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Lancet Oncol. 2018 Jan;19(1):127-138. doi: 10.1016/S1470-2045(17)30715-5. Epub 2017 Nov 17.

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

Collaborators (222)

Vandebroek A, Berliere M, Mitine C, Vuylsteke P, Borms M, D'Hondt R, Glorieux P, Mebis J, Verhoeven D, Coibion M, Forget F, Duck L, Verhoeven D, Wyendaele W, Barbeaux A, Salmon JP, Berteloot P, Vermeij J, Richard V, Cinieri S, Gianni L, Clerico M, Pinotti G, Bernardo A, Biganzoli L, Gennari A, Graiff C, Amadori D, Passalacqua R, Forbes J, Francis P, Foo S, Boyle F, Redfern A, van der Westhuizen A, Lewis C, Sharma S, Beale P, Byard I, Begbie S, Sardelic F, Abdi E, Clark D, Chindewere A, Della-Fiorentina S, Asghari R, Islam M, Na Teo L, White S, Gilbert L, Gardner K, Uhlmann C, Rauch D, Mannhart M, Buser K, Dedes K, Mueller A, Rageth C, Von Orelli S, Senn HJ, Pagani O, Pedrazzini A, Rochlitz C, Bodmer A, Anchisi S, Zaman K, von Moos R, Betticher D, Kralidas E, Popescu R, Fehr M, Nyman P, Jungquist A, Chamalidou C, Foukakis T, Dabrosin C, Valachis A, Lang I, Kahan Z, Retamales J, Torres UR, Fritis M, Sole S, Torres S, Letzkus J, Escobar P, Vigneaux I, Arancibia J, Cardemil JB, Huidobro P, Gomez H, Wetter J, Vorobiof D, McMichael G, Apffelstaedt J, Vorotnikov I, Schwartz J, Openshaw T, Bonnefoi H, Jacquin JP, Bonichon-Lamichhane N, Borstner S, Budrukkar A, Ewertz M, Quispe OZ, Vestlev PM, Danø H, Nielsen D, Jakobsen E, Hoejris I, Bogovic JA, Jensen BB, Aage Møller K, Stenbygaard EL, Sharma R, Bedi C, Bews-Hair M, Neades G, McKirdy M, Barber M, Alhasso A, Ritchie D, Fraser J, Scott L, Yuille F, Lannigan A, Murphy D, Shere M, Jackisch C, Tomé O, Steer S, Augustin D, Lübbe K, Jackisch C, Köcker-Korus H, Deuker JU, Stefek A, Just M, Rhein U, Bechtner C, Baerens DT, Schrader I, Grischke EM, Lorenz R, Dietz W, Thomalla J, Schilling J, Rempen A, Graf H, Doering G, Busch S, Heinrich G, Tesch H, Uleer C, Krabisch P, Rösel S, Kurbacher C, Ostertag H, Josten KM, Hielscher C, Gröll I, Mattner UM, Prechtl A, Lantzsch T, Ciruelos E, Garau I, Bellet M, Climent MA, López R, Virizuela JA, Bermejo B, Janez NM, Amillano K, Márquez R, Dorca J, Godes MJ, Gonzalez S, Ohno S, Aruga T, Yotsumoto D, Yamamoto Y, Aihara T, Morimoto T, Bando H, Masuda N, Toi M, Aogi K, Sato N, Okada M, Takahashi M, Tokunaga E, Iwata H, Fujita T, Fridrik M, Pristauz G, Hackl C, Singer C, Wette V, Gnant M, Thaler J, Greil R, Abendstein B, Heck D, Manfreda D, Sevelda P, Thiel I, Tuttlies F, Stöger H, Neunteufel W, Crown J, Kennedy J, Hill A, McCaffrey J, Murphy C, Coate L, Keane M, Martin M, O'Connor M, Duffy K, Ruepp B, Piccart M, Zardavas D.

Author information

1
International Breast Cancer Study Group, Milan, Italy; Division of Medical Senology, Milan, Italy. Electronic address: marco.colleoni@ieo.it.
2
International Breast Cancer Study Group Statistical Center, Boston, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA.
3
International Breast Cancer Study Group and Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
4
International Breast Cancer Study Group, Australia and New Zealand Breast Cancer Trials Group, and Box Hill and Maroondah Hospitals, Monash University, Melbourne, VIC, Australia.
5
International Breast Cancer Study Group and Lucerne Canton Hospital, Lucerne, Switzerland.
6
International Breast Cancer Study Group, Centre Hospitalier Universitaire de Liège, Liège University, Liège, Belgium.
7
International Breast Cancer Study Group and Multidisciplinary Breast Center, University Hospitals, Katholieke Universiteit Leuven, Leuven, Belgium.
8
International Breast Cancer Study Group and National Institute of Oncology, Budapest, Hungary.
9
International Breast Cancer Study Group and Centre Hospitalier Chrétien Clinique St Joseph, Liège, Belgium.
10
International Breast Cancer Study Group and ASST Spedali Civili di Brescia, Brescia, Italy.
11
Danish Breast Cancer Group and Rigshospitalet, Copenhagen, Denmark.
12
Scottish Cancer Trials Breast Group and The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
13
German Breast Group, Neu-Isenburg, Germany.
14
SOLTI Group and Fundación Instituto Valenciano de Oncologia, Valencia, Spain.
15
Japan Breast Cancer Research Group and Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
16
Austrian Breast & Colorectal Cancer Study Group and Department of Obstetrics and Gynecology, Medical University Innsbruck, Innsbruck, Austria.
17
Chilean Cooperative Group for Oncologic Research, Providencia, Santiago, Chile.
18
Cancer Trials Ireland and Cork University Hospital, Cork, Ireland.
19
International Breast Cancer Study Group and Centro di Riferimento Oncologico di Aviano, Aviano, Italy.
20
Medical Oncology Clinic, Institute Jules Bordet, Brussels, Belgium.
21
Swiss Group for Clinical Cancer Research, International Breast Cancer Study Group, and Breast Center St Gallen, St Gallen, Switzerland.
22
Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
23
International Breast Cancer Study Group Coordinating Center, Bern, Switzerland.
24
International Breast Cancer Study Group Coordinating Center, Bern, Switzerland; Bern University Hospital, Inselspital, Bern, Switzerland.
25
European Institute of Oncology, Milan, Italy; International Breast Cancer Study Group Central Pathology Office and University of Milan, Milan, Italy.
26
International Breast Cancer Study Group, Inselspital, Bern, Switzerland; Bern University Hospital, Inselspital, Bern, Switzerland.
27
International Breast Cancer Study Group Statistical Center, Boston, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Harvard T H Chan School of Public Health, Boston, MA, USA; Frontier Science & Technology Research Foundation, Boston, MA, USA.
28
International Breast Cancer Study Group and University of Sydney, Sydney, NSW, Australia.
29
International Breast Cancer Study Group and Hospital of Prato-AUSL Toscana Centro, Istituto Toscano Tumori, Prato, Italy.
30
International Breast Cancer Study Group Statistical Center, Boston, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
31
International Breast Cancer Study Group, Milan, Italy; European Institute of Oncology, Milan, Italy.

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.

PMID:
29158011
DOI:
10.1016/S1470-2045(17)30715-5
[Indexed for MEDLINE]

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