A Phase III Randomized Double Blind Study of Letrozole Versus Placebo in Women With Primary Breast Cancer Completing Five or More Years of Adjuvant Tamoxifen
- Compare the disease-free survival and overall survival of postmenopausal women with
primary breast cancer who have completed at least five years of adjuvant aromatase
inhibitor as initial therapy or after tamoxifen treated with letrozole or placebo.
- Compare the incidence of contralateral breast cancer in patients treated with these
- Evaluate the long-term clinical and laboratory safety of letrozole, in terms of lipid
profile, cardiovascular morbidity and mortality, incidence of bone fractures, change in
bone density, and common toxic effects, in this patient population.
- Compare the quality of life of patients treated with these regimens. Re-randomization
- Compare disease-free survival of patients who, after receiving at least 4.5 years of
letrozole, are re-randomized to receive an additional 5 years of letrozole vs placebo.
- Determine whether common genetic polymorphisms for genes encoding proteins involved in
pharmacokinetic and/or pharmacodynamic pathways for letrozole contribute to individual
variation in toxicity and efficacy of letrozole therapy.
OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients
are stratified according to receptor status (positive vs unknown), lymph node status
(negative vs positive vs unknown), prior adjuvant chemotherapy (yes vs no), interval between
last dose of aromatase inhibitor therapy and randomization (< 6 months vs 6 months-2 years),
and duration of prior tamoxifen use (0 years vs < 2 years vs 2-4.5 years vs > 4.5 years).
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. In both arms, treatment continues for
5 years in the absence of disease progression or unacceptable toxicity. Patients in arm
II may then be offered oral letrozole once daily for up to 5 years.
Quality of life is assessed at baseline, at 6 months, and then annually for 4.5 years.
- Double-blind, re-randomization:
Patients who complete ≥ 4.5 years of letrozole (arm I) and who did not experience recurrent
disease or new primary breast cancer, including ductal carcinoma in situ, may participate in
the double-blind, placebo-controlled, re-randomization portion of the study. Patients are
stratified according to lymph node status at enrollment (negative vs positive vs unknown),
prior adjuvant chemotherapy (yes vs no), and interval between last dose of letrozole and
re-randomization (<6 months vs 6 months to 2 years). Common genetic single nucleotide
polymorphisms for genes encoding proteins involved in pharmacokinetic and/or pharmacodynamic
pathways for letrozole are analyzed in order to determine if these single nucleotide
polymorphisms contribute to individual variation in toxicity and efficacy of letrozole
Quality of life is assessed as during the first randomization.
Patients are followed annually.
PROJECTED ACCRUAL: A total of 4,700 patients will be accrued for this study.
Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Paul E. Goss, MD, PhD
Massachusetts General Hospital
Canada: Health Canada