Benefit from letrozole as extended adjuvant therapy after sequential endocrine therapy: A randomized, phase III study of Gruppo Italiano Mammella (GIM).

Abstract

504 Background: The effect of extended adjuvant endocrine therapy (ET) with aromatase inhibitors (AI) after sequential ET with tamoxifen (Tam) followed by AI for 5 years is still controversial. We conduct a clinical trial to assess different durations of ET of letrozole after tam. Methods: The GIM4 LEAD (Gruppo Italiano Mammella 4- Letrozole adjuvant therapy duration study, ClinicalTrials.gov:NCT01064635 ) was a prospective, randomized, Italian multicentric trial. Post-menopausal patients (pts) with hormone receptor positive early breast cancer free of recurrence after 2-3 years of adjuvant tam, were randomized in a 1:1 ratio to receive 3-2 years (short arm, S) or 5 years (long arm, L) of letrozole. The primary study end point was disease-free survival (DFS). Results: Between August 2005 and May 2010, 2056 pts were randomly assigned to receive 3-2 years (n=1030) or 5 years (n=1026) of letrozole. Main patients characteristics in the S and L arms were, respectively: median age 60 vs 61 years, node negative 56 vs 56%, (neo)adjuvant chemotherapy 53.4 vs 54.1%. The median follow-up was 10 years (IQR range: 8.6-11.4). The 8-year DFS was 80% (95% CI:77.3-82.7) and 85% (95% CI:82.9-87.6) in the S and L arm, respectively (hazard ratio, HR 0.82; 95% CI:0.68-0.98; p=0.031). This effect did not change in a multivariate Cox model that included nodal status, grading and age. No evidence of interaction between random assignment and nodal status, age and grading was observed. Among 1960 pts evaluable for toxicity, osteoporosis was diagnosed in 47 (4.8%) in S arm and 81 (8.3%) pts in L arm (chi-square=9.88; p=0.002). Bone fractures occurred in 5 (0.5%) and 9 (0.9%) pts in S and L arm, respectively ( p=0.29, Fisher exact test). Conclusions: After 2-3 years of adjuvant tam, extended treatment with 5 years of letrozole resulted in significant improvement in DFS compared to the standard duration of 2-3 years of letrozole. Clinical trial information: NCT01064635.