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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01CA038567-07
Application #
3548558
Study Section
Special Emphasis Panel (SRC (L2))
Project Start
1984-09-30
Project End
1995-04-30
Budget Start
1992-09-01
Budget End
1993-04-30
Support Year
7
Fiscal Year
1992
Total Cost
Indirect Cost
Name
National Institute for the Study Care Tumors
Department
Type
DUNS #
City
Milan
State
Country
Italy
Zip Code
Formelli, Franca; Camerini, Tiziana; Cavadini, Elena et al. (2003) Fenretinide breast cancer prevention trial: drug and retinol plasma levels in relation to age and disease outcome. Cancer Epidemiol Biomarkers Prev 12:34-41
Formelli, F (2000) Quality control for HPLC assay and surrogate end point biomarkers from the fenretinide (4-HPR) breast cancer prevention trial. J Cell Biochem Suppl 34:73-9
Decensi, A; Bonanni, B; Guerrieri-Gonzaga, A et al. (2000) Chemoprevention of breast cancer: the Italian experience. J Cell Biochem Suppl 34:84-96
Decensi, A; Torrisi, R; Gozza, A et al. (1999) Effect of fenretinide on bone mineral density and metabolism in women with early breast cancer. Breast Cancer Res Treat 53:145-51
Veronesi, U; De Palo, G; Marubini, E et al. (1999) Randomized trial of fenretinide to prevent second breast malignancy in women with early breast cancer. J Natl Cancer Inst 91:1847-56
Torrisi, R; Parodi, S; Fontana, V et al. (1998) Effect of fenretinide on plasma IGF-I and IGFBP-3 in early breast cancer patients. Int J Cancer 76:787-90
Decensi, A; Torrisi, R; Fontana, V et al. (1998) Correlation between plasma transforming growth factor-beta 1 and second primary breast cancer in a chemoprevention trial. Eur J Cancer 34:999-1003
De Palo, G; Camerini, T; Marubini, E et al. (1997) Chemoprevention trial of contralateral breast cancer with fenretinide. Rationale, design, methodology, organization, data management, statistics and accrual. Tumori 83:884-94
Decensi, A; Fontana, V; Fioretto, M et al. (1997) Long-term effects of fenretinide on retinal function. Eur J Cancer 33:80-4
Mariani, L; Formelli, F; De Palo, G et al. (1996) Chemoprevention of breast cancer with fenretinide (4-HPR): study of long-term visual and ophthalmologic tolerability. Tumori 82:444-9

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