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 (<or=45, 46-55, and >or=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 <or= 0.05) in subjects <or= 45 years than in older subjects, and among subjects in the age range 46-55 years, they were significantly higher (P <or= 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 <or= 0.05), increased with age (>or=46 years versus <or=45 years) but only in disease-free subjects. Among subjects < 45 years, they were slightly, but significantly (P <or= 0.05), higher in those subjects in which breast cancer recurred. 4-HPR treatment caused a retinol level reduction, which was strongly (r >or= 0.71; P <or= 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.
RCT Entities:
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 (<or=45, 46-55, and >or=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 <or= 0.05) in subjects <or= 45 years than in older subjects, and among subjects in the age range 46-55 years, they were significantly higher (P <or= 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 <or= 0.05), increased with age (>or=46 years versus <or=45 years) but only in disease-free subjects. Among subjects < 45 years, they were slightly, but significantly (P <or= 0.05), higher in those subjects in which breast cancer recurred. 4-HPR treatment caused a retinol level reduction, which was strongly (r >or= 0.71; P <or= 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.