Clinical trial NCT01357772: Trial of Low Dose Tamoxifen in Women With Breast Intraepithelial Neoplasia - Long Term Follow-up
Official title: Randomized Placebo-controlled Phase III Trial of Low Dose Tamoxifen in Women With Breast Intraepithelial Neoplasia - Long Term Follow-up
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Carcinoma, Intraductal, Noninfiltrating
Recurrence, Local Neoplasm
Breast Neoplasms
Atypical Hyperplasia
Keywords: DCIS
tamoxifen
dose reduction
Lead sponsor: Ente Ospedaliero Ospedali Galliera
Sponsor class: OTHER
Collaborators: name: Associazione Italiana per la Ricerca sul Cancro
name: European Institute of Oncology
First posted: 2011-05-23
Enrollment: 500
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Women of age ≥ 18 and \< 75 years
2. 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
3. ECOG Performance status ≤ 1
4. Written informed consent

Exclusion Criteria:

1. Any type of malignancy, with the exclusion of non-melanoma skin cancer
2. Proliferative disorders of the endometrium such as atypical hyperplasia, endometriosis, unresected polyps, symptomatic myoma
3. Liver, kidney and heart function impairment grade ≥ 2 (CTCAE criteria v.3.0)
4. Any type of retinal disorders, severe cataract and glaucoma
5. 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.)
6. Use of tamoxifen, raloxifene or other selective estrogen receptor modulator (SERMs)
7. Use of anastrozole and other aromatase inhibitors (AI) in the last 12 months for ≥ 6 months
8. Dicoumarol anticoagulant therapy in progress
9. Active infections
10. Severe psychiatric disorders or inability to comply to the protocol procedures
11. Geographic inaccessibility or difficulties in ensuring adequate compliance
12. Women who are pregnant or breastfeeding
13. Any other factor which, at the discretion of the investigator, may controindicate the use of tamoxifen

Primary outcomes:
measure: Number of invasive breast cancer events and DCIS
timeFrame: 20 years
Secondary outcomes:
measure: Number of other non-invasive breast events
timeFrame: 20 years
measure: Metabolites of tamoxifen and hormone blood level (in a subgroup of women)
timeFrame: 20 years
measure: CYP2D6 polymorphisms analysis
timeFrame: 20 years
Other outcomes:
Locations:
city: Tortona
country: Italy
facility: Ospedali riuniti ASL AL - Ospedale SS. Antonio e Margherita
state: Alessandria
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo studio e la cura dei tumori
state: Forlì-Cesena
city: Carpi
country: Italy
facility: Ospedale di Carpi "Bernardino Ramazzini"
state: Modena
city: Bari
country: Italy
facility: IRCCS Istituto Tumori Giovanni Paolo II
city: Catanzaro
country: Italy
facility: Azienda Ospedaliera Mater Domini Catanzaro
city: Genoa
country: Italy
facility: E.O. Ospedali Galliera
city: Milan
country: Italy
facility: IEO - European Institute of Oncology IRCCS
city: Modena
country: Italy
facility: Azienda Ospedaliera-Universitaria Policlinico di Modena
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori IRCCS Fondazione G. Pascale
city: Pavia
country: Italy
facility: ICS Maugeri -Centro Medico di Pavia
city: Ravenna
country: Italy
facility: AUSL - Oncologia Medica
city: Torino
country: Italy
facility: Azienda Ospedaliera-Universitaria Città della Salute e della Scienza di Torino
city: Varese
country: Italy
facility: Azienda Socio-Sanitaria Territoriale Sette Laghi, Varese
city: Vicenza
country: Italy
facility: Azienda ULSS8 Berica
Study officials:
affiliation: E.O.Ospedali Galliera
name: Andrea DeCensi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: DeCensi A, Puntoni M, Johansson H, Guerrieri-Gonzaga A, Caviglia S, Avino F, Cortesi L, Ponti A, Pacquola MG, Falcini F, Gulisano M, Digennaro M, Cariello A, Cagossi K, Pinotti G, Lazzeroni M, Serrano D, Briata IM, Buttiron Webber T, Boni L, Bonanni B. Effect Modifiers of Low-Dose Tamoxifen in a Randomized Trial in Breast Noninvasive Disease. Clin Cancer Res. 2021 Jul 1;27(13):3576-3583. doi: 10.1158/1078-0432.CCR-20-4213. Epub 2021 Feb 19.
citation: Lazzeroni M, Serrano D, Dunn BK, Heckman-Stoddard BM, Lee O, Khan S, Decensi A. Oral low dose and topical tamoxifen for breast cancer prevention: modern approaches for an old drug. Breast Cancer Res. 2012 Oct 29;14(5):214. doi: 10.1186/bcr3233.
citation: DeCensi A, Johansson H, Helland T, Puntoni M, Macis D, Aristarco V, Caviglia S, Webber TB, Briata IM, D'Amico M, Serrano D, Guerrieri-Gonzaga A, Bifulco E, Hustad S, Soiland H, Boni L, Bonanni B, Mellgren G. Association of CYP2D6 genotype and tamoxifen metabolites with breast cancer recurrence in a low-dose trial. NPJ Breast Cancer. 2021 Mar 25;7(1):34. doi: 10.1038/s41523-021-00236-6.
citation: Lazzeroni M, Puntoni M, Guerrieri-Gonzaga A, Serrano D, Boni L, Buttiron Webber T, Fava M, Briata IM, Giordano L, Digennaro M, Cortesi L, Falcini F, Serra P, Avino F, Millo F, Cagossi K, Gallerani E, De Simone A, Cariello A, Aprile G, Renne M, Bonanni B, DeCensi A. Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Recurrence in Breast Noninvasive Neoplasia: A 10-Year Follow-Up of TAM-01 Study. J Clin Oncol. 2023 Jun 10;41(17):3116-3121. doi: 10.1200/JCO.22.02900. Epub 2023 Mar 14.
citation: DeCensi A, Puntoni M, Guerrieri-Gonzaga A, Caviglia S, Avino F, Cortesi L, Taverniti C, Pacquola MG, Falcini F, Gulisano M, Digennaro M, Cariello A, Cagossi K, Pinotti G, Lazzeroni M, Serrano D, Branchi D, Campora S, Petrera M, Buttiron Webber T, Boni L, Bonanni B. Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Local and Contralateral Recurrence in Breast Intraepithelial Neoplasia. J Clin Oncol. 2019 Jul 1;37(19):1629-1637. doi: 10.1200/JCO.18.01779. Epub 2019 Apr 11.