August 2013 at the University of California, San Diego. In addition ERCC1 and TS expression levels as determined by RNAseq and survival data for patients in TCGA were downloaded from the TCGA data portal. We found that patients with low expression of ERCC1 (n = 33) had significantly longer median OS (36.0 vs. 10.1 mo, HR 0.29, 95% CI .095 to .84, log-rank p = 9.0x10-6) and median time to treatment to failure (TTF) following first line chemotherapy (14.1 vs. 2.4 mo, HR 0.17, 95% CI 0.048 to 0.58, log-rank p = 5.3x10-4) relative to those with high expression (n = 4). After accounting for the covariates age, sex, tumor grade and ECOG performance status in a Cox proportional hazard model the association of low ERCC1 with longer OS (HR 0.18, 95% CI 0.14 to 0.26, p = 0.0448) and TTF (HR 0.16, 95% CI 0.14 to 0.21, p = 0.0053) remained significant. Patients with low TS expression (n = 29) had significantly longer median OS (36.0 vs. 14.8 mo, HR 0.25, 95% CI 0.074 to 0.82, log-rank p = 0.022) relative to those with high expression (n = 12). The combined low expression of ERCC1/TS was predictive of response in patients treated with FOLFOX (40% vs. 91%, RR 2.3, Fisher's exact test p = 0.03, n = 27), but not with FOLFIRI (71% vs. 71%, RR 1.0, Fisher's exact test p = 1, n = 14). Overall, these findings suggest that measurement of ERCC1 and TS expression has potential clinical utility in managing patients with metastatic colorectal cancer.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America; Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Michel B
authors.initials: MB
authors.lastname: Choueiri
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America; Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
authors.forename: John Paul
authors.initials: JP
authors.lastname: Shen
authors.affiliation: Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Gross
authors.affiliation: Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Justin K
authors.initials: JK
authors.lastname: Huang
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America; Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, California, United States of America; Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Trey
authors.initials: T
authors.lastname: Ideker
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America; Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Fanta
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D004268:DNA-Binding Proteins / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D013940:Thymidylate Synthase / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D013940:Thymidylate Synthase; C071447:ERCC1 protein, human; D004720:Endonucleases; D002955:Leucovorin; D005472:Fluorouracil