Intermittent Extended Letrozole Fails in Postmenopausal Breast Cancer

An intermittent dosing schedule with extended adjuvant letrozole did not improve disease-free survival (DFS) over continuous treatment with the agent in postmenopausal women with hormone receptor–positive breast cancer, according to the randomized phase III SOLE trial.

“The magnitude of the beneficial effect of 5 years of extended letrozole use in postmenopausal women who have previously received an aromatase inhibitor for 5 years is low,” wrote study authors led by Marco Colleoni, MD, of the European Institute of Oncology in Milan, Italy. That small effect may be partially due to acquired resistance, and animal studies suggest that such resistance can be reversed by discontinuing treatment.

The investigators tested whether discontinuing and restarting letrozole might improve outcomes. The trial included 4,884 women (4,851 in the intention-to-treat population), randomized to either continuous letrozole use (2.5 mg/day for 5 years; 2,426 patients) or to intermittent letrozole (2.5 mg/day for 9 months followed by a 3-month break in years 1–4, and 2.5 mg/day for all 12 months of year 5; 2,425 patients). The results were published in Lancet Oncology.

The median age at randomization was 60 years, and the median duration of previous endocrine therapy was 5.0 years.

After a median follow-up period of 60 months, the DFS rates did not differ between the two groups. The 5-year DFS rate was 85.8% with intermittent letrozole, and 87.5% with continuous therapy, for a hazard ratio (HR) of 1.08 (95% CI, 0.93–1.26; P = .31). The sites of DFS events were also no different between the groups, and subgroup analyses showed no differences between the treatments based on age, body mass index, tumor size or grade, estrogen/progesterone receptor or HER2 status of the primary tumor, and other factors. A multivariable analysis confirmed the primary analysis, with an HR of 1.07 (95% CI, 0.92–1.25).

Secondary outcomes also did not differ. There were similar numbers of breast cancer events in each group; 90.9% of intermittent patients were free from breast cancer at 5 years, compared with 91.2% in the continuous group. Distant recurrences were seen in 7% of each group. The HR for overall survival was 0.85 (95% CI, 0.68–1.06; P = .16).

The adverse event profile of letrozole was “as expected” and did not differ significantly between the two groups.

“We conclude that extended treatment with intermittent letrozole did not improve DFS vs treatment with continuous letrozole,” the authors wrote. “The safety, quality-of-life, and efficacy results of the intermittent administration provide clinically relevant information…and support the safety of this option for temporary treatment breaks in selected patients who might require them.”