Phenotype and Genotype of Advanced Premalignant Head and Neck Lesions After Chemopreventive Therapy

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Abstract
Background: The goal of chemoprevention is to reduce the risk of cancer development by reversing or blocking the tumorigenic process through the use of pharmacologic or natural agents. To determine the potential role of genetic alterations in assessing cancer risk and in evaluating 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 of 13-cis-retinoic acid, interferon alfa, and et-tocopherol administered for 12 months or until disease progression. Methods: We used polymerase chain reaction analysis of microsatellite DNA sequences in cells from precancerous lesions to determine the frequencies of genetic alterations—namely, loss of heterozygosity (LOH) and microsatellite instability—at chromosomal loci that are commonly deleted in head and neck cancer. Results : Prior to treatment, 17 (81%) of 21, eight (44%) of 18, and eight (42%) of 19 patients who were informative (i.e., heterozygous) at chromosomes 9p21, 3p14, and 17p13, respectively, exhibited LOH in at least one of their lesion biopsy specimens. Among nine patients who exhibited LOH at chromosome 9p21 in pretreatment biopsy specimens and who had completed at least 5 months of therapy, the genetic loss persisted in eight—including three of the four patients who exhibited complete histologic responses (i.e., no evidence of dysplasia in their biopsy specimens). Implication: Our data suggest that clinical and histologic assessments of the response to chemopreventive agents may be insufficient to determine their efficacy and that critical genetic alterations could be used as independent biomarkers to augment the ability to evaluate the efficacy of such agents. [J Nall Cancer Inst 1998;90:1545-51]