Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation (LIBER)

Prevention of Breast Cancer by Letrozole in Post-menopausal Women Carrying a BRCA1/BRCA2 Mutation

RATIONALE: Letrozole may prevent breast cancer in postmenopausal women with a BRCA1 or BRCA2 mutation.

PURPOSE: This randomized phase III trial is studying letrozole to see how well it works compared with a placebo in preventing breast cancer in postmenopausal women with a BRCA1 or BRCA2 mutation.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Hereditary Breast/Ovarian Cancer (brca1, brca2); brca1 Mutation Carrier; brca2 Mutation Carrier
• Intervention / Treatment: Drug: Placebo; Drug: letrozole

Detailed Description

OBJECTIVES:

Primary

• Evaluate the reduction of the incidence of invasive breast cancer in postmenopausal women with the BRCA1/BRCA2 mutation treated with letrozole.

Secondary

• Determine the reduction of the incidence of in situ breast cancer in these women.
• Determine the recurrence rate of local or metastatic disease in women who have had breast cancer.
• Determine the incidence of non-breast cancer, especially ovarian, colon, or endometrial cancer.
• Assess the tolerance of this drug in terms of lipid, cardiovascular, and bone effects.
• Determine the quality of life of women treated with this drug.
• Identify serological markers that allow early diagnosis of hereditary predisposition for breast cancer.
• Conduct pharmacogenetic analysis.
• Identify biomarkers or genes involved in the occurrence of cardiovascular and rheumatologic metabolic aromatase inhibitors.
• Study the phenotypic characteristics of cancers that occur during treatment with letrozole, in particular hormonal markers (estrogen and progesterone receptor) and expression profiles of resistance to therapy.

OUTLINE: This is a multicenter study. Patients are stratified according to nature of mutation (BRCA1 vs BRCA2), oophorectomy in premenopausal state (yes vs no), and prior breast cancer (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral letrozole once daily.
• Arm II: Patients receive oral placebo once daily. Treatment in both arms continues for 5 years in the absence of unacceptable toxicity or development of cancer or recurrent disease.

Blood samples are collected periodically for pharmacogenetic studies and analysis of biomarkers or genes associated with hereditary predisposition for breast cancer, toxicities, and resistance to therapy.

After completion of study treatment, patients are followed for 5 years.

• Study Type: Interventional
• Enrollment (Actual): 170
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Avignon, France, 84082
    • Institut Sainte Catherine
  • Caen, France, 14076
    • Centre Regional Francois Baclesse
  • Clermont-Ferrand, France, 63011
    • Centre Jean Perrin
  • Lille, France, 59020
    • Centre Oscar Lambret
  • Lyon, France, 69373
    • Centre Léon Bérard
  • Marseille, France, 13273
    • Marseille Institute of Cancer - Institut J. Paoli and I. Calmettes
  • Montpellier, France, 34295
    • Hopital Arnaud de Villeneuve
  • Nantes, France, 02
    • Centre Catherine de Sienne
  • Nice, France, 06189
    • Centre Antoine Lacassagne
  • Niort, France, 79021
    • Centre Hospitalier General de Niort
  • Paris, France, 75015
    • Hopital Saint Michel
  • Paris, France, 75181
    • Hotel Dieu de Paris
  • Paris, France, 75248
    • Institut Curie Hopital
  • Poitiers, France, 86021
    • CHU Poitiers
  • Reims, France, F-51100
    • Polyclinique de Courlancy
  • Rennes, France, 35042
    • Centre Eugène Marquis
  • Rouen, France, 76038
    • Centre Henri Becquerel
  • Saint Cloud, France, 92211
    • Centre René Huguenin
  • Saint-Étienne, France, 42055
    • CHU Sainte-Etienne - Hopital Nord
  • Strasbourg, France, 67065
    • Centre Paul Strauss
  • Toulouse, France, 31052
    • Institut Claudius Regaud
  • Vandoeuvre-les-Nancy, France, 54511
    • Centre Alexis Vautrin
  • Villejuif, France, F-94805
    • Institut Gustave Roussy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 69 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

DISEASE CHARACTERISTICS:

• Must meet the following criteria:

  • With or without invasive unilateral breast cancer more than 5 years ago, with no recurrence

    • No evidence of breast cancer by mammography or MRI within the past year
  • Carrier of the BRCA1/BRCA2 deleterious mutation (nonsense mutation or stop)
  • Refused preventive mastectomy
• No prior bilateral breast cancer
• No prior bilateral mastectomy
• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

Inclusion criteria:

• Menopausal status as indicated by 1 of the following criteria:

  • Age > 60 years
  • Bilateral oophorectomy
  • Age ≤ 60 years with no hysterectomy or amenorrhea within the past 12 months
  • Age ≤ 60 years with prior hysterectomy or FSH > 20 IU/L
• Eastern Cooperative Oncology Group (ECOG) or WHO performance status 0-1
• absolute neutrophil count (ANC) > 2,000/mm^3
• Platelet count > 100,000/mm^3
• Hemoglobin > 10 g/dL
• Bilirubin normal
• ALT and AST < 2.5 times upper limit of normal
• Creatinine clearance ≥ 60 mL/min
• Adequate cardiovascular function (e.g., no history of myocardial infarction, angina pectoris, or heart failure)
• No osteoporosis by bone density scan (DEXA) within the past 2 years or prior osteoporotic fracture (femur, lumbar spine T score > -2 DS)

Exclusion criteria:

• Invasive cancer diagnosed in the past 5 years, except for basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• Prior cerebrovascular accident
• Prior cardiac ischemia
• Hypersensitivity to letrozole or its excipients, especially titanium oxide
• Renal or hepatocellular insufficiency, cholestasis, or cytolysis
• Geographical, social, or psychological reasons that preclude medical monitoring in this study
• Deprived of liberty or guardianship

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• At least 3 months since prior and no concurrent hormone replacement therapy (e.g., thyroid-stimulating hormone)
• No prior hormonal therapy in the past year
• No concurrent participation in another therapeutic study with an experimental drug

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment arm; Letrozole, 1 tablet	Drug: letrozole; Other Names: Femara
Placebo Comparator: Placebo; Comparator, 1 tablet	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Survival without contralateral or unilateral invasive breast cancer at 5 years (prior breast cancer)	2017
Survival without invasive breast cancer at 5 years	2017

Secondary Outcome Measures

Outcome Measure	Time Frame
Invasive cancer-free survival at 10 years	2022
Breast cancer in situ-free survival at 5 and 10 years	2022
Relapse-free (local or metastatic disease) survival in patients with history of breast cancer at 5 and 10 years	2017 and 2022
Second cancer-free survival at 5 and 10 years	2017 and 2022
Event- free (local relapse or metastatic, contralateral, or second cancer) survival at 5 and 10 years	2017 and 2022
Overall survival at 5 and 10 years	2017 and 2022
Toxicity according to CTCAE version 3.0	2017 and 2022
Lipid tolerance or cardiovascular or bone event	2017 and 2022
Quality of life according to MRS and SF36 questionnaires	2017 and 2022

Collaborators and Investigators

• Sponsor: UNICANCER
• Investigators: Study Chair: Pascal Pujol, MD, Hopital Arnaud de Villeneuve

Publications and helpful links

General Publications

• Pujol P, Lasset C, Berthet P, Dugast C, Delaloge S, Fricker JP, Tennevet I, Chabbert-Buffet N, This P, Baudry K, Lemonnier J, Roca L, Mijonnet S, Gesta P, Chiesa J, Dreyfus H, Vennin P, Delnatte C, Bignon YJ, Lortholary A, Prieur F, Gladieff L, Lesur A, Clough KB, Nogues C, Martin AL; French Federation of Cancer Centres (FNCLCC). Uptake of a randomized breast cancer prevention trial comparing letrozole to placebo in BRCA1/2 mutations carriers: the LIBER trial. Fam Cancer. 2012 Mar;11(1):77-84. doi: 10.1007/s10689-011-9484-4.
• Pujol P, Mijonnet S, Karen S, et al.: Breast cancer prevention by letrozole in post menopausal BRCA1/2 mutations carriers: The Onco-03/LIBER trial. [Abstract] 32nd Annual San Antonio Breast Cancer Symposium, December 9-13, 2009, San Antonio, Texas. A-1048, 2009.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2008
• Primary Completion (Actual): June 1, 2019
• Study Completion (Actual): December 1, 2023

Study Registration Dates

• First Submitted: May 6, 2008
• First Submitted That Met QC Criteria: May 6, 2008
• First Posted (Estimated): May 7, 2008

Study Record Updates

• Last Update Posted (Estimated): February 21, 2024
• Last Update Submitted That Met QC Criteria: February 20, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: breast cancer; hereditary breast/ovarian cancer (BRCA1, BRCA2); BRCA2 mutation carrier; BRCA1 mutation carrier
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Breast Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Breast Neoplasms; Ovarian Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Letrozole
• Other Study ID Numbers: UC-0104/0701 - ONCO03; ONCO-03/0701 (Other Identifier: UNICANCER); EU-20806; NOVARTIS-FNCLCC-ONCO 03/0701; 2007-000687-24 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Unicancer will share de-identified individual data that underlie the results reported. A decision concerning the sharing of other study documents, including protocol and statistical analysis plan will be examined upon request.
• IPD Sharing Time Frame: Unicancer will consider access to study data upon written detailed request sent to Unicancer, from 6 months until 5 years after publication of summary data.
• IPD Sharing Access Criteria: The data shared will be limit to that required for independent mandated verification of the published results, the applicant will need authorization from Unicancer for personal access, and data will only be transferred after signing of a data access agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No