PHENOTYPE AND GENOTYPE OF ADVANCED PREMALIGNANT HEAD AND NECK LESIONSAFTER CHEMOPREVENTIVE THERAPY

Background: The goal of chemoprevention is to reduce the risk of cance r development by reversing or blocking the tumorigenic process through the use of pharmacologic or natural agents, To determine the potentia l role of genetic alterations in assessing cancer risk and in evaluati ng the efficacy of chemopreventive agents, we studied 22 patients with advanced premalignant lesions of the head and neck who were part of a prospective cancer prevention trial that is investigating a regimen o f 13-cis-retinoic acid, interferon alfa, and or-tocopherol administere d for 12 months or until disease progression. Methods: We used polymer ase chain reaction analysis of microsatellite DNA sequences in cells f rom precancerous lesions to determine the frequencies of genetic alter ations-namely, loss of heterozygosity (LOH) and microsatellite instabi lity-at chromosomal loci that are commonly deleted in head and neck ca ncer. Results: Prior to treatment, 17 (81%) of 21, eight (44%) of 18, and eight (42%) of 19 patients who were informative (i,e,, heterozygou s) at chromosomes 9p21, 3p14, and 17p13, respectively, exhibited LOH i n at least one of their lesion biopsy specimens. Among nine patients w ho exhibited LOH at chromosome 9p21 in pretreatment biopsy specimens a nd who had completed at least 5 months of therapy, the genetic loss pe rsisted in eight-including three of the four patients who exhibited co mplete histologic responses (i,e,, no evidence of dysplasia in their b iopsy specimens). Implication: Our data suggest that clinical and hist ologic assessments of the response to chemopreventive agents may be in sufficient to determine their efficacy and that critical genetic alter ations could be used as independent biomarkers to augment the ability to evaluate the efficacy of such agents.