Trial of Low Dose Tamoxifen in Women With Breast Intraepithelial Neoplasia - Long Term Follow-up (TAM-01)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Recurrence, Local Neoplasm; Atypical Hyperplasia
• Intervention / Treatment: Drug: Tamoxifen; Drug: placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 500
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Bari, Italy, 70124
    • IRCCS Istituto Tumori Giovanni Paolo II
  • Catanzaro, Italy, 88100
    • Azienda Ospedaliera Mater Domini Catanzaro
  • Genoa, Italy, 16128
    • E.O. Ospedali Galliera
  • Milan, Italy, 20100
    • IEO - European Institute of Oncology IRCCS
  • Modena, Italy, 41100
    • Azienda Ospedaliera-Universitaria Policlinico di Modena
  • Napoli, Italy, 80131
    • Istituto Nazionale Tumori IRCCS Fondazione G. Pascale
  • Pavia, Italy
    • ICS Maugeri -Centro Medico di Pavia
  • Ravenna, Italy, 48018
    • AUSL - Oncologia Medica
  • Torino, Italy, 10123
    • Azienda Ospedaliera-Universitaria Città della Salute e della Scienza di Torino
  • Varese, Italy, 21100
    • Azienda Socio-Sanitaria Territoriale Sette Laghi, Varese
  • Vicenza, Italy, 36100
    • Azienda ULSS8 Berica
  • Alessandria
    • Tortona, Alessandria, Italy, 15057
      • Ospedali riuniti ASL AL - Ospedale SS. Antonio e Margherita
  • Forlì-Cesena
    • Meldola, Forlì-Cesena, Italy, 47521
      • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
  • Modena
    • Carpi, Modena, Italy, 41012
      • Ospedale di Carpi "Bernardino Ramazzini"

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Andrea DeCensi
• Collaborators: European Institute of Oncology; Associazione Italiana per la Ricerca sul Cancro
• Investigators: Principal Investigator: Andrea DeCensi, MD, E.O.Ospedali Galliera

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): November 12, 2008
• Primary Completion (Actual): December 31, 2022
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: May 17, 2011
• First Submitted That Met QC Criteria: May 20, 2011
• First Posted (Estimated): May 23, 2011

Study Record Updates

• Last Update Posted (Actual): July 17, 2023
• Last Update Submitted That Met QC Criteria: July 13, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: tamoxifen; dose reduction; DCIS
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Neoplasms by Histologic Type; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Disease Attributes; Breast Diseases; Neoplastic Processes; Carcinoma in Situ; Neoplasms, Ductal, Lobular, and Medullary; Breast Carcinoma In Situ; Neoplasms; Breast Neoplasms; Recurrence; Hyperplasia; Carcinoma, Intraductal, Noninfiltrating; Neoplasm Recurrence, Local; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Bone Density Conservation Agents; Estrogen Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Tamoxifen
• Other Study ID Numbers: GAL 01; 2007-007740-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Authors are open to share data based on a request for collaboration that includes a data analysis plan.

Please send an e-mail to both: andrea.decensi@galliera.it; mpuntoni@ao.pr.it

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF