The specific aim of the present project is the search for an interaction between low-dose tamoxifen and the synthetic retinoid 4-HPR on a set of surrogate endpoint biomarkers (SEBs) in premenopausal women with in situ or minimally invasive breast cancer. This will be accomplished through a double-blind placebo controlled trial with a 2x2 factorial design, whereby women will be randomized to either placebo, or tamoxifen, 10 mg/day, or 4- HPR, 200 mg/day, or both agents for two years. Since both agents inhibit second primary breast cancer incidence as well as circulating IGF-l levels in premenopausal women and because there is substantial evidence for the critical role played by this growth factor in the pathophysiology of breast cancer, the main outcome measure is the change in plasma IGF-l after two years of intervention. Another important endpoint is he change in the percentage of mammographic density as assessed by quantitative measurement. Secondary endpoints are the change in epithelial dysplasia and Ki67 obtained by ultrasound-guided fine needle aspirate of the contralateral breast add the change in endometrial thickness and proliferation as valuated by transvaginal ultrasonography and pipelle aspiration curette. Finally, assessment of toxicity of the combination regimen is an important objective of the trial. A total of 300 women should be accrued in two years to detect an interaction of 10 ng/ml in plasma IGF-l and of 4% in mammographic density after two years of intervention (power = 90%, two-tailed 5% significance). It is reasonable to assume that a synergistic interaction upon plasma IGF-l and mammographic density could result in a substantial preventive effect on breast Carcinogenesis. The validity of SEBs will be further assessed by their baseline inter-relationships and also the correlations in the changes in these SEBs within the four treatment groups. The study may thus provide essential information on the activity of the combined treatment upon breast carcinogenesis and endometrial proliferation which may lead to the implementation of a safe and successful phase 111 intervention rial aimed at reducing breast cancer incidence in a broader population of at- risk women.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01CA077188-01
Application #
2558517
Study Section
Special Emphasis Panel (ZCA1-RLB-7 (O4))
Project Start
1997-09-30
Project End
2001-08-31
Budget Start
1997-09-30
Budget End
1998-08-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Istituto Europeo Di Oncologia
Department
Type
DUNS #
City
Milan
State
Country
Italy
Zip Code
20141
Johansson, Harriet; Gandini, Sara; Serrano, Davide et al. (2016) A pooled analysis of CYP2D6 genotype in breast cancer prevention trials of low-dose tamoxifen. Breast Cancer Res Treat 159:97-108
Johansson, Harriet; Bonanni, Bernardo; Gandini, Sara et al. (2013) Circulating hormones and breast cancer risk in premenopausal women: a randomized trial of low-dose tamoxifen and fenretinide. Breast Cancer Res Treat 142:569-78
Macis, Debora; Gandini, Sara; Guerrieri-Gonzaga, Aliana et al. (2012) Prognostic effect of circulating adiponectin in a randomized 2 x 2 trial of low-dose tamoxifen and fenretinide in premenopausal women at risk for breast cancer. J Clin Oncol 30:151-7
Johansson, Harriet; Gandini, Sara; Guerrieri-Gonzaga, Aliana et al. (2008) Effect of fenretinide and low-dose tamoxifen on insulin sensitivity in premenopausal women at high risk for breast cancer. Cancer Res 68:9512-8
Zanardi, S; Serrano, D; Argusti, A et al. (2006) Clinical trials with retinoids for breast cancer chemoprevention. Endocr Relat Cancer 13:51-68
Guerrieri-Gonzaga, Aliana; Robertson, Chris; Bonanni, Bernardo et al. (2006) Preliminary results on safety and activity of a randomized, double-blind, 2 x 2 trial of low-dose tamoxifen and fenretinide for breast cancer prevention in premenopausal women. J Clin Oncol 24:129-35
Johansson, Harriet; Baglietto, Laura; Guerrieri-Gonzaga, Aliana et al. (2004) Factors associated with circulating levels of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in 740 women at risk for breast cancer. Breast Cancer Res Treat 88:63-73
Decensi, Andrea; Serrano, Davide; Bonanni, Bernardo et al. (2003) Breast cancer prevention trials using retinoids. J Mammary Gland Biol Neoplasia 8:19-30
Serrano, Davide; Bonanni, Bernardo; Cazzaniga, Massimiliano et al. (2003) Pharmacological prevention of breast cancer: quo vadis? Breast 12:379-86
Veronesi, U; Decensi, A (2001) Retinoids for ovarian cancer prevention: laboratory data set the stage for thoughtful clinical trials. J Natl Cancer Inst 93:486-8

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