Breast cancer chemoprevention: studies with 4-HPR alone and in combination with tamoxifen using circulating growth...

Fenretinide (4-HPR), a synthetic derivative of retinoic acid, has proven effective at inhibiting in vitro breast cancer cell growth and preventing the progression of chemically induced mammary carcinoma in rodents. Our group has made a particular effort with regard to this molecule in clinical studies aimed at evaluating its pharmacology, toxicity, and efficacy in breast cancer prevention. We have demonstrated that 4-HPR blood levels remain constant during administration for as long as 5 years, that the drug accumulates in the human breast, and that it induces a significant decline of plasma insulin-like growth factor-I (IGF-I) levels. To date, 2,972 Stage I breast cancer patients have been randomized to evaluate the efficacy of a 5-year administration of 4-HPR to prevent new contralateral primary breast cancers. Compliance to protocol and treatment is high and tolerability of the drug is good; only 51 women out of 1,397 (3.6%) had to interrupt drug intake due to toxicity. The only potential limitation to the extensive use of 4-HPR is diminished dark adaptation, which occurs in about one-fourth of the patients and is dependent on the decline of plasma retinol below the threshold level of 100 ng/ml. Plasma levels of (4-methoxyphenyl)retinamide (4-MPR), the principal metabolite of 4-HPR, which are higher in elderly women with a high percentage of adipose tissue, are the major determinants of the retinol decrease. However, about 50% of the patients with altered dark-adaptometry are asymptomatic and the alterations are promptly reversible upon drug discontinuation.(ABSTRACT TRUNCATED AT 250 WORDS)