Basic Trial Information
Trial Description
     Summary
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

The long-lasting phase of precursors of invasive cancer, i.e. dysplasia or intraepithelial neoplasia (IEN), is particularly relevant among risk determinants. At present, about 15-20% of all breast cancers are diagnosed in a non-invasive phase. Despite their good prognosis, women with breast IEN (lobular and ductal intraepithelial neoplasia, LIN and DIN) have a 10-15/1000 annual risk of invasive disease (8-10 times the same age general population), and thus represent an important target for chemoprevention. In the NSABP-P1 trial, tamoxifen use at 20 mg/day was associated with a 86% reduction of invasive breast cancer in women with previous ADH (RR=0.14, 95% IC, 0.03-0.47) and with a 56% risk reduction in women with previous LCIS (RR=0.44, 95% IC, 0.16-1.06). However, tamoxifen use in this setting is hampered by serious adverse events attributable to its partial estrogenic activity, such as increased risk of endometrial cancer and of venous thromboembolism, which have significantly limited its broad use in chemoprevention.

To improve the risk-benefit ratio, the use of lower doses of the drug has been proposed. Recent trials from our group have shown that the dose can be reduced up to 1 mg/day with no loss of tamoxifen antiproliferative activity on breast cancer. By contrast, a dose of 5 mg/day does not increase endometrial proliferation and is associated with a decrease of the estrogenic activity of tamoxifen on IGF-I, SHBG and antithrombin-III, with a potential decrease of venous thromboembolic events. Moreover, tamoxifen exhibits a high tissue distribution, so that a dose of 5 mg/day attains at the breast tissue level a concentration 10 times higher than that needed to inhibit cell growth in vitro. The promising clinical activity of 5 mg/day of tamoxifen is supported by an ongoing 2x2 phase IIb trial of low-dose tamoxifen and fenretinide in premenopausal women, where tamoxifen lowers breast cancer events compared with placebo. The CYP2D6 enzyme mediates oxidation of N-desmethyl tamoxifen to endoxifen, the most active metabolite of tamoxifen. The SNP CYP2D6*4 (1846G>A) allele accounts for 75% of CYP2D6 poor metabolizer phenotype and poor metabolizers showed a trend to a higher risk to develop a breast event compared to wildtype.

Eligibility Criteria

Inclusion Criteria:

• Women of age < 75 years

• Women operated on for lobular (LIN 2 and 3) or ER positive or unknown ductal (DIN 1-3, excluded DIN 1a) intraepithelial neoplasia. Both incident (diagnosis within 12 months) and prevalent cases (diagnosis between previous 12 and 60 months) will be included, upon stratification.

• Written informed consent

Exclusion Criteria:

• Any type of malignancy, with the exclusion of CIN and non-melanoma skin cancer;

• Active proliferative disorders of the endometrium such as atypical hyperplasia, history of active endometriosis, unresected polyps;

• Alterations of metabolic, liver, renal and cardiac grade 2 function (NCI criteria grade 2 or higher);

• Any type of retinal disorders or severe cataract;

• Presence of significant risk factors for venous events, including immobilization within the last 3 months for longer than 2 weeks following surgery or trauma, deep venous thrombophlebitis or other significant VTE (pulmonary embolism, stroke, etc.);

• Use of tamoxifen, raloxifene or other SERMs within the last 4 weeks;

• Anticoagulant therapy in progress (heparin or dicoumarol);

• Active infections;

• Severe psychiatric disorders or inability to comply to the protocol procedures.

Trial Contact Information

Trial Lead Organizations/Sponsors

Ospedale Galliera

Italy
	Genoa
	Ospedale Galliera
		Andrea U De Censi, MD	Ph: 0039 563 Ext.4501
			Email: andrea.decensi@galliera.it
		Silvia Zanardi, MD	Sub-Investigator
		Mauro D'Amico, MD	Sub-Investigator
		Alessandra Gennari, MD	Sub-Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01357772
Information obtained from ClinicalTrials.gov on December 14, 2011

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