Editor’s pick of Jeroen Mebis, MD, PhD, Medical Oncologist, Jessa Hospital, Hasselt
In postmenopausal patients with breast cancer who received 2–3 years of tamoxifen, extended treatment with 5 years of letrozole resulted in a significant improvement in disease-free survival compared with the standard 2–3 years of letrozole. As such, the use of an aromatase inhibitor for 5 years after initial tamoxifen for 2–3 years should be considered as an optimal standard treatment for this patient population.
To date, aromatase inhibitors given upfront (instead of tamoxifen) for 5 years or given for 2–3 years after 2–3 years of tamoxifen are the standard initial adjuvant endocrine therapy for postmenopausal patients with hormone receptor-positive breast cancer. However, the benefit of extending aromatase inhibitor therapy beyond 5 years in the context of previous aromatase inhibitors, emerged as a clinically relevant question. A multicentre, open-label, randomised, phase III trial now aimed to compare extended therapy with letrozole for 5 years versus the standard duration of 2–3 years of letrozole in postmenopausal patients with breast cancer who have already received 2–3 years of tamoxifen.
The trial was conducted at 69 hospitals in Italy. Eligible patients were randomly allocated (1:1) to receive either 2-3 years of letrozole (control group, N= 1,030) after 2–3 years of tamoxifen or 5 years of letrozole (extended group, N= 1,026) after 2–3 years of tamoxifen. Letrozole was administered at a dose of 2.5 mg orally once a day. Women were eligible if they had met the following criteria; postmenopausal status at the time of study entry, stage I–III histologically proven and operable invasive hormone receptor-positive breast cancer, adjuvant tamoxifen therapy received for at least 2 years but no longer than 3 years and 3 months, no signs of disease recurrence, and Eastern Cooperative Oncology Group performance status of 2 or lower. Male patients were excluded from the trial. Neither participants, nor investigators were masked to treatment assignment.
After a median follow-up of 11.7 years, disease-free survival events occurred in 262 (25.4%) of 1,030 patients in the control group and 212 (20.7%) of 1,026 in the extended group. In the intention-to-treat population, the 12-year disease-free survival rate was significantly higher in the extended group, as compared to the control group (67% vs. 62%, HR[95%CI]: 0.78[0.65–0.93], p= 0.0064). The 12-year overall survival was 84% in the control group and 88% in the extended group (HR[95%CI]: 0.77[0.60-0.98], p= 0.036). Post-hoc analysis of disease-free survival and overall survival at 5 years and 10 years showed no differences between the two groups.
The most common grade 3 and 4 adverse events were arthralgia (2.2% in the control group vs 3.0% in the extended group) and myalgia (0.7% vs. 0.9%, respectively). Osteoporosis occurred in 4.7% of patients in the control group and in 8.3% of patients in the extended group. There was no difference in the incidence of bone fractures, hypercholesteraemia and cardiovascular events. Treatment-related serious adverse events were reported in three (0.3%) patients in the control group (atrial fibrillation, bone pain, and vomiting), and eight (0.8%) patients in the extended group (one pneumonia event, one macular degeneration, four thromboembolic events, and two cardiovascular events). No deaths related to toxic effects were observed.
In postmenopausal patients with breast cancer who received 2–3 years of tamoxifen, extended treatment with 5 years of letrozole resulted in a significant improvement in disease-free survival compared with the standard 2–3 years of letrozole. Sequential endocrine therapy with tamoxifen for 2–3 years followed by letrozole for 5 years should therefore be considered as one of the optimal standard endocrine treatments for postmenopausal patients with hormone receptor-positive breast cancer.
Del Mastro L, Mansutti M, Bisagni G, et al. Extended therapy with letrozole as adjuvant treatment of postmenopausal patients with early-stage breast cancer: a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22:1458-67.