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

on behalf of the SOLE Investigators

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)127-138
Number of pages12
JournalThe Lancet Oncology
Volume19
Issue number1
DOIs
Publication statusPublished - Jan 1 2018

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letrozole
Breast Neoplasms
Disease-Free Survival
Therapeutics

ASJC Scopus subject areas

  • Oncology

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

In: The Lancet Oncology, Vol. 19, No. 1, 01.01.2018, p. 127-138.

Research output: Contribution to journalArticle

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title = "Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer (SOLE): a multicentre, open-label, randomised, phase 3 trial",
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.",
author = "{on behalf of the SOLE Investigators} and Marco Colleoni and Weixiu Luo and Per Karlsson and Jacquie Chirgwin and Stefan Aebi and Guy Jerusalem and Patrick Neven and Erika Hitre and Graas, {Marie Pascale} and Edda Simoncini and Claus Kamby and Alastair Thompson and Sibylle Loibl and Joaqu{\'i}n Gavil{\'a} and Katsumasa Kuroi and Christian Marth and Bettina M{\"u}ller and Seamus O'Reilly and {Di Lauro}, Vincenzo and Andrea Gombos and Thomas Ruhstaller and Harold Burstein and Karin Ribi and J{\"u}rg Bernhard and Giuseppe Viale and Rudolf Maibach and Manuela Rabaglio-Poretti and Gelber, {Richard D.} and Coates, {Alan S.} and {Di Leo}, Angelo and Regan, {Meredith M.} and Aron Goldhirsch and An Vandebroek and Martine Berliere and Carine Mitine and Peter Vuylsteke and Marleen Borms and Randal D'Hondt and Philippe Glorieux and Jeroen Mebis and Didier Verhoeven and Michael Coibion and Frederic Forget and Lionel Duck and Didier Verhoeven and Wim Wyendaele and Annelore Barbeaux and Lorenzo Gianni and Antonio Bernardo and Dino Amadori",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/S1470-2045(17)30715-5",
language = "English",
volume = "19",
pages = "127--138",
journal = "The Lancet Oncology",
issn = "1470-2045",
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TY - JOUR

T1 - Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer (SOLE)

T2 - a multicentre, open-label, randomised, phase 3 trial

AU - on behalf of the SOLE Investigators

AU - Colleoni, Marco

AU - Luo, Weixiu

AU - Karlsson, Per

AU - Chirgwin, Jacquie

AU - Aebi, Stefan

AU - Jerusalem, Guy

AU - Neven, Patrick

AU - Hitre, Erika

AU - Graas, Marie Pascale

AU - Simoncini, Edda

AU - Kamby, Claus

AU - Thompson, Alastair

AU - Loibl, Sibylle

AU - Gavilá, Joaquín

AU - Kuroi, Katsumasa

AU - Marth, Christian

AU - Müller, Bettina

AU - O'Reilly, Seamus

AU - Di Lauro, Vincenzo

AU - Gombos, Andrea

AU - Ruhstaller, Thomas

AU - Burstein, Harold

AU - Ribi, Karin

AU - Bernhard, Jürg

AU - Viale, Giuseppe

AU - Maibach, Rudolf

AU - Rabaglio-Poretti, Manuela

AU - Gelber, Richard D.

AU - Coates, Alan S.

AU - Di Leo, Angelo

AU - Regan, Meredith M.

AU - Goldhirsch, Aron

AU - Vandebroek, An

AU - Berliere, Martine

AU - Mitine, Carine

AU - Vuylsteke, Peter

AU - Borms, Marleen

AU - D'Hondt, Randal

AU - Glorieux, Philippe

AU - Mebis, Jeroen

AU - Verhoeven, Didier

AU - Coibion, Michael

AU - Forget, Frederic

AU - Duck, Lionel

AU - Verhoeven, Didier

AU - Wyendaele, Wim

AU - Barbeaux, Annelore

AU - Gianni, Lorenzo

AU - Bernardo, Antonio

AU - Amadori, Dino

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

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