Treatment of former smokers with 9-cis-retinoic acid reverse loss of retinoic acid receptor-β expression in the bronchial epithelium

Results from a randomized placebo-controlled trial

Jonathan M. Kurie, Reuben Lotan, J. Jack Lee, Jin Soo Lee, Rodolfo C. Morice, Diane D. Liu, Xiao Chun Xu, Fadlo R. Khuri, Jae Y. Ro, Walter N. Hittelman, Garrett L. Walsh, Jack A. Roth, John D. Minna, Waun Ki Hong

Research output: Contribution to journalArticle

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Abstract

Background: Loss of retinoic acid receptor beta (RAR-β) expression in the broncial epithelium is considered a biomarker of preneoplasia. Retinoids can restore expression of this receptor and, presumably, halt the progression of carcinogenesis. This study was designed to investigate whether either of two retinoid-based regimens, 9-cis-retinoic acid (RA) or 13-cis-RA plus α-tocopherol (AT), could reverse RAR-β expression loss in former smokers after 3 months of treatment. Methods: Individuals (n = 226) who had smoked at least 20 pack-years and had ceased smoking for at least 12 months were randomly assigned to receive 3 months of daily oral 9-cis-RA (100 mg), 13-cis-RA (1 mg/kg) + AT (1200 IU), or placebo. Bronchoscopy and biopsy at six predetermined sites of the bronchial tree were performed before treatment and at 3 and 6 months thereafter. Specimens were evaluated for squamous metaplasia, dysplasia, and RAR-β expression. McNemar's test was used to test changes in RAR-β expression and squamous metaplasia within each treatment group, and a generalized estimating equations model was applied to model the treatment effect, adjusting for covariates. All statistical tests were two-sided. Results: A total of 177 assessable subjects completed at least 3 months of therapy and underwent at least the baseline and 3-month bronchoscopic evaluations with biopsies. RAR-β was detected in 69.7% of all baseline biopsy samples, and metaplasia was evident in 6.9% of all baseline samples from 240 subjects. Restoration of RAR-β expression (P = .03) and reduction of metaplasia (P = .01) were found in the 9-cis-RA group. After adjustment for years of smoking, packs/day smoked, and metaplasia, treatment with 9-cis-RA, but not with 13-cis-RA + AT, led to a statistically significant increase in RAR-β expression compared with placebo (P =.03). Conclusion: 9-cis-RA treatment can restore RAR-β expression in the bronchial epithelium of former smokers, raising the possibility that this retinoid has potential chemopreventive properties in former smokers.

Original languageEnglish (US)
Pages (from-to)206-214
Number of pages9
JournalJournal of the National Cancer Institute
Volume95
Issue number3
StatePublished - Feb 5 2003

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Retinoic Acid Receptors
Epithelium
Randomized Controlled Trials
Placebos
Metaplasia
Isotretinoin
Retinoids
Therapeutics
Biopsy
Smoking
Tocopherols
retinoic acid receptor beta
alitretinoin
Bronchoscopy
Carcinogenesis
Biomarkers

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Treatment of former smokers with 9-cis-retinoic acid reverse loss of retinoic acid receptor-β expression in the bronchial epithelium : Results from a randomized placebo-controlled trial. / Kurie, Jonathan M.; Lotan, Reuben; Lee, J. Jack; Lee, Jin Soo; Morice, Rodolfo C.; Liu, Diane D.; Xu, Xiao Chun; Khuri, Fadlo R.; Ro, Jae Y.; Hittelman, Walter N.; Walsh, Garrett L.; Roth, Jack A.; Minna, John D.; Hong, Waun Ki.

In: Journal of the National Cancer Institute, Vol. 95, No. 3, 05.02.2003, p. 206-214.

Research output: Contribution to journalArticle

Kurie, JM, Lotan, R, Lee, JJ, Lee, JS, Morice, RC, Liu, DD, Xu, XC, Khuri, FR, Ro, JY, Hittelman, WN, Walsh, GL, Roth, JA, Minna, JD & Hong, WK 2003, 'Treatment of former smokers with 9-cis-retinoic acid reverse loss of retinoic acid receptor-β expression in the bronchial epithelium: Results from a randomized placebo-controlled trial', Journal of the National Cancer Institute, vol. 95, no. 3, pp. 206-214.
Kurie, Jonathan M. ; Lotan, Reuben ; Lee, J. Jack ; Lee, Jin Soo ; Morice, Rodolfo C. ; Liu, Diane D. ; Xu, Xiao Chun ; Khuri, Fadlo R. ; Ro, Jae Y. ; Hittelman, Walter N. ; Walsh, Garrett L. ; Roth, Jack A. ; Minna, John D. ; Hong, Waun Ki. / Treatment of former smokers with 9-cis-retinoic acid reverse loss of retinoic acid receptor-β expression in the bronchial epithelium : Results from a randomized placebo-controlled trial. In: Journal of the National Cancer Institute. 2003 ; Vol. 95, No. 3. pp. 206-214.
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title = "Treatment of former smokers with 9-cis-retinoic acid reverse loss of retinoic acid receptor-β expression in the bronchial epithelium: Results from a randomized placebo-controlled trial",
abstract = "Background: Loss of retinoic acid receptor beta (RAR-β) expression in the broncial epithelium is considered a biomarker of preneoplasia. Retinoids can restore expression of this receptor and, presumably, halt the progression of carcinogenesis. This study was designed to investigate whether either of two retinoid-based regimens, 9-cis-retinoic acid (RA) or 13-cis-RA plus α-tocopherol (AT), could reverse RAR-β expression loss in former smokers after 3 months of treatment. Methods: Individuals (n = 226) who had smoked at least 20 pack-years and had ceased smoking for at least 12 months were randomly assigned to receive 3 months of daily oral 9-cis-RA (100 mg), 13-cis-RA (1 mg/kg) + AT (1200 IU), or placebo. Bronchoscopy and biopsy at six predetermined sites of the bronchial tree were performed before treatment and at 3 and 6 months thereafter. Specimens were evaluated for squamous metaplasia, dysplasia, and RAR-β expression. McNemar's test was used to test changes in RAR-β expression and squamous metaplasia within each treatment group, and a generalized estimating equations model was applied to model the treatment effect, adjusting for covariates. All statistical tests were two-sided. Results: A total of 177 assessable subjects completed at least 3 months of therapy and underwent at least the baseline and 3-month bronchoscopic evaluations with biopsies. RAR-β was detected in 69.7{\%} of all baseline biopsy samples, and metaplasia was evident in 6.9{\%} of all baseline samples from 240 subjects. Restoration of RAR-β expression (P = .03) and reduction of metaplasia (P = .01) were found in the 9-cis-RA group. After adjustment for years of smoking, packs/day smoked, and metaplasia, treatment with 9-cis-RA, but not with 13-cis-RA + AT, led to a statistically significant increase in RAR-β expression compared with placebo (P =.03). Conclusion: 9-cis-RA treatment can restore RAR-β expression in the bronchial epithelium of former smokers, raising the possibility that this retinoid has potential chemopreventive properties in former smokers.",
author = "Kurie, {Jonathan M.} and Reuben Lotan and Lee, {J. Jack} and Lee, {Jin Soo} and Morice, {Rodolfo C.} and Liu, {Diane D.} and Xu, {Xiao Chun} and Khuri, {Fadlo R.} and Ro, {Jae Y.} and Hittelman, {Walter N.} and Walsh, {Garrett L.} and Roth, {Jack A.} and Minna, {John D.} and Hong, {Waun Ki}",
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T1 - Treatment of former smokers with 9-cis-retinoic acid reverse loss of retinoic acid receptor-β expression in the bronchial epithelium

T2 - Results from a randomized placebo-controlled trial

AU - Kurie, Jonathan M.

AU - Lotan, Reuben

AU - Lee, J. Jack

AU - Lee, Jin Soo

AU - Morice, Rodolfo C.

AU - Liu, Diane D.

AU - Xu, Xiao Chun

AU - Khuri, Fadlo R.

AU - Ro, Jae Y.

AU - Hittelman, Walter N.

AU - Walsh, Garrett L.

AU - Roth, Jack A.

AU - Minna, John D.

AU - Hong, Waun Ki

PY - 2003/2/5

Y1 - 2003/2/5

N2 - Background: Loss of retinoic acid receptor beta (RAR-β) expression in the broncial epithelium is considered a biomarker of preneoplasia. Retinoids can restore expression of this receptor and, presumably, halt the progression of carcinogenesis. This study was designed to investigate whether either of two retinoid-based regimens, 9-cis-retinoic acid (RA) or 13-cis-RA plus α-tocopherol (AT), could reverse RAR-β expression loss in former smokers after 3 months of treatment. Methods: Individuals (n = 226) who had smoked at least 20 pack-years and had ceased smoking for at least 12 months were randomly assigned to receive 3 months of daily oral 9-cis-RA (100 mg), 13-cis-RA (1 mg/kg) + AT (1200 IU), or placebo. Bronchoscopy and biopsy at six predetermined sites of the bronchial tree were performed before treatment and at 3 and 6 months thereafter. Specimens were evaluated for squamous metaplasia, dysplasia, and RAR-β expression. McNemar's test was used to test changes in RAR-β expression and squamous metaplasia within each treatment group, and a generalized estimating equations model was applied to model the treatment effect, adjusting for covariates. All statistical tests were two-sided. Results: A total of 177 assessable subjects completed at least 3 months of therapy and underwent at least the baseline and 3-month bronchoscopic evaluations with biopsies. RAR-β was detected in 69.7% of all baseline biopsy samples, and metaplasia was evident in 6.9% of all baseline samples from 240 subjects. Restoration of RAR-β expression (P = .03) and reduction of metaplasia (P = .01) were found in the 9-cis-RA group. After adjustment for years of smoking, packs/day smoked, and metaplasia, treatment with 9-cis-RA, but not with 13-cis-RA + AT, led to a statistically significant increase in RAR-β expression compared with placebo (P =.03). Conclusion: 9-cis-RA treatment can restore RAR-β expression in the bronchial epithelium of former smokers, raising the possibility that this retinoid has potential chemopreventive properties in former smokers.

AB - Background: Loss of retinoic acid receptor beta (RAR-β) expression in the broncial epithelium is considered a biomarker of preneoplasia. Retinoids can restore expression of this receptor and, presumably, halt the progression of carcinogenesis. This study was designed to investigate whether either of two retinoid-based regimens, 9-cis-retinoic acid (RA) or 13-cis-RA plus α-tocopherol (AT), could reverse RAR-β expression loss in former smokers after 3 months of treatment. Methods: Individuals (n = 226) who had smoked at least 20 pack-years and had ceased smoking for at least 12 months were randomly assigned to receive 3 months of daily oral 9-cis-RA (100 mg), 13-cis-RA (1 mg/kg) + AT (1200 IU), or placebo. Bronchoscopy and biopsy at six predetermined sites of the bronchial tree were performed before treatment and at 3 and 6 months thereafter. Specimens were evaluated for squamous metaplasia, dysplasia, and RAR-β expression. McNemar's test was used to test changes in RAR-β expression and squamous metaplasia within each treatment group, and a generalized estimating equations model was applied to model the treatment effect, adjusting for covariates. All statistical tests were two-sided. Results: A total of 177 assessable subjects completed at least 3 months of therapy and underwent at least the baseline and 3-month bronchoscopic evaluations with biopsies. RAR-β was detected in 69.7% of all baseline biopsy samples, and metaplasia was evident in 6.9% of all baseline samples from 240 subjects. Restoration of RAR-β expression (P = .03) and reduction of metaplasia (P = .01) were found in the 9-cis-RA group. After adjustment for years of smoking, packs/day smoked, and metaplasia, treatment with 9-cis-RA, but not with 13-cis-RA + AT, led to a statistically significant increase in RAR-β expression compared with placebo (P =.03). Conclusion: 9-cis-RA treatment can restore RAR-β expression in the bronchial epithelium of former smokers, raising the possibility that this retinoid has potential chemopreventive properties in former smokers.

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