Author(s): William WN, Papadimitrakopoulou V, Lee JJ, Mao L, Cohen EE
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.