title: A phase IIa randomized, double-blind trial of erlotinib in inhibiting epidermal growth factor receptor signaling in aberrant crypt foci of the colorectum.
abstract: Colorectal cancer progresses through multiple distinct stages that are potentially amenable to chemopreventative intervention. Epidermal growth factor receptor (EGFR) inhibitors are efficacious in advanced tumors including colorectal cancer. There is significant evidence that EGFR also plays important roles in colorectal cancer initiation, and that EGFR inhibitors block tumorigenesis. We performed a double-blind randomized clinical trial to test whether the EGFR inhibitor erlotinib given for up to 30 days had an acceptable safety and efficacy profile to reduce EGFR signaling biomarkers in colorectal aberrant crypt foci (ACF), a subset of which progress to colorectal cancer, and normal rectal tissue. A total of 45 patients were randomized to one of three erlotinib doses (25, 50, and 100 mg) with randomization stratified by nonsteroidal anti-inflammatory drug (NSAID) use. There were no unanticipated adverse events with erlotinib therapy. Erlotinib was detected in both normal rectal mucosa and ACFs. Colorectal ACF phosphorylated ERK (pERK), phosphorylated EGFR (pEGFR), and total EGFR signaling changes from baseline were modest and there was no dose response. Overall, this trial did not meet is primary efficacy endpoint. Colorectal EGFR signaling inhibition by erlotinib is therefore likely insufficient to merit further studies without additional prescreening stratification or potentially longer duration of use.
authors.affiliation: Department of Statistics, University of California at Irvine, Irvine, California. Chao Family Comprehensive Cancer Center, University of California at Irvine, Irvine, California.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Gillen
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California at Irvine, Irvine, California.
authors.forename: Frank L
authors.initials: FL
authors.lastname: Meyskens
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California at Irvine, Irvine, California. Department of Medicine, VA Long Beach Health Care System, Long Beach, California.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Morgan
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California at Irvine, Irvine, California. Department of Epidemiology, University of California at Irvine, Irvine, California.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Zell
authors.affiliation: Department of Medicine, University of Illinois Medical Center at Chicago, Chicago, Illinois.
authors.forename: Robert
authors.initials: R
authors.lastname: Carroll
authors.affiliation: Department of Medicine, University of Illinois Medical Center at Chicago, Chicago, Illinois.
authors.forename: Richard
authors.initials: R
authors.lastname: Benya
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California at Irvine, Irvine, California.
authors.forename: Wen-Pin
authors.initials: WP
authors.lastname: Chen
authors.affiliation: Center for Molecular Medicine, University of Connecticut Health, Farmington, Connecticut.
authors.forename: Allen
authors.initials: A
authors.lastname: Mo
authors.affiliation: Astellas Pharmaceuticals, Long Island, New York.
authors.forename: Chris
authors.initials: C
authors.lastname: Tucker
authors.affiliation: Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York.
authors.forename: Asmita
authors.initials: A
authors.lastname: Bhattacharya
authors.affiliation: Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York.
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York.
authors.forename: Myra
authors.initials: M
authors.lastname: Arcilla
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California at Irvine, Irvine, California.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Wong
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California at Irvine, Irvine, California.
authors.forename: Jinah
authors.initials: J
authors.lastname: Chung
authors.affiliation: Department of Medicine, VA Long Beach Health Care System, Long Beach, California.
authors.forename: Rachel
authors.initials: R
authors.lastname: Gonzalez
authors.affiliation: Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland. Department of Surgery, Walter Reed National Military Medical Center, Bethesda, Maryland.
authors.forename: Luz Maria
authors.initials: LM
authors.lastname: Rodriguez
authors.affiliation: Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland.
authors.forename: Eva
authors.initials: E
authors.lastname: Szabo
authors.affiliation: Center for Molecular Medicine, University of Connecticut Health, Farmington, Connecticut.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Rosenberg
authors.affiliation: Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York. stl2012@med.cornell.edu.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Lipkin
mesh_terms: D058739:Aberrant Crypt Foci / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004311:Double-Blind Method; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D012007:Rectum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors