The extended use of aromatase inhibitor therapy beyond 5 years remains controversial. However, a new study found that extending letrozole use significantly improves disease-free survival in postmenopausal patients with breast cancer.
Extended treatment with 5 years of letrozole (Femara) significantly improves disease-free survival in postmenopausal patients with breast cancer who received 2 to 3 years of tamoxifen (Soltamox) compared to those who received the standard 2 to 3 years of letrozole, according to the phase 3 LEAD study published in The Lancet Oncology.
The use of aromatase inhibitor therapy beyond 5 years after previous aromatase inhibitors remains controversial. The phase 3 study (NCT01064635) was designed to determine the efficacy of 5 years of letrozole versus the standard 2 to 3 years.
The interventional, randomized, parallel assignment study had an actual enrollment of 2056 participants with an estimated study completion date of August 2022. The primary end point of the study is disease-free survival after the last patient enters the study. Secondary end points include overall survival and safety.
Patients were randomized 1:1 to receive letrozole for either 2 to 3 years or 5 years.
Patients were recruited from 68 hospitals across Italy. In order to participate, they must be postmenopausal, have stage I-III histologically proven and operable invasive, hormone receptor- positive disease, have received adjuvant tamoxifen therapy for at least 2 years but no longer than 3 years and 3 months, no signs of disease recurrence, and have an ECOG score of 0 to 2.
Of the 2056 patients randomly assigned, 1030 were placed into the control group and 1026 were placed into the experimental group. In the control group, 27 patients did not receive treatment and 224 discontinued treatment. Reasons for discontinuation include refusal (37), adverse events (AEs) (87), early relapse or death (35), and other causes (65). Treatment was completed in 779 patients. In the experimental group, 35 did not receive treatment and 409 discontinued treatment. Reasons for discontinuation included refusal (96), AEs (133), early relapse or death (65), and other causes (115). Treatment was continued in 582 patients.
The median age of patients in the control group was 60 (range, 54-67) and 61 (range, 54-68) in the experimental group. In the control group, tumor sizes included pT1 (68.3%), pT2 (25.3%), pt3-4 (3.3%), and unknown (3%). In the experimental group, tumor sizes included pT1 (68.5%), pT2 (24.6%), pT3-4 (4.2%), and other (2.7%). In the control group, breast-conserving surgery was performed in 75.4% of patients, mastectomy was performed in 22.5% of patients, and unknown surgery was performed in 1.5% of patients. In the experimental arm, 75.2% received breast-conserving surgery, 24% received a mastectomy, and unknown surgery was performed in 0.8% of patients.
Nodal status included pN0 (56.4% in the control group and 55.4% in the experimental group respectively), pN1-2-3 (39.9% vs. 55.4%), and unknown (3.7% vs. 2.9%). Tumor grade was also similar and included G1 (15.1% vs. 15.7%), G2 (54.8% vs. 57.4%), G3 (21.5% vs. 20.8%), and unknown (8.6% vs. 6.1%). Ki67 values included 1-14 (39.4% vs.41.4%), 15-19 (9.3% vs. 10.8%), and ≥20 (25.8% vs. 24.5%).
HR-positivity was seen in 83% of patients in the control arms versus 84.4% of patients in the experimental arm. In the control arm, 6.1% were HER2-positive versus 5.8% of patients in the experimental arm. Previous neoadjuvant or adjuvant chemotherapy was seen in 54.1% of patients in the control arm and 55.1% of patients in the experimental arm. In the control arm, the previous duration of tamoxifen was 2.4 years compared with 2.5 years in the experimental arm. Eighty percent of patients in each arm had a body mass index under 30.
The post-hoc analysis included 1890 patients. Patients with a DFS event or who were lost to follow-up were excluded. The 10-year DFS after treatment divergence was 59% in the control arm (95% CI, 53-64) and 68% in the experimental arm (95% CI, 63-72). At the median follow-up of 11.7 years, DFS events occurred in 23% of all patients. In the control, DFS events occurred in 25.4% if patients compared with 20.7% of patients in the experimental group. The 12-year DFS was 62% (95% CI, 57-66) in the control group and 67% in the experimental group (95% CI, 62-71) (HR 0.78, 95% CI, 0.65-0.93; P =0.0064). The 12-year overall survival was 84% in the control group and 88% in the experimental group.
In terms of safety, 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%). No differences in the rate of bone fractures, hypercholesterolaemia, and cardiovascular events were observed between the two group. No deaths related to toxicity in either arm was observed.
“The observation that the beneficial effect of extended duration of endocrine therapy was more pronounced in patients with node-negative disease in a subgroup analysis should be interpreted with caution because the finding was derived from a post-hoc analysis and this association has been not reported in other similar studies. On one hand, because we only enrolled patients free of recurrence after 2–3 years of tamoxifen, the population with early relapse, who were likely to be node-positive, was excluded, leaving only patients with better prognosis,” wrote the study authors.