title: Erlotinib and the Risk of Oral Cancer: The Erlotinib Prevention of Oral Cancer (EPOC) Randomized Clinical Trial.
abstract: OBJECTIVE
  Standard molecularly based strategies to predict and/or prevent oral cancer development in patients with oral premalignant lesions (OPLs) are lacking.
  
  
  OBJECTIVE
  To test if the epidermal growth factor receptor inhibitor erlotinib would reduce oral cancer development in patients with high-risk OPLs defined by specific loss of heterozygosity (LOH) profiles. Secondary objectives included prospective determination of LOH as a prognostic marker in OPLs.
  
  
  METHODS
  The Erlotinib Prevention of Oral Cancer (EPOC) study was a randomized, placebo-controlled, double-bind trial. Accrual occurred from November 2006 through July 2012, with a median follow-up time of 35 months in an ambulatory care setting in 5 US academic referral institutions. Patients with OPLs were enrolled in the protocol, and each underwent LOH profiling (N = 379); they were classified as high-risk (LOH-positive) or low-risk (LOH-negative) patients based on their LOH profiles and oral cancer history. The randomized sample consisted of 150 LOH-positive patients.
  
  
  METHODS
  Oral erlotinib treatment (150 mg/d) or placebo for 12 months.
  
  
  METHODS
  Oral cancer-free survival (CFS).
  
  
  RESULTS
  A total of 395 participants were classified with LOH profiles, and 254 were classified LOH positive. Of these, 150 (59%) were randomized, 75 each to the placebo and erlotinib groups. The 3-year CFS rates in placebo- and erlotinib-treated patients were 74% and 70%, respectively (hazard ratio [HR], 1.27; 95% CI, 0.68-2.38; P = .45). The 3-year CFS was significantly lower for LOH-positive compared with LOH-negative groups (74% vs 87%, HR, 2.19; 95% CI, 1.25-3.83; P = .01). Increased EGFR gene copy number correlated with LOH-positive status (P < .001) and lower CFS (P = .01). The EGFR gene copy number was not predictive of erlotinib efficacy. Erlotinib-induced skin rash was associated with improved CFS (P = .01).
  
  
  CONCLUSIONS
  In this trial, LOH was validated as a marker of oral cancer risk and found to be associated with increased EGFR copy number (the target of the intervention). Erlotinib did not, however, improve CFS in high-risk patients with LOH-positive or high-EGFR-gene-copy-number OPLs. These results support incorporation of LOH testing as a prognostic tool in routine clinical practice but do not support erlotinib use in this setting.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00402779.
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: William N
authors.initials: WN
authors.lastname: William
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Papadimitrakopoulou
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston3The Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore4Department of Oncology and Diagnostic Sciences, University.
authors.forename: Li
authors.initials: L
authors.lastname: Mao
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla6Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Ezra E W
authors.initials: EE
authors.lastname: Cohen
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Heather Y
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Gillenwater
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Jack W
authors.initials: JW
authors.lastname: Martin
authors.affiliation: Department of Pathology, University of Chicago, Chicago, Illinois.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Lingen
authors.affiliation: Department of Head and Neck Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jay O
authors.initials: JO
authors.lastname: Boyle
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.affiliation: Department of Diagnostic and Biomedical Sciences, The University of Texas School of Dentistry, Houston.
authors.forename: Nadarajah
authors.initials: N
authors.lastname: Vigneswaran
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston12Department of Palliative Care Medicine, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Nancy
authors.initials: N
authors.lastname: Shinn
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston13Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston13Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Ximing
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston14Levine Cancer Institute, Carolinas Healthcare System, Charlotte, North Carolina.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Kim
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston15INSERM U1052, Cancer Research Center of Lyon, Lyon, France16CNRS UMR 5286, Cancer Research Center of Lyon, Lyon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Saintigny
authors.affiliation: Section of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Chicago, Chicago, Illinois.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Blair
authors.affiliation: The Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore4Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore.
authors.forename: Timothy
authors.initials: T
authors.lastname: Meiller
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla18Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland.
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Myers
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Adel
authors.initials: A
authors.lastname: El-Naggar
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston5Moores Cancer Center, University of California San Diego, La Jolla.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
mesh_terms: D000284:Administration, Oral; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D011230:Precancerous Conditions / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States
chemical_list: D016588:Anticarcinogenic Agents; D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors