Fenretinide Breast Cancer Prevention Trial

Fenretinide Breast Cancer Prevention Trial

Drug and Retinol Plasma Levels in Relation to Age and Disease Outcome1

Istituto Nazionale Tumori, 20133 Milan, [F.F., T.C., E.C., V.A., M.G.V., G.D.P., M.G.D.M.]; S. Maugeri Foundation, Pavia [A.C.]; and Istituto Europeo di Oncologia, 20133 Milan [U.V.], Italy

Abstract

Objectives: To assess, in women participating in a breast cancer prevention trialon fenretinide (4-HPR), the relationship of drug and retinol levels with the risk of second breast malignancy, taking into account age and menopausal status.

Methods: In a multicenter prevention trial, women with early breast cancer were randomly assigned to receive no treatment or 200 mg of 4-HPR/day for 5 years. Blood was collected at baseline and on a yearly basis during intervention from women recruited at the Istituto Tumori (Milan, Italy; 818 and 756 in the 4-HPR and control arm, respectively, who accounted for 53% of the participants in the trial). The plasma concentrations of 4-HPR, its main metabolite N-(4-methoxyphenyl) retinamide, and retinol were assayed by high-performance liquid chromatography. Three age ranges (≤45, 46–55, and ≥56 years), menopausal status at baseline, and disease outcome at a median follow-up of 97 months were taken into account in the analysis.

Results: Baseline retinol levels were significantly lower (P ≤ 0.05) in subjects ≤ 45 years than in older subjects, and among subjects in the age range 46–55 years, they were significantly higher (P ≤ 0.001) in those in postmenopause than in those in premenopause. Baseline retinol levels were not related to the risk of a second breast malignancy. 4-HPR and N-(4-methoxyphenyl)retinamide levels were not affected by menopausal status. They slightly, but significantly (P ≤ 0.05), increased with age (≥46 years versus ≤45 years) but only in disease-free subjects. Among subjects < 45 years, they were slightly, but significantly (P ≤ 0.05), higher in those subjects in which breast cancer recurred. 4-HPR treatment caused a retinol level reduction, which was strongly (r ≥ 0.71; P ≤ 0.001) related to pretreatment retinol levels.

Conclusions: Retinol plasma levels increased with age and after menopause and were not related to breast cancer recurrence. 4-HPR levels were lower in subjects < 45 years than in older subjects. The inverse relationship between drug plasma levels and 4-HPR preventive effects observed in young women suggests a role for 4-HPR plasma sequestration in 4-HPR biological activity.

Footnotes

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↵1 Supported by NIH/National Cancer Institute Grants CA38567 and CA72286 and the Associazione Italiana per la Ricerca sul Cancro.
↵2 To whom requests for reprints should be addressed, at Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. Phone: 39-02-23902706; Fax: 39-02-23902692; E-mail: franca.formelli{at}istitutotumori.mi.it
↵3 The abbreviations used are: 4-HPR, fenretinide; 4-MPR, N-(L-methoxyphenyl)retinamide; BMI, body mass index; RBP, retinol binding protein.
↵4 Formelli et al., manuscript in preparation.
- Accepted October 10, 1902.
- Received June 17, 1902.
- Revision received September 18, 1902.