This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Conley, B. Articles by Zujewski, J. Search for Related Content PubMed PubMed Citation Articles by Conley, B. Articles by Zujewski, J.

Pilot Trial of the Safety, Tolerability, and Retinoid Levels of N-(4-hydroxyphenyl) Retinamide in Combination With Tamoxifen in Patients at High Risk for Developing Invasive Breast Cancer

From the Greenebaum Cancer Center, Divisions of Hematology and Oncology, and Department of Medicine, University of Maryland School of Medicine, Baltimore; Medicine Branch, Laboratory of Pathology, and Surgery Branch, Division of Clinical Sciences, National Cancer Institute (NCI); Pharmacy Department, Department of Radiology, Warren Grant Magnusen Clinical Center; and National Eye Institute, National Institutes of Health, Bethesda, MD.

Address reprint requests to JoAnne Zujewski, MD, Medicine Branch, Rm 12N226, Bldg 10 (Clinical Center), NCI, NIH, 9000 Rockville Pike, Bethesda, MD 20892; email zujewski{at}nih.gov

PURPOSE: N-(4-hydroxyphenyl) retinamide ([4-HPR], Fenretinide; R.W. Johnson Pharmaceutical Research Institute, Springhouse, PA) and tamoxifen (TAM) have synergistic antitumor and chemopreventive activity against mammary cancer in preclinical studies. We performed a pilot study of this combination in women at high risk for developing breast cancer.

PATIENTS AND METHODS: Thirty-two women were treated with four cycles of 4-HPR, 200 mg orally (PO) for 25 days of each 28-day cycle, and TAM, 20 mg PO once daily for 23 months beginning after 1 month of 4-HPR alone. Tolerability, dark adaptometry, tissue biopsies, and retinoid plasma concentrations (Cp) were evaluated.

RESULTS: Symptomatic reversible nyctalopia developed in two patients (6%) on 4-HPR, but 16 (73%) of 22 patients had reversible changes in dark adaptation, which correlated with relative decrease in Cp retinol (P .01). Four patients stopped treatment for side effects, and 84% of patients had hot flashes. Other commonly reported (grade 2) reversible toxicities included skin and ocular dryness, fatigue, and mood changes. Serum high-density lipoprotein increased and cholesterol decreased from baseline to month 4. Baseline mean ± SD Cp retinol was 708 ± 280 ng/mL. Mean ± SD Cp of 4-HPR, N-(4-methoxyphenyl) retinamide (4-MPR), and retinol after 1 month of 4-HPR were 0.34 ± 0.21 µmol/L, 0.28 ± 0.21 µmol/L, and 282 ± 127 ng/mL, respectively. Mean retinoid Cps did not change after 3 months of 4-HPR + TAM.

CONCLUSIONS: TAM administration did not affect Cp 4-HPR or 4-MPR. Reversible nyctalopia correlated with relative decrease in Cp retinol but was not symptomatic for most patients. TAM + 4-HPR has acceptable tolerability for this high-risk cohort.

This article has been cited by other articles:

				H. Johansson, S. Gandini, A. Guerrieri-Gonzaga, S. Iodice, M. Ruscica, B. Bonanni, M. Gulisano, P. Magni, F. Formelli, and A. Decensi Effect of Fenretinide and Low-Dose Tamoxifen on Insulin Sensitivity in Premenopausal Women at High Risk for Breast Cancer Cancer Res., November 15, 2008; 68(22): 9512 - 9518. [Abstract] [Full Text] [PDF]

				M. Golczak, A. Maeda, G. Bereta, T. Maeda, P. D. Kiser, S. Hunzelmann, J. von Lintig, W. S. Blaner, and K. Palczewski Metabolic Basis of Visual Cycle Inhibition by Retinoid and Nonretinoid Compounds in the Vertebrate Retina J. Biol. Chem., April 11, 2008; 283(15): 9543 - 9554. [Abstract] [Full Text] [PDF]

				P. G. Sreekumar, J. Zhou, J. Sohn, C. Spee, S. J. Ryan, B. J. Maurer, R. Kannan, and D. R. Hinton N-(4-hydroxyphenyl) Retinamide Augments Laser-Induced Choroidal Neovascularization in Mice Invest. Ophthalmol. Vis. Sci., March 1, 2008; 49(3): 1210 - 1220. [Abstract] [Full Text] [PDF]

				S Zanardi, D Serrano, A Argusti, M Barile, M Puntoni, and A Decensi Clinical trials with retinoids for breast cancer chemoprevention. Endocr. Relat. Cancer, March 1, 2006; 13(1): 51 - 68. [Abstract] [Full Text] [PDF]

				A. Guerrieri-Gonzaga, C. Robertson, B. Bonanni, D. Serrano, M. Cazzaniga, S. Mora, M. Gulisano, H. Johansson, F. Formelli, M. Intra, et al. Preliminary Results on Safety and Activity of a Randomized, Double-Blind, 2 x 2 Trial of Low-Dose Tamoxifen and Fenretinide for Breast Cancer Prevention in Premenopausal Women J. Clin. Oncol., January 1, 2006; 24(1): 129 - 135. [Abstract] [Full Text] [PDF]

				C J Fabian, B F Kimler, M S Mayo, and S A Khan Breast-tissue sampling for risk assessment and prevention Endocr. Relat. Cancer, June 1, 2005; 12(2): 185 - 213. [Abstract] [Full Text] [PDF]

				A. K. Gopal, J. M. Pagel, N. Hedin, and O. W. Press Fenretinide enhances rituximab-induced cytotoxicity against B-cell lymphoma xenografts through a caspase-dependent mechanism Blood, May 1, 2004; 103(9): 3516 - 3520. [Abstract] [Full Text] [PDF]

				A. L. Sabichi, M. R. Modiano, J. J. Lee, Y.-M. Peng, M.-J. Xu, H. Villar, W. S. Dalton, and S. M. Lippman Breast Tissue Accumulation of Retinamides in a Randomized Short-term Study of Fenretinide Clin. Cancer Res., July 1, 2003; 9(7): 2400 - 2405. [Abstract] [Full Text] [PDF]

				S. E. Singletary, E. N. Atkinson, A. Hoque, N. Sneige, A. A. Sahin, H. A. Fritsche Jr., R. Lotan, T. Lu, W. N. Hittelman, T. B. Bevers, et al. Phase II Clinical Trial of N-(4-Hydroxyphenyl)retinamide and Tamoxifen Administration before Definitive Surgery for Breast Neoplasia Clin. Cancer Res., September 1, 2002; 8(9): 2835 - 2842. [Abstract] [Full Text] [PDF]

				K. Wu, H.-T. Kim, J. L. Rodriquez, S. G. Hilsenbeck, S. K. Mohsin, X.-C. Xu, W. W. Lamph, J. G. Kuhn, J. E. Green, and P. H. Brown Suppression of Mammary Tumorigenesis in Transgenic Mice by the RXR-selective Retinoid, LGD1069 Cancer Epidemiol. Biomarkers Prev., May 1, 2002; 11(5): 467 - 474. [Abstract] [Full Text] [PDF]

				F. Formelli Correspondence re: M. Follen et al., A Randomized Clinical Trial of 4-Hydroxyphenylretinamide for High-Grade Squamous Intraepithelial Lesions of the Cervix. Clin. Cancer Res., 7: 3356-3365, 2001 Clin. Cancer Res., May 1, 2002; 8(5): 1310 - 1312. [Full Text] [PDF]

				J. A. Lawrence, P. C. Adamson, R. Caruso, C. Chow, D. Kleiner, R. F. Murphy, D. J. Venzon, M. Shovlin, M. Noone, M. Merino, et al. Phase I Clinical Trial of Alitretinoin and Tamoxifen in Breast Cancer Patients: Toxicity, Pharmacokinetic, and Biomarker Evaluations J. Clin. Oncol., May 15, 2001; 19(10): 2754 - 2763. [Abstract] [Full Text] [PDF]

				C. K. Chow, D. Venzon, E. C. Jones, A. Premkumar, J. O’Shaughnessy, and J. Zujewski Effect of Tamoxifen on Mammographic Density Cancer Epidemiol. Biomarkers Prev., September 1, 2000; 9(9): 917 - 921. [Abstract] [Full Text]

				R. T. Chlebowski Reducing the Risk of Breast Cancer N. Engl. J. Med., July 20, 2000; 343(3): 191 - 198. [Full Text] [PDF]