Trial of Low Dose Tamoxifen in Women With Breast Intraepithelial Neoplasia - Long Term Follow-up

Study Overview
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Brief Summary
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The aim of the study is to evaluate whether tamoxifen at a low dose of 5mg/d reduces in the long term the incidence of invasive breast cancer and ductal carcinoma in situ, DCIS (DIN 1c, 2, 3) of the breast, in woman operated for lobular intraepithelial neoplasia (LIN1, 2 and 3) or ER-positive ductal intraepithelial neoplasia (DIN 1b, DIN2, DIN3, 1a excluded) of the breast. To improve the risk-benefit ratio, the use of lower doses of the drug has been proposed. Biomarker trials revealed that 5 mg/d was noninferior to 20 mg/d in inhibiting proliferation of breast cancer and normal endometrial tissue. By contrast, the risk of endometrial cancer si dose-dependent, and the dose reduction can lead a substantial decrease. Morover a dose of 5 mg/day is associated with an overall decrease of the estrogenic activity of tamoxifen on insulin like growth factor (IGF-I), sex hormone-binding globulin (SHBG) and antithrombin-III, with a 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. A prospective cohort study also showed that 10 mg on alternate days halves recurrence of DCIS in postmenopausal women. It has been shown that the treatment of dysplasia or pre-cancer drives the reduction of the invasive neoplasms onset. This is a chemoprevention trial designed to validatate the low-dose Tamoxifen in women with diseases at high evolutionary risk. The demonstration of efficacy and safety of such a treatment for the prevention of the invasive breast cancer would lead improvements in term of survival and quality of life for the patients at increased risk.

Detailed Description
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Italian, multicenter, phase III trial: controlled, parallel group comparision, randomized (1:1) duble blind, tamoxifen 5 mg/d versus placebo administered for 3 years. A total of 500 women 75 years of age or younger with newly diagnosed non-invasive breast cancer have been included in the study. The long-term study implies a minimum 10 year follow up after treatment completion.

Official Title
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Randomized Placebo-controlled Phase III Trial of Low Dose Tamoxifen in Women With Breast Intraepithelial Neoplasia - Long Term Follow-up

Conditions
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Carcinoma, Intraductal, Noninfiltrating, Recurrence, Local Neoplasm, Breast Neoplasms, Atypical Hyperplasia

Intervention / Treatment
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* Drug: Tamoxifen
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women of age ≥ 18 and < 75 years Women operated on for lobular (LIN 2 and 3) or ER positive or unknown ductal DCIS, i.e DIN 1-3, but DIN 1a excluded) intraepithelial neoplasia in the 5 years (60 months) prior the inclusion in the study. Both incident (diagnosis < 12 months) and prevalent cases diagnosis ≥12, and < 60 months) will be included, including recurrent cases ECOG Performance status ≤ 1 Written informed consent Exclusion Criteria: Any type of malignancy, with the exclusion of non-melanoma skin cancer Proliferative disorders of the endometrium such as atypical hyperplasia, endometriosis, unresected polyps, symptomatic myoma Liver, kidney and heart function impairment grade ≥ 2 (CTCAE criteria v.3.0) Any type of retinal disorders, severe cataract and glaucoma Presence of significant risk factors for venous events, including immobilization after trauma within the last 3 months for longer than 2 weeks, deep venous thrombophlebitis or other significant venous thrombotic event,VTE (pulmonary embolism, stroke, etc.) Use of tamoxifen, raloxifene or other selective estrogen receptor modulator (SERMs) Use of anastrozole and other aromatase inhibitors (AI) in the last 12 months for ≥ 6 months Dicoumarol anticoagulant therapy in progress Active infections Severe psychiatric disorders or inability to comply to the protocol procedures Geographic inaccessibility or difficulties in ensuring adequate compliance Women who are pregnant or breastfeeding Any other factor which, at the discretion of the investigator, may controindicate the use of tamoxifen

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tamoxifen<br>tamoxifen at daily dose of 5 mg for a total treatment time of 3 years | Drug: Tamoxifen<br> <br> * Other names: Tamoxifen citrate (ATC code: L02BA01);|
| Placebo Comparator: placebo<br>placebo at daily dose of 5 mg for a total treatment time of 3 years | Drug: placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of invasive breast cancer events and DCIS | Number of neoplastic events, i.e., invasive breast cancer or ductal carcinoma in situ of the breast from the start of treatment up to at least 16 years from treatment initiation. | 20 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of other non-invasive breast events | Number of other non-invasive breast disorders (LCIS, atypical ductal or lobular hyperplasia), endometrial cancer, ovarian cancer, thromboembolic events; bone fractures, cardiovascular and thromboembolic events, clinically manifested cataracts and melanoma; change of mammographic density from the start of treatment up to at least 16 years from treatment initiation. | 20 years | 
| Metabolites of tamoxifen and hormone blood level (in a subgroup of women) | Blood concentrations of metabolites including circulating IGF-I,IGFBP-3, SHBG, hormones (testosterone, estradiol, SHBG, CRP), tamoxifen metabolites (4OH tamoxifen and endoxifen). | 20 years | 
| CYP2D6 polymorphisms analysis | Esploratory analisis of some SNPS of the cytochrome P450 genes involved in tamoxifen metabolism such as CYP2D6. | 20 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DCIS, tamoxifen, dose reduction