The main aim of this study is to evaluate the effectiveness of the synthetic retinoid 4-HPR (N-(4-hydroxyphenyl)retinamide) in preventing breast cancer. 4-HPR (fenretinide) was synthetized at the Johnson & Johnson Laboratories in the late Sixties and subsequently proven to be effective in inhibiting chemically induced mammary carcinomas in different experimental animals. Fenretinide has been shown to have an antiproliferative effect on rat mammary epithelium and to synergistically enhance the inhibition of carcinogenesis resulting from ovariectomy and tamoxifen. Additionally, 4-HPR resulted in toxicity studies in rats to be less toxic than retinyl esters and retinoic acid; it is neither mutagenic nor carcinogenic when given in mice at doses below one hundred times the dosage proposed for humans. Due to its peculiar concentration in the mammary gland and fat (also demonstrated in humans), 4-HPR is here proposed as the agent of choice for a breast cancer chemoprevention study. The design of the study is to orally administer for five years 200 mg daily of 4-HPR (with a three-day drug holiday at the end of each month) to stage I-II breast cancer patients between 33-68 years of age. This intervention schedule is to be randomly assigned versus no treatment in a population of 3,500-5,000 subjects, depending on the biological activity of the retinoid. The principal endpoint of the study is the possible decrease of incidence of new primaries in the contralateral breast. Local, regional and distant recurrences of the disease as well as new primaries in organs other than the breast will also be recorded and analyzed. No placebo is foreseen for the control arm as extensive data are already available on both acute and chronic toxicity of fenretinide: moreover, ethical considerations, too, do not recommend it due to the length of the trial. However, the protocol foresees a blind, unbiased review of all mammograms; cy- tological and histological examinations of all biopsied lumps are also performed by pathologists who do not know the patients who are being treated and those who are not. 1.160 in the 4-HPR arm and 1,148 in the control arm. At the same date, more than 50 patients had already completed the five-year intervention. Funding is requested to complete accrual and to continue the follow-up.
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