Clinical trial NCT00673335: Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
Official title: Prevention of Breast Cancer by Letrozole in Post-menopausal Women Carrying a BRCA1/BRCA2 Mutation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: brca1 Mutation Carrier
brca2 Mutation Carrier
Breast Cancer
Hereditary Breast/Ovarian Cancer (brca1, brca2)
Keywords: breast cancer
hereditary breast/ovarian cancer (BRCA1, BRCA2)
BRCA1 mutation carrier
BRCA2 mutation carrier
Lead sponsor: UNICANCER
Sponsor class: OTHER
First posted: 2008-05-07
Enrollment: 170
Sex: FEMALE
Minimum age (years): 40
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Survival without contralateral or unilateral invasive breast cancer at 5 years (prior breast cancer)
timeFrame: 2017
measure: Survival without invasive breast cancer at 5 years
timeFrame: 2017
Secondary outcomes:
measure: Invasive cancer-free survival at 10 years
timeFrame: 2022
measure: Breast cancer in situ-free survival at 5 and 10 years
timeFrame: 2022
measure: Relapse-free (local or metastatic disease) survival in patients with history of breast cancer at 5 and 10 years
timeFrame: 2017 and 2022
measure: Second cancer-free survival at 5 and 10 years
timeFrame: 2017 and 2022
measure: Event- free (local relapse or metastatic, contralateral, or second cancer) survival at 5 and 10 years
timeFrame: 2017 and 2022
measure: Overall survival at 5 and 10 years
timeFrame: 2017 and 2022
measure: Toxicity according to CTCAE version 3.0
timeFrame: 2017 and 2022
measure: Lipid tolerance or cardiovascular or bone event
timeFrame: 2017 and 2022
measure: Quality of life according to MRS and SF36 questionnaires
timeFrame: 2017 and 2022
Other outcomes:
Locations:
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Caen
country: France
facility: Centre Regional Francois Baclesse
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lyon
country: France
facility: Centre Leon Berard
city: Marseille
country: France
facility: Marseille Institute of Cancer - Institut J. Paoli and I. Calmettes
city: Montpellier
country: France
facility: Hopital Arnaud de Villeneuve
city: Nantes
country: France
facility: Centre Catherine de Sienne
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Niort
country: France
facility: Centre Hospitalier General de Niort
city: Paris
country: France
facility: Hopital Saint Michel
city: Paris
country: France
facility: Hotel Dieu de Paris
city: Paris
country: France
facility: Institut Curie Hopital
city: Poitiers
country: France
facility: CHU Poitiers
city: Reims
country: France
facility: Polyclinique De Courlancy
city: Rennes
country: France
facility: Centre Eugene Marquis
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint Cloud
country: France
facility: Centre Rene Huguenin
city: Saint-Étienne
country: France
facility: CHU Sainte-Etienne - Hopital Nord
city: Strasbourg
country: France
facility: Centre Paul Strauss
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Vandoeuvre-les-Nancy
country: France
facility: Centre Alexis Vautrin
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: Hopital Arnaud de Villeneuve
name: Pascal Pujol, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.