Intermittent Regimen ‘Feasible’ For Adjuvant Letrozole

Extending adjuvant endocrine therapy with letrozole achieves similar disease-free survival whether given continuously or on an intermittent schedule

medwireNews: Extended adjuvant treatment using intermittent rather than continuous letrozole does not alter disease-free survival (DFS) in postmenopausal women with hormone receptor (HR)-positive, lymph-node-positive operable breast cancer, SOLE trial findings indicate.

The results did not support earlier animal study findings indicating treatment withdrawal can reverse letrozole resistance, explain Marco Colleoni, from the European Institute of Oncology in Milan, Italy, and co-workers in The Lancet Oncology.

But they believe that the trial has shown that an intermittent letrozole regimen is “feasible” and “represents a possible option in selected patients who could benefit from temporary treatment breaks – namely, those who have side-effects during extended endocrine treatment.”

The phase III trial included 4884 women who were free from breast cancer after undergoing surgery with or without radiotherapy, followed by 4–6 years of adjuvant endocrine therapy with an oestrogen receptor modulator and/or an aromatase inhibitor.

After a median follow-up of 60 months, DFS was 85.8% for the 2425 women who had been randomly assigned to receive letrozole 2.5 mg/day for 9 months followed by a 3-month break for the first 4 years of treatment, followed by continuous therapy in year 5.

This did not significantly differ from the 87.5% DFS rate achieved by the 2426 patients who were given letrozole 2.5 mg/day continuously over 5 years, report the SOLE investigators.

The authors observe that the treatment interruption was chosen arbitrarily, that up to 16% of patients in the intermittent group did not pause treatment each year, and that duration of follow-up may be insufficient to show a difference.

In addition, Rowan Chlebowski, from the City of Hope National Medical Center in Duarte, California, USA, and Kathy Pan, from the Los Angeles Biomedical Research Institute in Torrance, California, write in an accompanying comment that the biochemical definition of postmenopausal status used in the trial means that patients who had previously used only tamoxifen might have regained ovarian function with or without resuming menses.

“Premenopausal oestrogen concentration would then probably preclude any letrozole anticancer effect in either randomisation group”, they suggest, adding that the maximum duration of oestrogen deprivation in tamoxifen-only users was 9 months before letrozole was paused, whereas aromatase inhibitor users may have had up to 7 years of oestrogen deprivation before their first 3-month break.

“Whether or not that relatively short 3-month interruption would be sufficient to drive the suggestion of benefit in the intermittent letrozole group is a question that could be explored in post-hoc analyses”, the commentators write.

Nevertheless, the study investigators say that adverse events were “as expected” and comparable in the intermittent and continuous letrozole treatment arms. Hypertension (24 vs 21%) and arthralgia (6 vs 6%) were the most common grade 3–5 events.

Furthermore, a quality of life substudy with 956 of the SOLE participants revealed a small but consistent pattern in the first 12 months of treatment among those on intermittent therapy, indicating fewer changes in patient-reported symptoms and quality of life indicators for than those using continuous letrozole.

These included significantly less worsening in vaginal problems, musculoskeletal pain, sleep disturbance, physical wellbeing and mood. And after 24 months, intermittent letrozole was associated with greater improvements in hot flushes than continuous treatment.

“The intermittent administration of extended adjuvant letrozole is an attractive approach considering potentials for reduced economic cost and improved quality of life”, conclude Marco Colleoni et al.

However, they caution that findings for extending endocrine therapy with letrozole may be relevant only to women at intermediate or high risk of relapse: “The magnitude of the beneficial effect of extended letrozole use in postmenopausal women who previously received an aromatase inhibitor during the first 5 years is low and should be weighed against the side-effects.”


Colleoni M, Luo W, Karlsson P, et al. Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer (SOLE): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol; Advance online publication 17 November 2017. DOI:

Chlebowski RT, Pan K. Complexity of intermittent letrozole adjuvant therapy. Lancet Oncol; Advance online publication 17 November 2017. DOI:

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