The Lancet
Oncology: VOLUME 22,
ISSUE 10, P1458-1467, OCTOBER 01, 2021
Background
The benefit of extending aromatase inhibitor therapy beyond
5 years in the context of previous aromatase inhibitors remains controversial.
We 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.
Methods
This multicentre, open-label, randomised, phase 3 trial was
done at 69 hospitals in Italy. Women were eligible if they were postmenopausal
at the time of study entry, had stage I–III histologically proven and operable
invasive hormone receptor-positive breast cancer, had received adjuvant
tamoxifen therapy for at least 2 years but no longer than 3 years and 3 months,
had no signs of disease recurrence, and had an Eastern Cooperative Oncology
Group performance status of 2 or lower. Patients were randomly assigned (1:1)
to receive 2–3 years (control group) or 5 years (extended group) of letrozole
(2·5 mg orally once a day). Randomisation, with stratification by centre, with
permuted blocks of size 12, was done with a centralised, interactive,
internet-based system that randomly generated the treatment allocation.
Participants and investigators were not masked to treatment assignment. The
primary endpoint was invasive disease-free survival in the intention-to-treat
population. Safety analysis was done for patients who received at least 1 month
of study treatment. This trial was registered with EudraCT, 2005-001212-44,
and ClinicalTrials.gov, NCT01064635.
Findings
Between Aug 1, 2005, and Oct 24, 2010, 2056 patients were
enrolled and randomly assigned to receive letrozole for 2–3 years (n=1030;
control group) or for 5 years (n=1026; extended group). After a median
follow-up of 11·7 years (IQR 9·5–13·1), disease-free survival events occurred
in 262 (25·4%) of 1030 patients in the control group and 212 (20·7%) of 1026 in
the extended group. 12-year disease-free survival was 62% (95% CI 57–66) in the
control group and 67% (62–71) in the extended group (hazard ratio 0·78, 95% CI
0·65–0·93; p=0·0064). The most common grade 3 and 4 adverse events were
arthralgia (22 [2·2%] of 983 patients in the control group vs 29
[3·0%] of 977 in the extended group) and myalgia (seven [0·7%] vs nine
[0·9%]). There were three (0·3%) serious treatment-related adverse events in
the control group and eight (0·8%) in the extended group. No deaths related to
toxic effects were observed.
Interpretation
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 be considered as one of
the optimal standard endocrine treatments for postmenopausal patients with
hormone receptor-positive breast cancer.
