The aim of this study is to evaluate the effectiveness of the synthetic retinoid, fenretinide N-(4hydroxyphenyl) retinamide, HPR, in preventing contralateral primaries in patients already operated on for breast cancer. HPR is a derivative of retinoic acid and it has been shown to inhibit N-nitroso-N-methylurea induced mammary carcinogenesis. It also exhibits an antiproliferative effect on rat mammary epithelium that may be involved in HPR inhibition of mammary carcinogenesis. HPR has also been found to block the combined proliferative effects of insulin and prolactin upon the mammary epithelium growing in vitro. Moreover, HPR is a relatively non toxic retinoid which, unlike many other retinoids, does not accumulate in the liver but in adipose tissure and in the breast. The applicant institution has confirmed this targeted concentration also in humans and has completed a one year randomized Phase I study on 101 breast cancer patients indicating that the recommended dose for fenretinide is 200mg/day with a three day drug holiday every month to prevent the risk of impaired night vision. Due -Lo the unique concentration of HPR, the Milan Cancer institute started in March 1987 a randomized clinical trial to evaluate the capability of this retinoid to reduce the incidence of contralateral breast cancer which is about 1% per year for about ten years after surgery. The applicant institution and its branches in Northern Italy plan to randomize up to 5,000 breast cancer patients with negative axillary lymphnodes, no evidence of disease and who did not receive any adjuvant endocrine or chemotherapy treatment. Patients are randomized for HPR 200mg/d by versus control and followed up every five months with physical examination and annual chest X-rays, bone scan or skeleton X-rays every 18 months and annual mammography of the contralateral breast. The follow-up will be continued for at least seven,years. Since March 1987,314 patients have been randomized in the treated group and 310 in the control group. No contralateral primaries have been recorded.
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