In the Italian phase III GIM4 trial reported in The Lancet Oncology, Lucia Del Mastro, MD, and colleagues found that 5 years vs 2 to 3 years of adjuvant letrozole significantly prolonged invasive disease–free survival in postmenopausal women with early-stage breast cancer who had already completed treatment with 2 to 3 years of adjuvant tamoxifen.
The multicenter open-label trial included 2,056 patients with hormone receptor–positive disease who had received tamoxifen for at least 2 years and no longer than 3 years and 3 months. They were randomly assigned between August 2005 and October 2010 to receive letrozole at 2.5 mg once a day for 5 years (extended group, n = 1,026) or 2 to 3 years (control group, n = 1,030).
Lucia Del Mastro, MD
The primary endpoint was invasive disease–free survival in the intention-to-treat population. Safety analysis was performed among patients who received at least 1 month of study treatment.
Median duration of letrozole treatment was 5.0 years (interquartile range [IQR] = 2.5–5.0 years) in the extended group and 2.4 years (IQR = 1.9–2.8 years) in the control group. Bisphosphonate treatment was received by 16.1% of the extended group and 11.7% of the control group.
At a median follow-up of 11.7 years (IQR = 9.5–13.1 years), disease-free survival events occurred in 212 patients (20.7%) in the extended group vs 262 (25.4%) in the control group. Disease-free survival at 12 years was 67% (95% confidence interval [CI] = 62%–71%) in the extended group vs 62% (95% CI = 57%–66%) in the control group (hazard ratio [HR] = 0.78, 95% CI = 0.65–0.93, P = .0064). Rates at 5 and 10 years were 92% vs 92% and 79% vs 74%, respectively.
Death occurred in 116 patients (11.1%) in the extended group vs 147 (14.3%) of the control group. Overall survival at 12 years was 88% (95% CI = 86%–90%) in the extended group vs 84% (95% CI = 82%–87%) in the control group (HR = 0.77, 95% CI = 0.60–0.98, P = .036). Rates at 5 and 10 years were 97% vs 97% and 91% vs 90%, respectively.
The most common grade 3 or 4 adverse events in the extended group were arthralgia (3.0% vs 2.2% in the control group) and myalgia (0.9% vs 0.7%). Osteoporosis occurred in 8.3% vs 4.7% of patients. No significant difference was observed between the groups in the incidence of bone fracture (0.9% vs 0.5%, P = .28), hypercholesterolemia (2.0% vs 3.1%, P = .17), or cardiovascular events (0.6% vs 0.1%, P = .069).
Adverse events led to discontinuation of treatment in 14.4% vs 8.9% of patients. Treatment-related serious adverse events occurred in eight patients (0.8%) in the extended group (thromboembolic events in 4, cardiovascular events in 2, pneumonia in 1, and macular degeneration in 1) and in three (0.3%) in the control group (atrial fibrillation, bone pain, and vomiting, all in 1 patient each). No treatment-related deaths were reported.
The investigators concluded, “In postmenopausal patients with breast cancer who received 2 to 3 years of tamoxifen, extended treatment with 5 years of letrozole resulted in a significant improvement in disease-free survival compared with the standard 2 to 3 years of letrozole. Sequential endocrine therapy with tamoxifen for 2 to 3 years followed by letrozole for 5 years should be considered as one of the optimal standard endocrine treatments for postmenopausal patients with hormone receptor–positive breast cancer.”
Lucia Del Mastro, MD, of the Dipartimento di Medicina Interna e Specialità Mediche, Università di Genoa, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by the Italian Ministry of Health and Novartis. For full disclosures of the study authors, visit thelancet.com.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.