Breast Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy; Department of Internal Medicine and Medical Specialities, School of Medicine, University of Genoa, Genoa, Italy.
Department of Oncology, ASUFC Santa Maria Della Misericordia, Udine, Italy.
Lancet Oncol. 2021 Oct;22(10):1458-1467. doi: 10.1016/S1470-2045(21)00352-1. Epub 2021 Sep 17.
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.
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.
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.
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.
Novartis and the Italian Ministry of Health.
For the Italian translation of the abstract see Supplementary Materials section.
在先前使用芳香化酶抑制剂治疗的情况下，延长芳香化酶抑制剂治疗时间超过 5 年的获益仍存在争议。我们旨在比较接受他莫昔芬治疗 2-3 年后的绝经后乳腺癌患者中，延长来曲唑治疗 5 年与标准 2-3 年的来曲唑治疗的效果。
这是一项在意大利 69 家医院进行的多中心、开放标签、随机、3 期临床试验。符合条件的女性在研究入组时处于绝经后状态，组织学证实为 I-III 期可手术的激素受体阳性乳腺癌，接受了至少 2 年但不超过 3 年 3 个月的辅助他莫昔芬治疗，无疾病复发迹象，东部肿瘤协作组表现状态为 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 mg 口服，每天一次）治疗。随机分组按中心分层，使用大小为 12 的置换块，通过一个中央、互动、基于互联网的系统进行，该系统随机生成治疗分配。参与者和研究者对治疗分配不知情。主要终点是在意向治疗人群中的无侵袭性疾病生存。对接受至少 1 个月研究治疗的患者进行安全性分析。这项试验在 EudraCT（2005-001212-44）和 ClinicalTrials.gov（NCT01064635）注册。
在 2005 年 8 月 1 日至 2010 年 10 月 24 日期间，共纳入 2056 例患者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；延长组）。中位随访 11.7 年后（IQR 9.5-13.1），对照组有 262 例（25.4%）和延长组有 212 例（20.7%）患者发生无疾病生存事件。对照组 12 年无疾病生存率为 62%（95%CI 57-66），延长组为 67%（62-71）（风险比 0.78，95%CI 0.65-0.93；p=0.0064）。最常见的 3 级和 4 级不良事件是关节痛（对照组 983 例中有 22 例[2.2%]，延长组 977 例中有 29 例[3.0%]）和肌痛（对照组 7 例[0.7%]，延长组 9 例[0.9%]）。对照组有 3 例（0.3%）严重治疗相关不良事件，延长组有 8 例（0.8%）。未观察到与毒性相关的死亡。
在接受他莫昔芬治疗 2-3 年的绝经后乳腺癌患者中，与标准的 2-3 年来曲唑治疗相比，延长来曲唑治疗 5 年可显著改善无病生存。接受他莫昔芬治疗 2-3 年后序贯内分泌治疗，然后再接受来曲唑治疗 5 年，应被视为绝经后激素受体阳性乳腺癌患者的一种最佳标准内分泌治疗方法。
诺华公司和意大利卫生部。
