This trial is active, not recruiting.

Condition intraepithelial carcinoma
Treatments tamoxifen, placebo
Phase phase 3
Sponsor Andrea DeCensi
Collaborator Associazione Italiana per la Ricerca sul Cancro
Start date November 2008
End date December 2019
Trial size 1400 participants
Trial identifier NCT01357772, GAL 01


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 National Surgical Adjuvant Breast and Bowel Project (NSABP-P1 trial), tamoxifen use at 20 mg/day was associated with a 86% reduction of invasive breast cancer in women with previous atypical ductal hyperplasia (ADH) (RR=0.14, 95% IC, 0.03-0.47) and with a 56% risk reduction in women with previous Lobular Carcinoma in situ (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 insulin like growth factor (IGF-I), sex hormone-binding globulin (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 cytochromeP450 2D6 (CYP2D6) enzyme mediates oxidation of N-desmethyl tamoxifen to endoxifen, the most active metabolite of tamoxifen. The single nucleotide polymorphism (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.

United States No locations recruiting
Other countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking double blind (subject, caregiver, investigator)
Primary purpose prevention
tamoxifen at daily dose of 5 mg for a total treatment time of 3 years
at daily dose of 5 mg for a total treatment time of 3 years
(Placebo Comparator)
placebo at daily dose of 5 mg for a total treatment time of 3 years
placebo at daily dose of 5 mg for a total treatment time of 3 years

Primary Outcomes

Incidence of invasive breast cancer
time frame: 36 months

Secondary Outcomes

Incidence of other non-invasive breast disorders
time frame: 36 months
To determine CYP2D6 genotype
time frame: 36 months

Eligibility Criteria

Female participants from 18 years up to 75 years old.

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 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 venous thrombotic event (VTE) (pulmonary embolism, stroke, etc.); - Use of tamoxifen, raloxifene or other selective estrogen receptor modulator (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.

Additional Information

Official title Randomized Placebo-controlled Phase III Trial of Low Dose Tamoxifen in Women With Breast Intraepithelial Neoplasia
Principal investigator Andrea De Censi, MD
Description The time interval between Study Start Date (November 2008) and Study First Release (May 17, 2011) was related to bureaucratic problems.
Trial information was received from ClinicalTrials.gov and was last updated in August 2015.
Information provided to ClinicalTrials.gov by Ente Ospedaliero Ospedali Galliera.