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

NCT01357772 | Active Not Recruiting Phase 3 DMC

• 2 other identifiers: GAL 012007-007740-10
• Study Type: interventional
• Target: 500
• Locations: 1 country
• Sites: 14

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.

Conditions

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

Keywords

DCIS; tamoxifen; dose reduction

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Number of other non-invasive breast events

  20 years

• Metabolites of tamoxifen and hormone blood level (in a subgroup of women)

  20 years

• CYP2D6 polymorphisms analysis

  20 years

Study Arms (2)

Tamoxifen

EXPERIMENTAL

tamoxifen at daily dose of 5 mg for a total treatment time of 3 years

Drug: Tamoxifen

placebo

PLACEBO COMPARATOR

placebo at daily dose of 5 mg for a total treatment time of 3 years

Drug: placebo

Interventions

Tamoxifen DRUG

Also known as: Tamoxifen citrate (ATC code: L02BA01)

Tamoxifen

placebo DRUG

placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Women of age ≥ 18 and \< 75 years
• ECOG Performance status ≤ 1
• Written informed consent

You may not qualify if:

• 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

Sponsors & Collaborators

• Andrea DeCensi: lead
• Associazione Italiana per la Ricerca sul Cancro: collaborator
• European Institute of Oncology: collaborator

Study Sites (14)

Ospedali riuniti ASL AL - Ospedale SS. Antonio e Margherita

Tortona, Alessandria, 15057, Italy

Location

Istituto Scientifico Romagnolo per lo studio e la cura dei tumori

Meldola, Forlì-Cesena, 47521, Italy

Location

Ospedale di Carpi "Bernardino Ramazzini"

Carpi, Modena, 41012, Italy

Location

IRCCS Istituto Tumori Giovanni Paolo II

Bari, 70124, Italy

Location

Azienda Ospedaliera Mater Domini Catanzaro

Catanzaro, 88100, Italy

Location

E.O. Ospedali Galliera

Genoa, 16128, Italy

Location

IEO - European Institute of Oncology IRCCS

Milan, 20100, Italy

Location

Azienda Ospedaliera-Universitaria Policlinico di Modena

Modena, 41100, Italy

Location

Istituto Nazionale Tumori IRCCS Fondazione G. Pascale

Napoli, 80131, Italy

Location

ICS Maugeri -Centro Medico di Pavia

Pavia, Italy

Location

AUSL - Oncologia Medica

Ravenna, 48018, Italy

Location

Azienda Ospedaliera-Universitaria Città della Salute e della Scienza di Torino

Torino, 10123, Italy

Location

Azienda Socio-Sanitaria Territoriale Sette Laghi, Varese

Varese, 21100, Italy

Location

Azienda ULSS8 Berica

Vicenza, 36100, Italy

Location

Related Publications (6)

• 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.

  PMID: 33608319 RESULT

• 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.

  PMID: 23106852 RESULT

• 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.

  PMID: 33767162 RESULT

• 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.

  PMID: 36917758 RESULT

• Carbone A, Oliva M, Puntoni M, Guerrieri-Gonzaga A, Briata IM, Lazzeroni M, Serrano D, Giordano L, Digennaro M, Cortesi L, Millo F, Cagossi K, Aprile G, Serra P, Gallerani E, Bonanni B, DeCensi A. Effect of low-dose tamoxifen on benign gynecological and breast conditions in a phase III trial in non-invasive breast cancer. J Natl Cancer Inst. 2025 Aug 28:djaf250. doi: 10.1093/jnci/djaf250. Online ahead of print.

  PMID: 40880294 DERIVED

• 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.

  PMID: 30973790 DERIVED

Related Links

• PubMed ID: 33608319
• PubMed ID: 23106852
• PubMed ID: 33767162
• PMID: 36917758

MeSH Terms

Conditions

Carcinoma, Intraductal, Noninfiltrating; Neoplasm Recurrence, Local; Breast Neoplasms

Interventions

Tamoxifen

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Breast Carcinoma In Situ; Carcinoma in Situ; Neoplasms, Ductal, Lobular, and Medullary; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms by Site; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• Andrea DeCensi, MD

  E.O.Ospedali Galliera

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Medical Oncology Director

Study Record Dates

• First Submitted: May 17, 2011
• First Posted: May 23, 2011
• Study Start: November 12, 2008
• Primary Completion: December 31, 2022
• Study Completion (Estimated): December 31, 2028
• Last Updated: July 17, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF

Locations

IT (14)