Fenretinide in breast-cancer chemoprevention (review)

Fenretinide (4-HPR), a synthetic amide derivative of retinoic acid, has proven effective in preventing chemically induced mammary carcinoma in rodents. During the past years, 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 retinol and insulinlike growth factor-I (IGF-I) levels. Accrual of the phase III study was closed on July 31, 1993 including 2,972 Stage I breast cancer patients. The aim is 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%) have interrupted drug intake due to toxicity. The only remarkable adverse effect of 4-HPR administration 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. However, about 50% of the patients with altered dark-adaptometry are asymptomatic and the alterations of dark adaptation are promptly reversible upon drug discontinuation. Plasma level of N-(4-methoxyphenyl) retinamide (4-MPR), the principal metabolite of 4-HPR, which tends to be higher in women over 55 years with a high percentage of adipose tissue, is the major determinant of both retinol and IGF-I decrease. Since the combination of 4-HPR with the antioestrogen tamoxifen has shown a synergistic activity in preclinical models, it is currently an important avenue of clinical investigation in an attempt to prevent breast cancer. Moreover, a dose reduction of one or both agents in an effort to minimise toxicity while maintaining activity, would represent a major improvement in cancer chemoprevention.