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

Barbara Conley, Joyce O'Shaughnessy, Sheila Prindiville, Julia Lawrence, Catherine Chow, Elizabeth Jones, Maria J. Merino, Muriel I. Kaiser-Kupfer, Rafael C. Caruso, Marvin Podgor, Barry Goldspiel, David Venzon, David Danforth, Suhlan Wu, Marianne Noone, Jennifer Goldstein, Kenneth H. Cowan, Jo Anne Zujewski

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)275-283
Number of pages9
JournalJournal of Clinical Oncology
Volume18
Issue number2
DOIs
StatePublished - Jan 2000
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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