Placebo-controlled trial of 13-cis-retinoic acid activity on retinoic acid receptor-beta expression in a population at high risk:: Implications for chemoprevention of lung cancer

Purpose: To establish the incidence of abnormalities in the expression of retinoic acid receptor-beta (RAR beta) in branchial cells and determine the capacity of 13-cis-retinoic acid (13-CRA) to correct such abnormalities. Patients and Methods: One hundred eighty-eight smokers had a medical indication for bronchoscopy and were studied with branchial brushings. Branchial brushing sampler were obtained for cytology analysis and for molecular analysis, After RNA was extracted, RAR beta sequences were amplified by reverse transcriptase polymerase chain reaction and Southern blots were performed to assess RAR beta expression, forty-four eligible individuals with diminished RARE expression consented to double-blind randomization to receive a placebo or 13-CRA 30 mg orally daily for 6 months. A second bronchoscopy was performed at the end of the treatment period, An analysis of variance was used to analyze changes in RAR beta expression before and after treatment. Results: The 6-month treatment course was completed by 27 patients, and results were obtained for a total of 18 patients (eight patients treated with 13-CRA and ten treated with the placebo). in the placebo group, there war no difference between the! results of RAR beta expression before and after treatment (P = .43), In the 13-CRA group, there was an upregulation of RAR beta expression at the end of 13-CRA treatment (P = .001). Cytologic changes were uncommon. Toxicities were primarily of grade 1. Palatal brushings were compared with branchial brushings in 40 smokers. A perfect correlation of the results of RAR beta expression was obtained from 27 patients. Conclusion: RARE expression is frequently decreased in the branchial epithelium of smokers and is upregulated at the end of 13-CRA treatment. These results support undertaking a phase III chemoprevention trial of 13-CRA treatment for lung cancer. (C) 1999 by American Society of Clinical Oncology.