Intermittent or continuous extended adjuvant endocrine therapy led to virtually identical long-term survival in hormone receptor (HR)-positive breast cancer, according to an updated analysis of a randomized trial.

Disease-free survival (DFS) at 7 years was 81.4% with intermittent extended letrozole and 81.5% with continuous treatment. The results mirrored previously reported 5-year DFS, which also did not differ between the treatment groups (85.8% vs 87.5%). Because the trial tested for superiority of the intermittent dosing schedule, the outcome was negative.

Patients randomized to intermittent dosing had less deterioration of symptom control and quality of life (QoL). That advantage of intermittent dosing, combined with the lack of difference in disease control, offers reassurance to patients who need to interrupt extended treatment, reported Guy Jerusalem, MD, of the University of Liége in Belgium, and colleagues, in the Annals of Oncology.

“The small number of events reported during the additional two years of follow-up demonstrated that the late recurrence rate after endocrine therapy remains relatively low and prolongation of follow-up would be unlikely to demonstrate an advantage of late intermittent therapy,” the author wrote. “[The trial] was not designed as a noninferiority study. Had it been so, the observed confidence intervals of the hazard ratio for DFS with intermittent therapy would fit within the success parameters of most noninferiority trials.”

Background, Trial Design

Jerusalem and colleagues reported findings from 7 years of follow-up in the SOLE trial to evaluate two strategies of extended endocrine therapy after surgery for early HR-positive breast cancer in postmenopausal women. When enrollment in the trial began in 2007, multiple studies of extended adjuvant endocrine therapy were underway. In general, the trials addressed the question of whether additional therapy beyond the standard 5 years would improve long-term outcomes.

The accumulation of evidence has shown that the benefits of extended treatment are modest, especially in terms of reducing the risk of distant metastasis. Because of that, recommendations for 10 years of adjuvant therapy remain controversial, the authors noted.

Beyond comparing the effect of intermittent versus continuous treatment on DFS, the trial examined the impact of temporary treatment cessation on estrogen levels. In some patients with early HR-positive breast cancer, secondary resistance occurs after at least 2 years of endocrine therapy or during the first year after the end of adjuvant therapy, the authors stated.

In animal models, intermittent dosing of letrozole can reverse aromatase inhibitor (AI) resistance. SOLE investigators hypothesized that intermittent dosing during extended treatment with letrozole would reflect the favorable effects AI resistance observed in animal studies and lead to improved DFS, as compared with continuous treatment. To test the hypothesis, they conducted a substudy to evaluate estrogen levels before and during treatment and determine whether the treatment-free interval was sufficient to allow restoration of circulating estrogen levels.

Data analysis for SOLE included 4,851 postmenopausal women who had completed 4 to 6 years of adjuvant endocrine therapy for early breast cancer. They were randomized 1:1 to an additional 5 years of continuous or intermittent (9 months on, 3 months off) treatment with letrozole. The total patient population included 104 patients in the estrogen substudy.

Key Findings

The primary endpoint was 5-year DFS. The analysis showed no significant difference between the treatment groups. At that point, the trial had low rates of DFS events (14%) and breast cancer events (9%). Investigators decided to continue follow-up until 1 year after all patients had completed treatment (median follow-up of 84 months).

With the longer follow-up, DFS remained similar for the two treatment arms (HR 1.03, 95% CI 0.91-1.17). The breast cancer-free interval also was similar (88.6% vs 88.0%), as was the 7-year distant recurrence-free interval (91.6% vs 90.4%) and 7-year OS (90.6% vs 89.6%).

Data for the estrogen substudy showed no significant change in estrogen levels from month 9 to month 12 in patients assigned to continuous treatment. In contrast, estrogen levels rose by 141% from month 9 to month 12 in the patients on intermittent therapy. Recovery in the intermittent group was evident at month 10.5 (123% vs month 9).

Although SOLE failed to meet the primary endpoint, the data showed that intermittent dosing is at least as good as continuous treatment with respect to DFS, said Bora Lim, MD, of Baylor College of Medicine in Houston. The QoL advantages observed with intermittent dosing are particularly relevant given the known side effects of aromatase inhibitors (such as hot flashes and arthralgias).

“In some studies, adherence to aromatase inhibitors is as low as 62%, meaning that 38% of patients might have dropped out because of side effects, some without even telling their doctors,” Lim, who was not involved in the study, told MedPage Today. “Some patients may not even take the full dose of an aromatase inhibitor. Yet, we may continue to see benefit, so we have to ask how important is it for us to continue to push forward.”

The estrogen substudy touched on the biologic effects of estrogen on tumor growth, which is another important issue, she continued.

“We know that if you stop an aromatase inhibitor for a certain period of time, you’re going to see the surge or rebound in estrogen. What does that mean biologically?” said Lim. “Do you think it is beneficial, because some previous studies showed that low estrogen may interfere with cancer growth. So is it beneficial or is it harmful? I think there’s a multifactorial aspect to this and we are looking into this.”

The potential QoL benefits of intermittent dosing are worth a discussion among investigators and practicing oncologists to determine whether it is something that should be adopted in the near future, Lim added. On the other hand, the clinical course of early breast cancer can span 25 to 30 years in some cases. Some people will question whether a 7-year follow-up is adequate to make a change in practice.