William N William1, Vassiliki Papadimitrakopoulou1, J Jack Lee2, Li Mao3, Ezra E W Cohen4, Heather Y Lin2, Ann M Gillenwater5, Jack W Martin5, Mark W Lingen6, Jay O Boyle7, Dong M Shin8, Nadarajah Vigneswaran9, Nancy Shinn10, John V Heymach1, Ignacio I Wistuba11, Ximing Tang11, Edward S Kim12, Pierre Saintigny13, Elizabeth A Blair14, Timothy Meiller15, J Silvio Gutkind16, Jeffrey Myers5, Adel El-Naggar17, Scott M Lippman18. 1. Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston. 2. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston. 3. 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. 4. Moores Cancer Center, University of California San Diego, La Jolla6Department of Medicine, University of Chicago, Chicago, Illinois. 5. Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston. 6. Department of Pathology, University of Chicago, Chicago, Illinois. 7. Department of Head and Neck Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. 8. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia. 9. Department of Diagnostic and Biomedical Sciences, The University of Texas School of Dentistry, Houston. 10. 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. 11. 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. 12. Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston14Levine Cancer Institute, Carolinas Healthcare System, Charlotte, North Carolina. 13. 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. 14. Section of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Chicago, Chicago, Illinois. 15. The Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore4Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore. 16. 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. 17. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston. 18. 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.
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.
RCT Entities:
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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