Extended Adjuvant Intermittent Letrozole Versus Continuous Letrozole

Extended Adjuvant Intermittent Letrozole Versus Continuous Letrozole in Postmenopausal Women With Breast Cancer (SOLE): A Multicentre, Open-Label, Randomised, Phase 3 trial

Colleoni M, Luo W, Karlsson P, et al; SOLE Investigators
Lancet Oncol. 2018;19:127-138

Study Summary

The optimal duration of adjuvant therapy for postmenopausal women with estrogen receptor-positive (ER+) early-stage breast cancer is unknown. Adjuvant therapy with aromatase inhibitors (AIs) after 5 years of tamoxifen has been shown to improve outcomes. However, the magnitude of benefit for women who were previously treated with AIs has not been well characterized, with one study (the MA.17R trial) showing a possible benefit^[1] and another (NSABP B-42) showing no improvement.^[2] In addition, animal models of breast cancer have shown that resistance to AIs can be overcome by withdrawal of therapy followed by reintroduction.

The SOLE study was designed to explore whether extended intermittent use of an AI, letrozole, would improve breast cancer outcomes compared with continuous use in postmenopausal women. It was a multicenter, open-label, phase 3 randomized, controlled trial that enrolled 4884 women between 2007 and 2012 at 240 sites in 22 countries. Participants were postmenopausal women with ER+, node-positive breast cancer who had undergone local therapy and had completed 4-6 years of adjuvant therapy and clinically had "no evidence of disease." Women were randomly assigned to a continuous schedule or to an intermittent schedule consisting of 9 months of use, followed by a 3-month drug holiday for years 1-4 and continuous use for year 5 of the study. The primary endpoint was disease-free survival.

Of the enrolled women, 4851 comprised the intention-to-treat population and were randomly assigned to continuous versus intermittent use of letrozole for 5 years. After a median follow-up of 60 months, disease-free survival was 86% in the intermittent group and 87.5% in the continuous group, and the difference was not statistically significant. There were no significant differences in serious adverse events.

The investigators concluded that extended use of AIs on a continuous versus intermittent schedule yielded similar outcomes in terms of reduction of recurrence risk, and no significant differences in adverse events were noted. This schedule presents an interesting option for postmenopausal women with ER+ breast cancer who could benefit from treatment breaks.

Viewpoint

The SOLE trial is the first study to directly compare extended intermittent letrozole use with extended continuous letrozole use. This study showed that in postmenopausal women with ER+ breast cancer, extended use of letrozole (defined as endocrine therapy given after completion of 4-6 years of an AI or tamoxifen) is feasible and represents an option for women who may benefit from periodic built-in breaks in treatment schedules to overcome common side effects of therapy.

The investigators hypothesized that they would see benefits from intermittent therapy and were disappointed to see no effect. That said, their study has now created an option for clinicians and patients treated with upfront AIs, who are debating whether or not to extend adjuvant endocrine therapy past the 5-year point, in the absence of clear demonstration of benefit from prior trials.

This study differs from previous studies that included women at lower risk, because it enrolled only women who were node-positive at diagnosis. The investigators point out that their study included three patient cohorts defined by prior adjuvant endocrine therapy. Randomization was stratified according to prior use of selective estrogen receptor modulators (SERMs) only, AIs only, or both SERMs and AIs used in a sequential fashion. For the subgroup who had previously used only an AI, the data shows that extension with intermittent letrozole use had a pattern toward reduced risk for breast cancer events and death compared with continuous letrozole. No effect was seen for those who had been exposed to SERMs and AIs, and a detrimental effect was noted for those who had previously been only on a SERM.

These results support the use of "pauses" in treatment for patients whose previous adjuvant therapy included an AI. This study, and the accompanying editorial by Chlebowski and Pan,^[3] remind us of the complexity of responses to therapy for women with ER+ breast cancer, especially those who received a diagnosis when they were pre- or perimenopausal and for whom the optimal timing and combination of endocrine therapy is still a matter of controversy.