Biologic correlates of a biochemoprevention trial in advanced upper aerodigestive tract premalignant lesions

Objective: To identify tissue biomarkers that might be used to assess an individual's cancer risk and response to chemoprevention, we studied in dysplastic lesions of the larynx and the p.o. cavity, a series of biomarkers extensively used in previous chemoprevention trials, including chromosome polysomy (CP), proliferative status, p53 expression and gene mutations, and loss of heterozygosity at 9p, 3p, and 17p. Method: Biopsies from 32 participants in a prospective chemoprevention trial using 13-cis-retinoic acid, IFN-α, and α-tocopherol for 12 months (20 with vocal cord and 12 with p.o. cavity lesions) were analyzed for p53 and Ki-67 expression by immunohistochemistry, loss of heterozygosity by PCR amplification, p53 mutations by PCR-based direct sequencing, and CP by in situ hybridization. Results: High CP (≥4% cells with more than three chromosome copies per nucleus) was more common in p.o. (8 of 10) than laryngeal lesions (4 of 16; P = 0.01), and so was a combination of CP ≥ 4% and parabasal layer p53 labeling index ≥ 0.2 (P = 0.02). Low CP was a significant predictor of complete histological response (8 of 14 cases with low versus 1 of 12 cases with high CP; P = 0.01). A trend for histological progression or cancer development was observed in cases with high CP and parabasal layer p53 labeling index. Conclusion: Low CP, more frequently observed in laryngeal lesions, appears to be a predictor of response to chemoprevention and could be used as a screening tool to identify suitable candidates for such approaches. Further investigation of biological parameters of response and cancer risk is warranted.