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.

Study Details

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.

Disease-Free Survival

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.

Adverse Events

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.