DFS Benefit Similar With Extended Intermittent or Continuous Letrozole in HR+ Breast Cancer

Extended adjuvant endocrine therapy via intermittent administration of letrozole did not improve disease-free survival vs continuous use in postmenopausal patients with hormone receptor–positive breast cancer, but represents a valid approach for those who require or prefer a treatment interruption.

Extended adjuvant endocrine therapy via intermittent administration of letrozole did not improve disease-free survival vs continuous use in postmenopausal patients with hormone receptor (HR)–positive breast cancer, but represents a valid approach for those who require or prefer a treatment interruption, according to data from the phase 3 SOLE trial (NCT00553410) and the SOLE-EST substudy (NCT01281137) published in the Annals of Oncology.1

Results showed that among the intent-to-treat (ITT) populations from SOLE (n = 4851) and SOLE-EST (n = 103), the estimated 7-year disease-free survival (DFS) rate was 81.4% (95% CI, 79.0%-83.0%) in the intermittent cohort vs 81.5% (95% CI, 79.8%-83.1%) in the continuous cohort (HR, 1.03; 95% CI, 0.91%-1.17%).

“Despite a large number of patients enrolled on this study, the small proportion of DFS events observed during the follow-up time did not reveal differences between treatment groups,” Guy Jerusalem, MD, PhD, of Universitaire du Sart Tilman, and colleagues, wrote. “Clinically, the association of similar outcomes with modest improvements in quality of life will be reassuring to patients and clinicians who may for various reasons need or choose to interrupt extended adjuvant therapy.”

Late recurrences experienced by postmenopausal women with HR-positive breast cancer led to the extension of adjuvant endocrine therapy with agents like letrozole, from 5 years to 10 years. However, the benefit produced with extended treatment, particularly after previous use of aromatase inhibitors in the adjuvant setting, have been modest—specifically in terms of reducing the incidence of distant metastases. Studies performed in animal models have shown that resistance to AIs could be reversed with intermittent administration of letrozole because estrogen levels were found to be restored during treatment interruption.

As such, investigators launched the SOLE study to examine continuous letrozole given for 5 years vs intermittent letrozole administered over a 5-year period in postmenopausal women who were disease free after having previously received 4 to 6 years of adjuvant endocrine therapy. The trial sought to prove that 3-month treatment-free intervals during the 5-year period of receiving letrozole would result in improved DFS.

The SOLE-EST substudy was launched to examine changes in circulating estrogen levels before and during the interruption period, as well as its relationship with baseline clinical factors, quality of life, and grip strength. The hypothesis was that during the interruption period, the circulating estrogen levels would restore, as they did in the animal models.

The multinational, open-label, randomized SOLE trial was conducted at 240 Breast International Group-affiliated centers throughout 22 countries. To be eligible for enrollment, premenopausal patients needed to have unilateral, lymph node–positive, steroid HR–positive, operable breast cancer and be disease free at the time of enrollment with no evidence of recurrence prior to randomization. Patients were also required to have completed 4 to 6 years of prior treatment with adjuvant endocrine therapy. A total of 4884 patients were enrolled between 2007 and 2012.

The SOLE-EST study was conducted at 14 centers in Belgium, Australia, and Italy, and enrolled 104 patients between 2011 and 2012. Any patient eligible to participate in the SOLE trial was offered enrollment to the substudy, although it was not mandatory.

Those enrolled on the SOLE trial were randomized 1:1 to the continuous arm where they received oral letrozole at a daily dose of 2.5 mg for 5 years, or the intermittent arm where they were given oral letrozole at a daily dose of 2.5 mg for 9 months followed by 3 months of interruption in years 1 through 4, and a daily dose of 2.5 mg in year 5. For the SOLE-EST substudy, patients who underwent randomization to the continuous or intermittent arms in the SOLE trial were enrolled in a 1:3 ratio.

The primary end point of the SOLE trial was DFS. Secondary end points included breast cancer-free interval (BCFI), distant recurrence-free interval (DRFI), and overall survival (OS). For SOLE-EST, primary end points included the percentage of change in 17β-estradiol (E2) estrogen levels from baseline at 9 months, 10.5 months, and 12 months from randomization, as well as the percentage change in E2 from 9 months to 10.5 months and 12 months to characterize E2 recovery following treatment interruption. Secondary assessments focused on looking for associations between baseline characteristics, quality of life score changes, and grip strength changes with recovery of E2 levels.

Of the 4851 patients in the ITT population for the SOLE study, 2426 were randomized to the continuous arm and 2425 were randomized to the intermittent arm.

The median age of patients enrolled in both trials was 60 years (range, 53-69), and the majority were overweight or obese (58.4% in SOLE, 62.1% in SOLE-EST). More patients in the SOLE-EST population had received an aromatase inhibitor as their most recent prior endocrine therapy vs the SOLE population, at 92.2% vs 79.4%. Additionally, the duration of time from the end of prior therapy to randomization was comparable. Specifically, 71.2% of those on SOLE had 1 month or less of treatment interruption vs 78.6% in SOLE-EST.

The median follow-up for both SOLE and SOLE-EST was 84 months. Additional data from the SOLE study showed that the estimated 7-year BCFI was 88.6% (95% CI, 87.2%-89.9%) in the intermittent arm vs 88.0% (95% CI, 86.5%-89.3%) in the continuous arm (HR, 0.99; 95% CI, 0.84-1.17). Moreover, the estimated 7-year DRFI in the intermittent and continuous arms was 91.6% (95% CI, 90.4%-92.7%) and 90.4% (95% CI, 89.1%-91.6%), respectively (HR, 0.91; 95% CI, 0.76-1.10). The estimated 7-year OS was 90.6% (95% CI, 89.3%-91.8%) in the intermittent arm compared with 89.6% (95% CI, 88.2%-90.8%) in the continuous arm.

Subgroup analyses showed that the DRFI tended to be better in the intermittent arm if the most recent prior endocrine therapy received was an aromatase inhibitor and if the agent was given for a longer duration. DRFI tended to be worse in the intermittent arm if they received a recent selective estrogen receptor modulator, had a shorter duration of an aromatase inhibitor, or were very young.

In SOLE-EST, investigators collected blood samples from 103 patients at baseline. Levels of E2, E1, and E1S demonstrated variability according to select characteristics, as anticipated. A lower circulating E2 concentration was observed in older women, those who most recently received an aromatase inhibitor, who had a longer duration of treatment with an aromatase inhibitor, or who more recently stopped previous endocrine therapy. Moreover, E2 was found to be slightly higher in women who were overweight.

Ninety of these patients—21 in the continuous arm, 69 in the intermittent arm—were included in analyses of hormone levels over time. Reductions in median estrogen levels from randomization to 9 months of letrozole treatment were comparable between the arms. Th median levels of E2, E1, and E1S were 30%, 60%, and 35%, respectively.

At 12 months, those in the intermittent arm experienced recovered estrogen concentration; those in the continuous arm had the same reduction of estrogen as they did at the 9-month time point. Moreover, an increase in E2 was noted as early as 10.5 months. Women who were overweight or obese were observed to have a better recovery of E2 level during treatment interruption with letrozole than those who were of a normal weight. These patients also had a bigger decrease in E2 between baseline and 9 months.


  1. Jerusalem G, Farah S, Courtois A, et al. Continuous vs intermittent extended adjuvant letrozole for breast cancer: final results of randomized phase 3 SOLE (study of letrozole extension) and SOLE estrogen substudy. Ann Oncol. Published online August 9, 2021. doi:10.1016/j.annonc.2021.07.017