Final results of the Study of Letrozole Extension (SOLE) indicate that treatment with intermittent letrozole did not show superiority in terms of disease-free survival (DFS) compared with continuous treatment in the extended adjuvant setting for postmenopausal women with hormone receptor-positive breast cancers. In SOLE Estrogen Substudy, circulating oestrogen level was restored 6 weeks after interruption of extended treatment with letrozole. Clinically, the association of similar outcomes with modest improvements in quality of life (QoL) is reassuring to patients and clinicians, who may for various reasons need or choose to interrupt extended adjuvant treatment, according to Prof. Guy Jerusalem of the CHU Liège and Liège University in Liège, Belgium and the SOLE investigators who published the study findings on 9 August 2021 in the Annals of Oncology.

Late recurrences in postmenopausal women with hormone receptor-positive breast cancer led to studying extension of adjuvant endocrine treatment. In 2007 when the SOLE was started, the benefit of extending adjuvant endocrine treatment to 10 years was under evaluation in different phase III international clinical studies. However, the benefit of extended treatment is rather modest, especially in terms of reduction of distant metastases, and the recommendations for 10 years of adjuvant treatment remain controversial.

The authors explained in the study background that avoidance or delayed development of resistance represents the main objective of extended endocrine treatment. Animal model studies showed that resistance can be reversed by intermittent treatment suggesting the prolongation of the tumour cells sensitivity due to the restoration of oestrogens level during the interruption of the treatment.

Based on these data, the International Breast Cancer Study Group (IBCSG) launched the SOLE, a multinational, open-label, phase III randomised study in 240 centres of the Breast International Group-affiliated cooperative groups from 22 countries. It was designed to compare continuous letrozole for 5 years with intermittent letrozole over a 5-year period among postmenopausal women who were disease-free following 4 to 6 years of prior adjuvant endocrine treatment with selective oestrogen receptor modulator and/or aromatase inhibitor for endocrine-responsive, node-positive operable breast cancer.

The hypothesis was that introducing 3-month treatment-free intervals during the course of 5 years of extended letrozole would reflect the results seen in animal models and improve DFS. Thus, the statistical design tested rather superiority than non-inferiority.

In 2017, the study primary analysis after 5 years median follow-up showed that extended intermittent treatment with letrozole did not improve DFS compared with continuous treatment.

SOLE Estrogen Substudy was activated in three countries (Belgium, Australia and Italy). It was conducted to document changes in circulating oestrogen levels before and during the initial 3-month treatment interruption and its relationship with some baseline clinical factors, QoL and grip strength. Results of this substudy are presented now for the first time and represent the first study to measure the modification of circulating oestrogen levels during an interruption of extended endocrine treatment in patients with breast cancer.

SOLE enrolled 4884 postmenopausal women with hormone receptor-positive, lymph node-positive, operable breast cancer between December 2007 and October 2012. Among them, 104 patients were enrolled in SOLE Estrogen Substudy. It was required that included patients undergone local treatment and have completed 4-6 years of adjuvant endocrine treatment. Patients were randomised between continuous letrozole 2.5 mg/day orally for 5 years and intermittent letrozole 2.5 mg/day during 9 months followed by a 3-month interruption in years 1-4 and then 2.5 mg/day during the year 5.

Intention-to-treat population included 4851 women in SOLE, of whom 2425 in intermittent and 2426 in continuous letrozole groups, and 103 women in SOLE Estrogen Substudy, of whom 78 in intermittent and 25 in continuous letrozole groups.

After a median follow-up of 84 months, 7-year DFS was 81.4% in intermittent and 81.5% in continuous groups (hazard ratio 1.03; 95% confidence interval 0.91-1.17).

Reported side effects were similar in both groups, prompted the study team to conclude that extended treatment with intermittent letrozole is safe for postmenopausal women with hormone receptor-positive breast cancers.

Circulating oestrogen level was restored 6 weeks after interruption of extended treatment with letrozole.

The authors concluded that extended adjuvant endocrine treatment with intermittent administration of letrozole did not improve DFS compared to its continuous use despite the recovery of circulating oestrogen level. However, similar DFS coupled with previously reported advantages in QoL suggest that extended intermittent treatment is a valid option for patients who need or prefer a treatment interruption.

SOLE received financial support for study conduction from Novartis and the IBCSG. Novartis provided drug supply. The coordinating study group, IBCSG was supported by Frontier Science and Technology Research Foundation, Swiss Group for Clinical Cancer Research, Cancer Research Switzerland, Oncosuisse, Cancer League Switzerland and the Foundation for Clinical Cancer Research of Eastern Switzerland. SOLE Estrogen Substudy was partially funded by the Belgian Foundation Against Cancer, Breast Cancer Trials Australia and New Zealand and Susan G. Komen for the Cure.


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. Annals of Oncology; Published online 9 August 2021. DOI: