Journal of the National Cancer Institute Advance Access published online on October 30, 2007
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djm205
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© The Author 2007. Published by Oxford University Press.
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Proliferative Changes in the Bronchial Epithelium of Former Smokers Treated With Retinoids
Affiliations of authors: Department of Experimental Therapeutics (WNH, HI), Department of Biostatistics (JJL, DDL), Department of Thoracic/Head and Neck Medical Oncology (JMK, JSL, RL, FK, AB, WKH), Department of Pulmonary Medicine (RCM), Department of Thoracic and Cardiovascular Surgery (GW, JAR), Department of Pathology (JYR), University of Texas M. D. Anderson Cancer Center, Houston, TX; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX (JM)
Correspondence to: Walter N. Hittelman, PhD, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Box 19, 1515 Holcombe Blvd, Houston, TX 77030 (e-mail: whittelm{at}mdanderson.org).
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 
-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 -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 -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 -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 -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.
| CONTEXT AND CAVEATS Prior knowledge Retinoids have antiproliferative activity in vitro and have chemoprotective activity in the upper aerodigestive tract. Study design
Three-arm, double-blind, placebo-controlled randomized chemoprevention trial among former smokers to examine the ability of a 3-month treatment of 9-cis-retinoic acid (RA), 13-cis-RA and Contribution
In per-subject analyses, treatment with 13-cis-RA and Implications Because the subject is the unit of chemopreventive treatment and the associations from per-subject analyses were weaker than those from the per-site analyses, more research is required before firm conclusions can be drawn about the chemopreventive effect of both treatments. Limitations The Ki-67 labeling index is an intermediate marker of response. Former smokers generally have low proliferation levels in their bronchial epithelium; in subjects with the lowest pretreatment proliferation indices, a statistically significant reduction in proliferation was especially difficult to detect.
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. The Ki-67 labeling index, a measure of cell proliferation, was a secondary endpoint. Analyses were done with the subject or the biopsy site being the analysis unit.Manuscript received April 3, 2007; revised August 23, 2007; accepted September 26, 2007.
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J Natl Cancer Inst 2007 99: 1565-1567.
J Natl Cancer Inst 2007 99: 1561.
J Natl Cancer Inst 2007 99: 1561.
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