Proliferative Changes in the Bronchial Epithelium of Former Smokers Treated With Retinoids

• Published in: JNCI : Journal of the National Cancer Institute 2007-11, Vol.99 (21), p.1603-1612
• Main Authors: Hittelman, Walter N., Liu, Diane D., Kurie, Jonathan M., Lotan, Reuben, Lee, Jin Soo, Khuri, Fadlo, Ibarguen, Heladio, Morice, Rodolfo C., Walsh, Garrett, Roth, Jack A., Minna, John, Ro, Jae Y., Broxson, Anita, Hong, Waun Ki, Lee, J. Jack
• Format: Article
• Language: English
• Subjects: Adult; Aged; alpha-Tocopherol - therapeutic use; Anticarcinogenic Agents - therapeutic use; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Biomarkers - metabolism; Bronchi - drug effects; Bronchi - immunology; Cell Proliferation - drug effects; Chemotherapy; Double-Blind Method; Female; Humans; Immunohistochemistry; Isotretinoin - therapeutic use; Ki-67 Antigen - metabolism; Male; Medical sciences; Middle Aged; Multivariate Analysis; Pharmacology. Drug treatments; Research Design; Respiratory Mucosa - drug effects; Respiratory Mucosa - immunology; Smoking; Smoking Cessation; Tretinoin - therapeutic use; Tumors
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/djm205

Background Retinoids have shown antiproliferative and chemopreventive activity. We analyzed data from a randomized, placebo-controlled chemoprevention trial to determine whether a 3-month treatment with either 9-cis-retinoic acid (RA) or 13-cis-RA and α-tocopherol reduced Ki-67, a proliferation biomarker, in the bronchial epithelium. Methods Former smokers (n = 225) were randomly assigned to receive 3 months of daily oral 9-cis-RA (100 mg), 13-cis-RA (1 mg/kg) and α-tocopherol (1200 IU), or placebo. Bronchoscopic biopsy specimens obtained before and after treatment were immunohistochemically assessed for changes in the Ki-67 proliferative index (i.e., percentage of cells with Ki-67–positive nuclear staining) in the basal and parabasal layers of the bronchial epithelium. Per-subject and per–biopsy site analyses were conducted. Multicovariable analyses, including a mixed-effects model and a generalized estimating equations model, were used to investigate the treatment effect (Ki-67 labeling index and percentage of bronchial epithelial biopsy sites with a Ki-67 index ≥ 5%) with adjustment for multiple covariates, such as smoking history and metaplasia. Coefficient estimates and 95% confidence intervals (CIs) were obtained from the models. All statistical tests were two-sided. Results In per-subject analyses, Ki-67 labeling in the basal layer was not changed by any treatment; the percentage of subjects with a high Ki-67 labeling in the parabasal layer dropped statistically significantly after treatment with 13-cis-RA and α-tocopherol treatment (P = .04) compared with placebo, but the drop was not statistically significant after 9-cis-RA treatment (P = .17). A similar effect was observed in the parabasal layer in a per-site analysis; the percentage of sites with high Ki-67 labeling dropped statistically significantly after 9-cis-RA treatment (coefficient estimate = −0.72, 95% CI = –1.24 to –0.20; P = .007) compared with placebo, and after 13-cis-RA and α-tocopherol treatment (coefficient estimate = −0.66, 95% CI = –1.15 to –0.17; P = .008). Conclusions In per-subject analyses, treatment with 13-cis-RA and α-tocopherol, compared with placebo, was statistically significantly associated with reduced bronchial epithelial cell proliferation; treatment with 9-cis-RA was not. In per-site analyses, statistically significant associations were obtained with both treatments.