Five years of extended treatment with the aromatase inhibitor letrozole significantly improved disease-free survival (DFS) compared with the standard duration of 2 to 3 years in postmenopausal patients with breast cancer who had already received 2 to 3 years of tamoxifen, according to results from a phase III trial.
After a median follow-up of 11.7 years, DFS events occurred in 20.7% of patients in the extended group and 25.4% of patients in the control group. The 12-year DFS rates were 67% and 62%, respectively (HR 0.78, 95% CI 0.65-0.93, P=0.0064), reported Lucia Del Mastro MD, of the University of Genoa in Italy.
This reduction in the risk of disease recurrence demonstrated in the extended group did not change in a multivariate Cox model (HR 0.79, 95% CI 0.66-0.95, P=0.014), and was consistent across subgroups, she added.
The 12-year overall survival rates were 88% in the extended group and 84% in the control group (HR 0.77, 95% CI 0.60-0.98, P=0.036).
“This regimen can be considered as one of the optimal standard endocrine treatments for postmenopausal patients with hormone receptor-positive breast cancer,” Del Mastro said during a presentation at the virtual annual congress of the European Society for Medical Oncology.
The study was simultaneously published in Lancet Oncology.
Del Mastro and colleagues noted that the optimal duration of extended therapy remains unclear because of differences in duration among competing studies addressing this question. However, she pointed out that the IDEAL and ABCSG-16 trials demonstrated that extended therapy for 10 years was not superior to 7-8 years.
“We can consider the duration of 7 to 8 years as the optimal duration of extended therapy, with a good compromise between efficacy and toxicity,” she noted.
The trial “provides additional strong evidence to support extended aromatase inhibitor treatment in postmenopausal patients for a total duration of 7 to 8 years,” agreed designated discussant Monica Arnedos, MD, PhD, of Institut Bergonié in Bordeaux, France.
GIM4 was a multicenter, open-label, randomized, phase III trial conducted at 69 hospitals across Italy. Women were eligible if they were postmenopausal at the time of study entry, had stage I to III histologically proven and operable invasive hormone receptor-positive breast cancer, 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.
From Aug. 1, 2005 to Oct. 24, 2010, 2,056 patients (median age 61) were randomly assigned to receive either 5 years of letrozole (n=1,026; extended group) or 2 to 3 years of letrozole (n=1,030; control group) after 2 to 3 years of tamoxifen.
Del Mastro and colleagues also performed a post-hoc landmark analysis that excluded patients with a DFS event or those lost to follow-up before treatment divergence. The 10-year DFS rate after treatment divergence was 68% in the extended group versus 59% in the control group (HR 0.73, 95% CI 0.60-0.90, P=0.0022).
As for toxicity, the most common grade 3 and 4 adverse events were arthralgia (3.0% in the extended group vs 2.2% in the control group) and myalgia (0.9% vs 0.7%, respectively).
Arnedos noted that 37% of patients in the extended arm and 19% in the control arm discontinued treatment early. “We have important issues with compliance,” she observed. “It is important to invest in programs that try to provide the necessary support for patients to go through the endocrine treatment and improve adherence.”
In an accompanying commentary, Rachel Yung, MD, and Nancy Davidson, MD, both of the Fred Hutchinson Cancer Research Center in Seattle, suggested that another area of focus should be on identifying biomarkers that could better inform the optimal duration of therapy.
“Current strategies test the tumor at diagnosis, which does not account for subsequent modifiable factors such as adherence or lifestyle effects,” they wrote. “Other approaches, such as detection of circulating tumor cells or circulating tumor DNA several years after diagnosis, which are prognostic for late recurrence, could be evaluated as predictors for the benefit of extended therapy.”
This study was funded by Novartis, which provided the letrozole. This work was also supported by grants from the Italian Ministry of Health.
Del Mastro reported receiving honoraria and non-financial support from Roche, Novartis, Pfizer, Merck Sharp & Dohme, Genomic Health, Takeda, Ipsen, Eisai, Eli Lilly, Celgene, Pierre Fabre, Seagen, Daiichi Sankyo, Exact Sciences, and Amgen.
Other co-authors reported multiple relationships with industry.
Arnedos reported relationships with Novartis, AstraZeneca, Pfizer, and Roche.
Yung and Davidson reported no disclosures.