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Original Investigation
February 2016

Erlotinib and the Risk of Oral CancerThe Erlotinib Prevention of Oral Cancer (EPOC) Randomized Clinical Trial

Author Affiliations
  • 1Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston
  • 2Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston
  • 3The Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore
  • 4Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore
  • 5Moores Cancer Center, University of California San Diego, La Jolla
  • 6Department of Medicine, University of Chicago, Chicago, Illinois
  • 7Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston
  • 8Department of Pathology, University of Chicago, Chicago, Illinois
  • 9Department of Head and Neck Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
  • 10Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia
  • 11Department of Diagnostic and Biomedical Sciences, The University of Texas School of Dentistry, Houston
  • 12Department of Palliative Care Medicine, The University of Texas MD Anderson Cancer Center, Houston
  • 13Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston
  • 14Levine Cancer Institute, Carolinas Healthcare System, Charlotte, North Carolina
  • 15INSERM U1052, Cancer Research Center of Lyon, Lyon, France
  • 16CNRS UMR 5286, Cancer Research Center of Lyon, Lyon, France
  • 17Section of Otolaryngology−Head and Neck Surgery, Department of Surgery, University of Chicago, Chicago, Illinois
  • 18Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
  • 19Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston
JAMA Oncol. 2016;2(2):209-216. doi:10.1001/jamaoncol.2015.4364
Abstract

Importance  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.

Design  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.

Interventions  Oral erlotinib treatment (150 mg/d) or placebo for 12 months.

Main Outcomes and Measures  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 and Relevance  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.

Trial Registration  clinicaltrials.gov Identifier: NCT00402779

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