Background

The benefit of extending aromatase inhibitor therapy beyond 5 years in the context of previous aromatase inhibitors remains controversial. We aimed to compare extended therapy with letrozole for 5 years versus the standard duration of 2–3 years of letrozole in postmenopausal patients with breast cancer who have already received 2–3 years of tamoxifen.

Methods

This multicentre, open-label, randomised, phase 3 trial was done at 69 hospitals in Italy. Women were eligible if they were postmenopausal at the time of study entry, had stage I–III histologically proven and operable invasive hormone receptor-positive breast cancer, had received adjuvant tamoxifen therapy for at least 2 years but no longer than 3 years and 3 months, had no signs of disease recurrence, and had an Eastern Cooperative Oncology Group performance status of 2 or lower. Patients were randomly assigned (1:1) to receive 2–3 years (control group) or 5 years (extended group) of letrozole (2·5 mg orally once a day). Randomisation, with stratification by centre, with permuted blocks of size 12, was done with a centralised, interactive, internet-based system that randomly generated the treatment allocation. Participants and investigators were not masked to treatment assignment. The primary endpoint was invasive disease-free survival in the intention-to-treat population. Safety analysis was done for patients who received at least 1 month of study treatment. This trial was registered with EudraCT, 2005-001212-44, and ClinicalTrials.gov, NCT01064635.

Findings

Between Aug 1, 2005, and Oct 24, 2010, 2056 patients were enrolled and randomly assigned to receive letrozole for 2–3 years (n=1030; control group) or for 5 years (n=1026; extended group). After a median follow-up of 11·7 years (IQR 9·5–13·1), disease-free survival events occurred in 262 (25·4%) of 1030 patients in the control group and 212 (20·7%) of 1026 in the extended group. 12-year disease-free survival was 62% (95% CI 57–66) in the control group and 67% (62–71) in the extended group (hazard ratio 0·78, 95% CI 0·65–0·93; p=0·0064). The most common grade 3 and 4 adverse events were arthralgia (22 [2·2%] of 983 patients in the control group vs 29 [3·0%] of 977 in the extended group) and myalgia (seven [0·7%] vs nine [0·9%]). There were three (0·3%) serious treatment-related adverse events in the control group and eight (0·8%) in the extended group. No deaths related to toxic effects were observed.

Interpretation

In postmenopausal patients with breast cancer who received 2–3 years of tamoxifen, extended treatment with 5 years of letrozole resulted in a significant improvement in disease-free survival compared with the standard 2–3 years of letrozole. Sequential endocrine therapy with tamoxifen for 2–3 years followed by letrozole for 5 years should be considered as one of the optimal standard endocrine treatments for postmenopausal patients with hormone receptor-positive breast cancer.

Funding

Novartis and the Italian Ministry of Health.

Translation

For the Italian translation of the abstract see Supplementary Materials section.

中文翻译：

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来曲唑延长治疗作为绝经后早期乳腺癌患者的辅助治疗：一项多中心、开放标签、随机、3 期试验

背景

在先前使用芳香酶抑制剂的情况下，延长芳香酶抑制剂治疗超过 5 年的益处仍存在争议。我们的目的是在已经接受 2-3 年他莫昔芬治疗的绝经后乳腺癌患者中比较来曲唑延长治疗 5 年与来曲唑标准治疗时间 2-3 年。

方法

这项多中心、开放标签、随机、3 期试验在意大利的 69 家医院进行。如果女性在进入研究时已绝经，患有 I-III 期组织学证实且可手术的侵袭性激素受体阳性乳腺癌，接受他莫昔芬辅助治疗至少 2 年但不超过 3 年零 3 个月，则符合条件，没有疾病复发的迹象，并且东部肿瘤协作组的体能状态为 2 或更低。患者被随机分配 (1:1) 接受 2-3 年（对照组）或 5 年（延长组）来曲唑（2·5 毫克，每天口服一次）。随机化，按中心分层，大小为 12 的置换块，是通过一个集中的、交互式的、基于互联网的系统完成的，该系统随机生成治疗分配。参与者和研究人员没有对治疗分配不知情。主要终点是意向治疗人群的侵袭性无病生存期。对接受至少 1 个月研究治疗的患者进行安全性分析。该试验在 EudraCT，2005-001212-44 和 ClinicalTrials.gov，NCT01064635 注册。

发现

2005 年 8 月 1 日至 2010 年 10 月 24 日期间，2056 名患者被纳入并随机分配接受来曲唑治疗 2-3 年（n=1030；对照组）或 5 年（n=1026；扩展组）。中位随访 11·7 年（IQR 9·5–13·1）后，对照组 1030 名患者中有 262 名（25·4%）和 212 名（20·7%）发生无病生存事件。 ) 的 1026 在扩展组中。对照组的 12 年无病生存率为 62%（95% CI 57-66），扩展组为 67%（62-71）（风险比 0·78，95% CI 0·65-0· 93；p=0·0064)。最常见的3级和（22 [2·2％]的983例，对照组在4个不良事件是关节痛VS经扩展群组中29 [3·0％]的977）和肌痛（7 [0·7％ ]对九 [0·9%]）。对照组发生了 3 起 (0·3%) 严重的治疗相关不良事件，扩展组发生了 8 起 (0·8%)。没有观察到与毒性作用相关的死亡。

解释

在接受 2-3 年他莫昔芬治疗的绝经后乳腺癌患者中，与标准的 2-3 年来曲唑治疗相比，5 年来曲唑延长治疗可显着提高无病生存率。他莫昔芬连续内分泌治疗 2-3 年，然后来曲唑治疗 5 年，应被视为绝经后激素受体阳性乳腺癌患者的最佳标准内分泌治疗方法之一。

资金

诺华和意大利卫生部。

翻译

有关摘要的意大利语翻译，请参阅补充材料部分。