Continuous versus intermittent extended adjuvant letrozole for breast cancer: final results of randomized phase III SOLE (Study of Letrozole Extension) and SOLE Estrogen Substudy.
JERUSALEM, Guy; Farah, S; Courtois, Audreyet al.
2021 • In Annals of Oncology, 32 (10), p. 1256-1266
[en] 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.
Disciplines :
Oncology
Author, co-author :
JERUSALEM, Guy ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'oncologie médicale
Farah, S; International Breast Cancer Study Group Statistical Center, Division of Biostatistics, Dana-Farber Cancer Institute, Boston, USA
Courtois, Audrey ; Université de Liège - ULiège > Département des sciences cliniques > Chirurgie cardio-vasculaire et thoracique
Chirgwin, J; Breast Cancer Trials-Australia and New Zealand, University of Newcastle, Callaghan, Australia, Box Hill and Maroondah Hospitals, Monash University, Clayton, Australia
Aebi, S; Division of Medical Oncology, Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland, Faculty of Medicine, University of Bern, Bern, Switzerland
Karlsson, P; Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Neven, P; Gynecologic Oncology and Multidisciplinary Breast Center, University Hospitals UZ-Leuven, KU Leuven, Leuven, Belgium
Hitre, E; Department of Medical Oncology and Clinical Pharmacology "B", National Institute of Oncology, Budapest, Hungary
Graas, M P; Montlégia Hospital, Liège, Belgium
Simoncini, E; ASST Spedali Civili di Brescia, Brescia, Italy
Abdi, E; The Tweed Hospital, Griffith University Gold Coast, Tweed Heads, Australia
Kamby, C; Danish Breast Cancer Group and Rigshospitalet, Copenhagen, Denmark
Thompson, A; Scottish Cancer Trials Breast Group and Division of Surgical Oncology, Baylor College of Medicine, Houston, USA
Loibl, S; German Breast Group Forschungs GmbH, Neu-Isenburg, Germany
Gavilá, J; SOLTI Group and Fundación Instituto Valenciano de Oncologia, Valencia, Spain
Kuroi, K; Japan Breast Cancer Research Group and Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
Marth, C; Austrian Breast & Colorectal Cancer Study Group and Department of Obstetrics and Gynecology, Medical University Innsbruck, Innsbruck, Austria
Müller, B; Chilean Cooperative Group for Oncologic Research (GOCCHI), Providencia, Santiago, Chile
O'Reilly, S; Cancer Trials Ireland, Dublin, Ireland, University College Cork, Cork University Hospital, Cork, Ireland
Ruhstaller, T; International Breast Cancer Study Group, Bern, Switzerland, Swiss Group for Clinical Cancer Research SAKK, Bern, Switzerland, Breast Center St. Gallen, St. Gallen, Switzerland, Faculty of Medicine, University of Basel, Basel, Switzerland
Burstein, H J; Medical Oncology Department, CHU Liège, Liège University, Liège, Belgium, Harvard Medical School, Boston, USA, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
Rabaglio, M; International Breast Cancer Study Group, Bern, Switzerland, Swiss Group for Clinical Cancer Research SAKK, Bern, Switzerland, Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Ruepp, B; International Breast Cancer Study Group, Bern, Switzerland
Ribi, K; International Breast Cancer Study Group, Bern, Switzerland
Viale, G; Department of Pathology, University of Milan, Milan, Italy, IEO European Institute of Oncology IRCCS, Milan, Italy
Gelber, R D; International Breast Cancer Study Group Statistical Center, Division of Biostatistics, Dana-Farber Cancer Institute, Boston, USA, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA, Harvard TH Chan School of Public Health, Boston, USA, Frontier Science Foundation, Boston, USA
Coates, A S; International Breast Cancer Study Group, Bern, Switzerland, NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia
Loi, S; International Breast Cancer Study Group, Bern, Switzerland, Peter MacCallum Cancer Center, University of Melbourne, Melbourne, Australia
Goldhirsch, A; International Breast Cancer Study Group, Bern, Switzerland, IEO European Institute of Oncology, IRCCS, Milan, Italy
Regan, M M ✱; International Breast Cancer Study Group Statistical Center, Division of Biostatistics, Dana-Farber Cancer Institute, Boston, USA, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
Colleoni, M ✱; International Breast Cancer Study Group, Bern, Switzerland, Division of Medical Senology, IEO, European Institute of Oncology, IRCCS, Milan, Italy
✱ These authors have contributed equally to this work.
Language :
English
Title :
Continuous versus intermittent extended adjuvant letrozole for breast cancer: final results of randomized phase III SOLE (Study of Letrozole Extension) and SOLE Estrogen Substudy.
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.SOLE is a Breast International Group (BIG) trial, BIG 01-07. We thank the patients, physicians, nurses, trial coordinators, and pathologists who participated in the SOLE clinical trial and SOLE-EST substudy. This work was supported by Novartis and the International Breast Cancer Study Group (IBCSG) (no grant numbers). Novartis provided drug supply. Support for the coordinating group, IBCSG: Frontier Science and Technology Research Foundation (FSTRF; no grant number), Swiss Group for Clinical Cancer Research (SAKK; no grant number), Cancer Research Switzerland (no grant number), Oncosuisse (no grant number), Cancer League Switzerland (no grant number), and the Foundation for Clinical Cancer Research of Eastern Switzerland (OSKK; no grant number). SOLE-EST was partially funded by the Belgian Foundation against Cancer (no grant number), Breast Cancer Trials Australia and New Zealand (no grant number), and Susan G. Komen for the Cure [grant number SAC 110040] to AG. 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. After publication, access to de-identified individual participant data may be requested by researchers by submitting a proposal (to stat_center@ibcsg.org), which will be reviewed for scientific merit and feasibility in accordance with IBCSG guidelines for collaborative research and data sharing policy.This work was supported by Novartis and the International Breast Cancer Study Group (IBCSG) (no grant numbers). Novartis provided drug supply. Support for the coordinating group, IBCSG: Frontier Science and Technology Research Foundation (FSTRF; no grant number), Swiss Group for Clinical Cancer Research (SAKK; no grant number), Cancer Research Switzerland (no grant number), Oncosuisse (no grant number), Cancer League Switzerland (no grant number), and the Foundation for Clinical Cancer Research of Eastern Switzerland (OSKK; no grant number). SOLE-EST was partially funded by the Belgian Foundation against Cancer (no grant number), Breast Cancer Trials Australia and New Zealand (no grant number), and Susan G. Komen for the Cure [grant number SAC 110040] to AG.
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