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Background: Late recurrences in postmenopausal women with hormone receptor-positive breast cancers remain an important challenge. Avoidance or delayed development of resistance represents the main objective in extended endocrine therapy (ET). In animal models, resistance was reversed with restoration of circulating estrogen levels during interruption of letrozole treatment. This phase III, randomized, open-label Study of Letrozole Extension (SOLE) studied the effect of extended intermittent letrozole treatment in comparison with continuous letrozole. In parallel, the SOLE estrogen substudy (SOLE-EST) analyzed the levels of estrogen during the interruption of treatment., Patients and Methods: SOLE enrolled 4884 postmenopausal women with hormone receptor-positive, lymph node-positive, operable breast cancer between December 2007 and October 2012 and among them, 104 patients were enrolled in SOLE-EST. They must have undergone local treatment and have completed 4-6 years of adjuvant ET. Patients were randomized between continuous letrozole (2.5 mg/day orally for 5 years) and intermittent letrozole treatment (2.5 mg/day for 9 months followed by a 3-month interruption in years 1-4 and then 2.5 mg/day during all of year 5)., Results: Intention-to-treat population included 4851 women in SOLE (n = 2425 in the intermittent and n = 2426 in the continuous letrozole groups) and 103 women in SOLE-EST (n = 78 in the intermittent and n = 25 in the continuous letrozole groups). After a median follow-up of 84 months, 7-year disease-free survival (DFS) was 81.4% in the intermittent group and 81.5% in the continuous group (hazard ratio: 1.03, 95% confidence interval: 0.91-1.17). Reported adverse events were similar in both groups. Circulating estrogen recovery was demonstrated within 6 weeks after the stop of letrozole treatment., Conclusions: Extended adjuvant ET by intermittent administration of letrozole did not improve DFS compared with continuous use, despite the recovery of circulating estrogen levels. The similar DFS coupled with previously reported quality-of-life advantages suggest intermittent extended treatment is a valid option for patients who require or prefer a treatment interruption., Competing Interests: Disclosure GJ reported receiving contracted research support from Novartis within the submitted work; personal fees from Daiichi Sankyo and Abbvie; non-financial support from Medimmune and Merck KGaA; personal fees and non-financial support from Lilly, Amgen, Bristol Myers Squibb (BMS), AstraZeneca; and grants, personal fees and non-financial support from Novartis, Roche, and Pfizer from outside submitted work. PK reported receiving non-financial support from PFS Genomics; and honoraria from Prelude Dx and Roche (all outside the submitted work). PN reported receiving institutional payments or non-financial support from Novartis, Pfizer, Lilly, Amgen, and Roche. ES reported receiving advisory fees and a traveling grant from Pfizer, Genomic Health, Lilly, and Novartis. CK reported receiving consulting or advisory fees from Roche, Pfizer, AstraZeneca, and Daiichi-Sankyo. SL reported receiving salary from GBG Forschungs GmbH; consulting fees (to institution) from BMS, Roche, Puma, Seattle Genetics, AstraZeneca, Novartis, Lilly, Pfizer, Daiichi, EirGenix, and Samsung; contracted research support from Austrian Breast & Colorectal Study Group, AstraZeneca, Amgen, Celgene, Daiichi, Immunomedics, NSABP Foundation, Novartis, Pfizer, and Roche. KK reported receiving honoraria from Taiho Pharmaceutical, Eisai, and Chugai Pharmaceutical. CM reported receiving honoraria from Novartis. SOR reported receiving honoraria from Novartis. TR reported receiving consulting fees/honoraria from Roche–Genentech, Novartis, Lilly, AstraZeneca, and Pfizer. GV reported receiving consulting or advisory fees from Novartis, Roche-Genentech, MSD Oncology, Pfizer, and AstraZeneca. RDG reported receiving research funding (to institution) from Novartis, Pfizer, Ipsen, Merck, Celgene, Ferring, Roche, and AstraZeneca to partially support his salary. SL reported receiving research funding (to institution) from Novartis, BMS, Merck, Roche–Genentech, Puma Biotechnology, Pfizer, Eli Lilly, Nektar Therapeutics, AstraZeneca, and Seattle Genetics; serving as a consultant (not compensated) for Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca, and Roche–Genentech; serving as a consultant (paid to institution) for Aduro Biotech, Novartis, GlaxoSmithKline, Roche–Genentech, Puma Biotechnology, AstraZeneca, Silverback Therapeutics, and G1 Therapeutics; serving as a Scientific Advisory Board Member of Akamara Therapeutics; and receiving support from the National Breast Cancer Foundation of Australia Endowed Chair and the Breast Cancer Research Foundation, New York. MMR reported receiving research funding (to institution) from Novartis, Pfizer, AstraZeneca, Ipsen, TerSera, Pierre Fabre, Merck, Roche, BMS, and Bayer, consulting fees (to institution) from BMS, Ipsen; and consulting fees/honoraria from BMS, Tolmar Pharmaceuticals. MC reported receiving research funding (to institution) from Roche. All other authors have declared no conflicts of interest., (Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)