对于绝经后早期乳腺癌女性，需要使用来曲唑（芳香酶抑制剂）延长辅助内分泌治疗避免复发，但是长期使用来曲唑可能引起耐药。根据既往乳腺癌动物模型研究发现，连续使用来曲唑引起的耐药，可被间歇使用来曲唑而逆转。因此，有研究者假设，间歇使用来曲唑与连续使用来曲唑相比，对于绝经后早期乳腺癌女性的延长辅助内分泌治疗可以改善结局。
2017年11月17日，英国《柳叶刀》肿瘤学分册在线发表国际乳腺癌研究协作组（IBCSG）多中心非盲随机平行三期研究（SOLE）报告，比较了间歇或连续使用来曲唑延长绝经后早期乳腺癌女性辅助内分泌治疗的有效性和安全性。
该多中心非盲随机平行三期研究（SOLE）于2007年12月5日～2012年10月8日在22个国家240个中心（学术、一级、二级、三级医疗中心）入组任何年龄、激素受体阳性、淋巴结阳性、可手术乳腺癌、已接受局部治疗（手术±放疗）并已完成4～6年辅助内分泌治疗（包括他莫昔芬）的绝经后女性4884例，入组时无乳腺癌临床证据、无疾病复发证据，按1∶1随机分配接受连续使用来曲唑（每天2.5mg口服5年）或间歇使用来曲唑（第1～4年每天2.5mg口服9个月停用3个月→第5年每天2.5mg口服12个月）。
由主要研究者或指定者在各自中心通过国际乳腺癌研究协作组互联网系统进行随机分组，根据既往内分泌治疗类型（仅用芳香酶抑制剂、仅用选择性雌激素受体调节剂、二者联合）进行分层，区组大小为四，并按机构进行平衡。治疗分配非盲。
主要终点为无病生存，通过意向治疗原则使用分层对数秩检验进行分析。参与研究期间，愿意接受治疗人群之中，所有实际接受研究方案治疗的患者均进行安全性分析。该研究在美国政府临床研究数据库、欧盟临床研究数据库的注册编号分别为：NCT 00553410、EudraCT 2007-001370-88，并且正在进行患者长期随访。该研究由诺华和国际乳腺癌研究小组（IBCSG）提供资助。
经过中位随访60（四分位距：53～72）个月，愿意接受治疗4851例：
间歇组2425例无病生存率85.8%（95%置信区间：84.2～87.2）
连续组2426例无病生存率87.5%（95%置信区间：86.0～88.8）
复发风险比：1.08（95%置信区间：0.93～1.26，P=0.31）
实际接受治疗4828例，其中间歇组2417例、连续组2411例，不良事件报告如预期且相似，最常见的3～5级不良事件：
高血压：584例（24%）、517例（21%）
关节痛：136例（6%、151例（6%）
脑缺血：24例（1%）、30例（1%）
脑出血：9例（<1%）、7例（<1%）
心脏缺血：19例（1%）、21例（1%）
研究治疗期间死亡23例（<1%），其中间歇组13例（<1%）、连续组10例（<1%）。
因此，对于绝经后激素受体阳性乳腺癌患者，延长间歇使用来曲唑与连续使用来曲唑相比，并不能改善无病生存。不过，使用来曲唑延长辅助内分泌治疗（包括间歇给药）的替代方案可能有安全性和经济学的意义，并且对于可能需要临时中断来曲唑治疗的选择性患者，SOLE研究结果证实其安全性。
对此，加利福尼亚希望之城国家医学中心、洛杉矶生物医学研究所（位于加利福尼亚大学海港医学中心）发表同期评论：间歇来曲唑辅助治疗的复杂性，认为SOLE研究结果为延长辅助内分泌辅疗提供了新证据，但是该研究入组了既往用过他莫昔芬（选择性雌激素受体调节剂）的患者，使该研究结果的解释变得复杂化。根据亚组分析，既往仅用过芳香酶抑制剂有利于间歇组，既往仅用过选择性雌激素受体调节剂有利于连续组，虽然统计学意义不大，但是临床意义仍然值得考虑。
Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer (SOLE): a multicentre, open-label, randomised, phase 3 trial.
Marco Colleoni, Weixiu Luo, Per Karlsson, Jacquie Chirgwin, Stefan Aebi, Guy Jerusalem, Patrick Neven, Erika Hitre, Marie-Pascale Graas, Edda Simoncini, Claus Kamby, Alastair Thompson, Sibylle Loibl, Joaquín Gavilá, Katsumasa Kuroi, Christian Marth, Bettina Müller, Seamus O'Reilly, Vincenzo Di Lauro, Andrea Gombos, Thomas Ruhstaller, Harold Burstein, Karin Ribi, Jürg Bernhard, Giuseppe Viale, Rudolf Maibach, Manuela Rabaglio-Poretti, Richard D Gelber, Alan S Coates, Angelo Di Leo, Meredith M Regan, Aron Goldhirsch; SOLE Investigators.
International Breast Cancer Study Group, Milan, Italy; European Institute of Oncology, Milan, Italy; 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; University of Gothenburg, Gothenburg, Sweden; Australia and New Zealand Breast Cancer Trials Group, Box Hill and Maroondah Hospitals, Monash University, Melbourne, VIC, Australia; Lucerne Canton Hospital, Lucerne, Switzerland; Centre Hospitalier Universitaire de Liège, Liège University, Liège, Belgium; Multidisciplinary Breast Center, University Hospitals, Katholieke Universiteit Leuven, Leuven, Belgium; National Institute of Oncology, Budapest, Hungary; Centre Hospitalier Chrétien Clinique St Joseph, Liège, Belgium; ASST Spedali Civili di Brescia, Brescia, Italy; Danish Breast Cancer Group, Rigshospitalet, Copenhagen, Denmark; Scottish Cancer Trials Breast Group, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; German Breast Group, Neu-Isenburg, Germany; SOLTI Group, Fundación Instituto Valenciano de Oncologia, Valencia, Spain; Japan Breast Cancer Research Group, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan; Austrian Breast & Colorectal Cancer Study Group, Medical University Innsbruck, Innsbruck, Austria; Chilean Cooperative Group for Oncologic Research, Providencia, Santiago, Chile; Cancer Trials Ireland and Cork University Hospital, Cork, Ireland; Centro di Riferimento Oncologico di Aviano, Aviano, Italy; Institute Jules Bordet, Brussels, Belgium; Swiss Group for Clinical Cancer Research, Breast Center St Gallen, St Gallen, Switzerland; International Breast Cancer Study Group Coordinating Center, Bern, Switzerland; Bern University Hospital, Inselspital, Bern, Switzerland; University of Milan, Milan, Italy; Frontier Science & Technology Research Foundation, Boston, MA, USA; University of Sydney, Sydney, NSW, Australia; Hospital of Prato-AUSL Toscana Centro, Istituto Toscano Tumori, Prato, Italy.
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.
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