Surrogate end-point biomarker analysis in a retinol chemoprevention trial in current and former smokers with bronchial dysplasia

Epidemiological studies suggested that vitamin A may be protective against lung cancer, however, recent chemoprevention trials with β-carotene, a precursor of vitamin A, demonstrated enhancement of lung carcinogenesis among smokers. Whether vitamin A is beneficial or harmful in chemoprevention of lung cancer in smokers has not been resolved. This study was designed to determine the effect of retinol alone in current and former smokers using bronchial dysplasia, nuclear morphometry and retinoic acid receptor-β (RAR-β) mRNA expression as surrogate end-point biomarkers (SEBs). Eighty-one current or former smokers with a smoking history of ≥30 pack-years were randomized to receive either placebo or retinol (50,000 IU per day) for six months. Fluorescence bronchoscopy was performed prior to treatment to localize areas suggestive of dysplasia. At least 4 bronchial biopsies were taken per subject including at least two biopsies from apparently normal areas. The same areas were precisely re-biopsied after 6 months. Any new areas suggestive of dysplasia were also biopsied. Changes in the SEBs were assessed before and after treatment. At baseline, the frequency of biopsies negative for RAR-β expression was: normal (23%), hyperplasia (28%), metaplasia (41%), mild dysplasia (41%), and moderate/severe dysplasia (44%). There was no significant difference in the regression rate between the retinol and placebo groups using histopathology and nuclear morphometry as SEBs. The likelihood of regression was found to be lower in those who continued to smoke during the study (OR=1.86 for those smoking >10 cigarettes per day, p=0.084 to OR=0.95, p=0.26 for those smoking 20+ per day compared to ex-smokers). Retinol was not effective in the up-regulation of RAR-β in lesions with bronchial dysplasia. We postulate that the lack of effect of retinol on RAR-β expression among individuals who continued to smoke while taking retinol may be due to suppressive effect of tobacco smoke constituents on RAR-β expression and/or altered cellular metabolism of retinol to retinoic acid and its isomers.