Journal Article
. 2017 Nov; 19(1):127-138.
doi: 10.1016/S1470-2045(17)30715-5.

Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer (SOLE): a multicentre, open-label, randomised, phase 3 trial

Marco Colleoni 1 Weixiu Luo 2 Per Karlsson 3 Jacquie Chirgwin 4 Stefan Aebi 5 Guy Jerusalem 6 Patrick Neven 7 Erika Hitre 8 Marie-Pascale Graas 9 Edda Simoncini 10 Claus Kamby 11 Alastair Thompson 12 Sibylle Loibl 13 Joaquín Gavilá 14 Katsumasa Kuroi 15 Christian Marth 16 Bettina Müller 17 Seamus O'Reilly 18 Vincenzo Di Lauro 19 Andrea Gombos 20 Thomas Ruhstaller 21 Harold Burstein 22 Karin Ribi 23 Jürg Bernhard 24 Giuseppe Viale 25 Rudolf Maibach 23 Manuela Rabaglio-Poretti 26 Richard D Gelber 27 Alan S Coates 28 Angelo Di Leo 29 Meredith M Regan 30 Aron Goldhirsch 31 SOLE Investigators  
Affiliations
  • PMID: 29158011
  •     22 citations

Abstract

Background: In animal models of breast cancer, resistance to continuous use of letrozole can be reversed by withdrawal and reintroduction of letrozole. We therefore hypothesised that extended intermittent use of adjuvant letrozole would improve breast cancer outcome compared with continuous use of letrozole in postmenopausal women.

Methods: We did the multicentre, open-label, randomised, parallel, phase 3 SOLE trial in 240 centres (academic, primary, secondary, and tertiary care centres) in 22 countries. We enrolled postmenopausal women of any age with hormone receptor-positive, lymph node-positive, and operable breast cancer for which they had undergone local treatment (surgery with or without radiotherapy) and had completed 4-6 years of adjuvant endocrine therapy. They had to be clinically free of breast cancer at enrolment and without evidence of recurrent disease at any time before randomisation. We randomly assigned women (1:1) to treatment groups of either continuous use of letrozole (2·5 mg/day orally for 5 years) or intermittent use of letrozole (2·5 mg/day orally for 9 months followed by a 3-month break in years 1-4 and then 2·5 mg/day during all 12 months of year 5). Randomisation was done by principal investigators or designee at respective centres through the internet-based system of the International Breast Cancer Study Group, was stratified by type of previous endocrine therapy (aromatase inhibitors only vs selective oestrogen receptor modulators only vs both therapies), and used permuted block sizes of four and institutional balancing. No one was masked to treatment assignment. The primary endpoint was disease-free survival, analysed by the intention-to-treat principle using a stratified log-rank test. All patients in the intention-to-treat population who initiated protocol treatment during their period of trial participation were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00553410, and EudraCT, number 2007-001370-88; and long-term follow-up of patients is ongoing.

Findings: Between Dec 5, 2007, and Oct 8, 2012, 4884 women were enrolled and randomised after exclusion of patients at a non-adherent centre, found to have inadequate documentation of informed consent, immediately withdrew consent, or randomly assigned to intervention groups in error. 4851 women comprised the intention-to-treat population that compared extended intermittent letrozole use (n=2425) with continuous letrozole use (n=2426). After a median follow-up of 60 months (IQR 53-72), disease-free survival was 85·8% (95% CI 84·2-87·2) in the intermittent letrozole group compared with 87·5% (86·0-88·8) in the continuous letrozole group (hazard ratio 1·08, 95% CI 0·93-1·26; p=0·31). Adverse events were reported as expected and were similar between the two groups. The most common grade 3-5 adverse events were hypertension (584 [24%] of 2417 in the intermittent letrozole group vs 517 [21%] of 2411 in the continuous letrozole group) and arthralgia (136 [6%] vs 151 [6%]). 54 patients (24 [1%] in the intermittent letrozole group and 30 [1%] in the continuous letrozole group) had grade 3-5 CNS cerebrovascular ischaemia, 16 (nine [<1%] vs seven [<1%]) had grade 3-5 CNS haemorrhage, and 40 (19 [1%] vs 21 [1%]) had grade 3-5 cardiac ischaemia. In total, 23 (<1%) of 4851 patients died while on trial treatment (13 [<1%] of 2417 patients in the intermittent letrozole group vs ten [<1%] of 2411 in the continuous letrozole group).

Interpretation: In postmenopausal women with hormone receptor-positive breast cancer, extended use of intermittent letrozole did not improve disease-free survival compared with continuous use of letrozole. An alternative schedule of extended adjuvant endocrine therapy with letrozole, including intermittent administration, might be feasible and the results of the SOLE trial support the safety of temporary treatment breaks in selected patients who might require them.

Funding: Novartis and the International Breast Cancer Study Group.

Update Breast Cancer 2018 (Part 1) - Primary Breast Cancer and Biomarkers.
Florin-Andrei Taran, Andreas Schneeweiss, +19 authors, Florian Schütz.
Geburtshilfe Frauenheilkd, 2018 Mar 27; 78(3). PMID: 29576629    Free PMC article.
Current Status of Extended Adjuvant Endocrine Therapy in Early Stage Breast Cancer.
Irene E G van Hellemond, Sandra M E Geurts, Vivianne C G Tjan-Heijnen.
Curr Treat Options Oncol, 2018 Apr 29; 19(5). PMID: 29704066    Free PMC article.
Review.
Optimal management of luminal breast cancer: how much endocrine therapy is long enough?
Elisabetta Munzone, Marco Colleoni.
Ther Adv Med Oncol, 2018 Jul 07; 10. PMID: 29977350    Free PMC article.
Review.
Aromatase inhibitors and risk of cardiovascular events in breast cancer patients: a systematic review and meta-analysis.
Yang He, Jianhua Zhang, +5 authors, Dongsheng Hong.
BMC Pharmacol Toxicol, 2019 Oct 31; 20(1). PMID: 31665091    Free PMC article.
Systematic Review.
Successful Targeted Therapies for Breast Cancer: the Worcester Foundation and Future Opportunities in Women's Health.
Balkees Abderrahman, V Craig Jordan.
Endocrinology, 2018 Jun 23; 159(8). PMID: 29931061    Free PMC article.
Review.
Quality of life under extended continuous versus intermittent adjuvant letrozole in lymph node-positive, early breast cancer patients: the SOLE randomised phase 3 trial.
Karin Ribi, Weixiu Luo, +27 authors, SOLE Investigators.
Br J Cancer, 2019 Apr 11; 120(10). PMID: 30967649    Free PMC article.
Patient Experience Captured by Quality-of-Life Measurement in Oncology Clinical Trials.
Alyson Haslam, Diana Herrera-Perez, Jennifer Gill, Vinay Prasad.
JAMA Netw Open, 2020 Mar 05; 3(3). PMID: 32129865    Free PMC article.
Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG Oncology/NSABP B-42): a randomised, double-blind, placebo-controlled, phase 3 trial.
Eleftherios P Mamounas, Hanna Bandos, +17 authors, Norman Wolmark.
Lancet Oncol, 2018 Dec 05; 20(1). PMID: 30509771    Free PMC article.
Breast cancer: are long-term and intermittent endocrine therapies equally effective?
Jutta Engel, Gabriele Schubert-Fritschle, Rebecca Emeny, Dieter Hölzel.
J Cancer Res Clin Oncol, 2020 May 31; 146(8). PMID: 32472445    Free PMC article.
Review.
Management of hormone receptor-positive, HER2-negative early breast cancer.
Elaine M Walsh, Karen L Smith, Vered Stearns.
Semin Oncol, 2020 Jun 18; 47(4). PMID: 32546323    Free PMC article.
Review.
AGO Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2019.
Nina Ditsch, Michael Untch, +42 authors, Achim Wöckel.
Breast Care (Basel), 2019 Sep 29; 14(4). PMID: 31558897    Free PMC article.
Review.
Highlights of the 16th St Gallen International Breast Cancer Conference, Vienna, Austria, 20-23 March 2019: personalised treatments for patients with early breast cancer.
Consuelo Morigi.
Ecancermedicalscience, 2019 Jul 10; 13. PMID: 31281421    Free PMC article.
Endocrine Therapy in Early Breast Cancer.
Katja Krauss, Elmar Stickeler.
Breast Care (Basel), 2020 Sep 29; 15(4). PMID: 32982643    Free PMC article.
Review.
CYP27A1 expression is associated with risk of late lethal estrogen receptor-positive breast cancer in postmenopausal patients.
Siker Kimbung, Maria Inasu, +8 authors, Signe Borgquist.
Breast Cancer Res, 2020 Nov 13; 22(1). PMID: 33176848    Free PMC article.
Targeting tumor resistance mechanisms.
Louise Gerard, Laurent Duvivier, Jean-Pierre Gillet.
Fac Rev, 2021 Mar 05; 10. PMID: 33659924    Free PMC article.
Review.
Clinical validity of clinical treatment score 5 (CTS5) for estimating risk of late recurrence in unselected, non-trial patients with early oestrogen receptor-positive breast cancer.
Juliet Richman, Alistair Ring, Mitch Dowsett, Ivana Sestak.
Breast Cancer Res Treat, 2020 Nov 23; 186(1). PMID: 33222093    Free PMC article.
Anti-estrogenic and anti-aromatase activities of citrus peels major compounds in breast cancer.
Dina M El-Kersh, Shahira M Ezzat, +4 authors, Mohey M Elmazar.
Sci Rep, 2021 Mar 31; 11(1). PMID: 33782546    Free PMC article.
Risk of recurrence among patients with HR-positive, HER2-negative, early breast cancer receiving adjuvant endocrine therapy: A systematic review and meta-analysis.
Elizabeth M Salvo, Abril Oliva Ramirez, +4 authors, Imtiaz A Samjoo.
Breast, 2021 Mar 08; 57. PMID: 33677313    Free PMC article.
A rude awakening from tumour cells.
Fatima Cardoso, Giuseppe Curigliano.
Nature, 2018 Feb 01; 554(7690). PMID: 32094835
Sleep and endocrine therapy in breast cancer.
Kathleen Van Dyk, Hadine Joffe, Judith E Carroll.
Curr Opin Endocr Metab Res, 2021 Jun 08; 18. PMID: 34095605    Free PMC article.
Aromatase Inhibitor-Associated Musculoskeletal Syndrome: Understanding Mechanisms and Management.
Tara Hyder, Christopher C Marino, +2 authors, Adam M Brufsky.
Front Endocrinol (Lausanne), 2021 Aug 14; 12. PMID: 34385978    Free PMC article.
Review.
Preventive drug therapy and contralateral breast cancer: summary of the evidence of clinical trials and observational studies.
Annet Bens, Rikke Langballe, +3 authors, Lene Mellemkjaer.
Acta Oncol, 2019 Aug 09; 58(11). PMID: 31393200    Free PMC article.
Review.