MUTAGEN SENSITIVITY AS A RISK FACTOR FOR 2ND MALIGNANT-TUMORS FOLLOWING MALIGNANCIES OF THE UPPER AERODIGESTIVE TRACT

Background: Second malignant tumors in patients successfully treated for an initial cancer of the upper aerodigestive tract are an important cause of morbidity and mortality. Biologic markers capable of identifying high-risk subgroups of patients who could be targeted for intensive clinical surveillance, therefore, have immense therapeutic and prognostic relevance, We previously demonstrated in a pilot study of 84 patients with cancers of the upper aerodigestive tract that mutagen sensitivity was a significant predictor of risk of developing second malignant tumors. Purpose: We extended the study to include 278 patients diagnosed with previously untreated cancers of the upper aerodigestive tract from 1987 to August 1993. Methods: For each patient, base-line (pretreatment) mutagen sensitivity was measured in vitro in 50 metaphases established from peripheral lymphocyte cultures. Patients with an average of more than 1 chromosomal break/cell were deemed mutagen hypersensitive. Cox proportional hazards analysis was used to predict the risk of developing second malignant turners associated with mutagen sensitivity. Results: Overall, 44% of the case group exhibited mutagen hypersensitivity. There mere no differences in the distribution of mutagen hypersensitivity by site, sex, stage of disease, or smoking status. There were 17 synchronous and 11 metachronous cancers, of which 15 (54%) were smoking-related malignancies. Sixteen (13.1%) of the mutagen-sensitive patients developed second malignant tumors, compared with 12 (7.7%) of the nonsensitive patients. The mean break/cell value (+/-SD) for patients developing second malignant turners was 1.17 (+/-0.54), compared with 0.98 (+/-0.44) for patients with only one cancer (P =.04). Mutagen hypersensitivity conferred a relative risk of 2.67 (95% confidence interval = 1.22-5.79) of developing second malignant tumors. Conclusions: Mutagen hypersensitivity increases the risk of developing second malignant tumors. Implications: Future research should focus on the molecular mechanisms underlying mutagen sensitivity.