Neoadjuvant letrozole in postmenopausal estrogen and/or progesterone receptor positive breast cancer:: A phase IIb/III trial to investigate optimal duration of preoperative endocrine therapy

Background: In recent years, preoperative volume reduction of locally advanced breast cancers, resulting in higher rates of breast-conserving surgery (BCS), has become increasingly important also in postmenopausal women. Clinical interest has come to center on the third-generation nonsteroidal aromatase inhibitors (AIs), including letrozole, for such neoadjuvant endocrine treatment. This usually lasts 3-4 months and has been extended to up to 12 months, but optimal treatment duration has not been fully established. Methods: This study was designed as a multicenter, open-label, single-arm, exploratory phase IIb/III clinical trial of letrozole 2.5 mg, one tablet daily, for 4-8 months. The primary objective was to investigate the effect of neoadjuvant treatment duration on tumor regression and BCS eligibility to identify optimal treatment duration. Tumor regression ( by clinical examination, mammography, and ultrasound), shift towards BCS eligibility, and safety assessments were the main outcome measures. Standard parametric and nonparametric descriptive statistics were performed. Results: Letrozole treatment was received by 32 of the enrolled 33 postmenopausal women ( median ( range): 67.0 ( 56 - 85) years) with unilateral, initially BCS-ineligible primary breast cancer ( clinical stage >= T2, N0, M0). Letrozole treatment duration in the modified intent-to-treat ( ITT; required 4 months' letrozole treatment) analysis population ( 29 patients) was 4 months in 14 patients and > 4 months in 15 patients. The respective per-protocol ( PP) subgroup sizes were 14 and 11. The majority of partial or complete responses were observed at 4 months, though some beneficial responses occurred during prolonged letrozole treatment. Compared with baseline, median tumor size in the ITT population was reduced by 62.5% at Month 4 and by 70.0% at final study visit ( Individual End). Similarly, in the PP population, respective reductions were 64.0% and 67.0%. Whereas initially all patients were mastectomy candidates, letrozole treatment enabled BCS ( lumpectomy) in 22 ITT ( 75.9%) and 18 PP ( 72.0%) patients. Conclusion: Over half of patients become BCS-eligible within 4 months of preoperative letrozole treatment. While prolonged treatment for up to 8 months can result in further tumor volume reduction in some patients, there is no clear optimum for treatment duration. Letrozole has a favorable overall safety and tolerability profile.