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

• ClinicalTrials.gov Identifier: NCT01357772
• Recruitment Status: Active, not recruiting
• First Posted: May 23, 2011
• Last Update Posted: April 4, 2022
• Sponsor: Andrea DeCensi
• Collaborators: Associazione Italiana per la Ricerca sul Cancro; European Institute of Oncology
• Information provided by (Responsible Party): Andrea DeCensi, Ente Ospedaliero Ospedali Galliera

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Carcinoma, Intraductal, Noninfiltrating; Recurrence, Local Neoplasm; Breast Neoplasms; Atypical Hyperplasia	Drug: Tamoxifen; Drug: placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 500 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• Official Title: Randomized Placebo-controlled Phase III Trial of Low Dose Tamoxifen in Women With Breast Intraepithelial Neoplasia - Long Term Follow-up
• Study Start Date: November 12, 2008
• Estimated Primary Completion Date: December 31, 2028
• Estimated Study Completion Date: December 31, 2028

Arms and Interventions

Arm	Intervention/treatment
Experimental: Tamoxifen; tamoxifen at daily dose of 5 mg for a total treatment time of 3 years	Drug: Tamoxifen; Other Name: 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

Outcome Measures

Primary Outcome Measures :

1. Number of invasive breast cancer events and DCIS [ Time Frame: 20 years ]
   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

Secondary Outcome Measures :

1. Number of other non-invasive breast events [ Time Frame: 20 years ]
   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.
2. Metabolites of tamoxifen and hormone blood level (in a subgroup of women) [ Time Frame: 20 years ]
   Blood concentrations of metabolites including circulating IGF-I,IGFBP-3, SHBG, hormones (testosterone, estradiol, SHBG, CRP), tamoxifen metabolites (4OH tamoxifen and endoxifen).
3. CYP2D6 polymorphisms analysis [ Time Frame: 20 years ]
   Esploratory analisis of some SNPS of the cytochrome P450 genes involved in tamoxifen metabolism such as CYP2D6

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

Italy

Istituto Scientifico Romagnolo per lo studio e la cura dei tumori

Meldola, Forlì-Cesena, Italy, 47521

Ospedale di Carpi "Bernardino Ramazzini"

Carpi, Modena, Italy, 41012

IRCCS Ospedale Oncologico di Bari - Istituto tumori "G. Paolo II"

Bari, Italy, 70124

E.O. Ospedali Galliera

Genoa, Italy, 16128

Istituto Europeo di Oncologia

Milano, Italy, 20100

A. O. Universitaria Policlinico di Modena

Modena, Italy, 41100

Istituto nazionale per lo studio e la cura dei tumori, IRCCS "Fondazione Pascale"

Napoli, Italy, 80131

AUSL - Oncologia Medica

Ravenna, Italy, 48018

A.O. Universitaria S. Giovanni Battista - "Le Molinette"

Torino, Italy, 10123

Presidio Ospedaliero "SS. Antonio e Margherita"

Tortona, Italy, 15057

Azienda ULSS8 Berica

Vicenza, Italy, 36100

Sponsors and Collaborators

Andrea DeCensi

Associazione Italiana per la Ricerca sul Cancro

European Institute of Oncology

Investigators

• Principal Investigator: Andrea De Censi, MD; E.O.Ospedali Galliera

More Information

Additional Information:

PubMed ID: 33608319 

PubMed ID: 23106852 

PubMed ID: 33767162 

Publications of Results:

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. Review.

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, Søiland 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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Andrea DeCensi, Medical Oncology Director, Ente Ospedaliero Ospedali Galliera
• ClinicalTrials.gov Identifier: NCT01357772
• Other Study ID Numbers: GAL 01
• First Posted: May 23, 2011
• Last Update Posted: April 4, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

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

• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Keywords provided by Andrea DeCensi, Ente Ospedaliero Ospedali Galliera:

DCIS; tamoxifen; dose reduction

Additional relevant MeSH terms:

Neoplasms; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Neoplasm Recurrence, Local; Recurrence; Hyperplasia; Disease Attributes; Pathologic Processes; Neoplasms by Site; Breast Diseases; Skin Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Breast Carcinoma In Situ; Carcinoma in Situ; Neoplasms, Ductal, Lobular, and Medullary; Neoplastic Processes; Tamoxifen; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Bone Density Conservation Agents