乳腺癌术后内分泌治疗最佳方案？
众所周知，对于激素受体阳性早期乳腺癌绝经后女性，为了减少术后复发风险，至少需要完成5年内分泌治疗。不过，由于超过一半的复发被诊断于内分泌治疗5年后，故有必要进一步延长术后内分泌治疗。2021年7月29日，美国《新英格兰医学杂志》在线发表奥地利的ABCSG-16（SALSA）研究结果表明，对于完成术后5年内分泌治疗的激素受体阳性早期乳腺癌绝经后女性，用阿斯利康的非甾体类芳香化酶抑制剂阿那曲唑延长5年与2年相比，获益相似，副作用风险较高。那么，用诺华的非甾体类芳香化酶抑制剂来曲唑进行乳腺癌术后内分泌治疗需要多少年？
2021年9月17日，英国《柳叶刀》肿瘤学分册在线发表意大利热那亚大学圣马蒂诺综合医院、乌迪内大学圣玛丽医院、雷焦艾米利亚地区医院、都灵大学医院坎迪奥罗癌症研究所、法恩扎医院、埃莱娜王后肿瘤研究治疗研究所、费拉拉大学圣安娜医院、比萨大学圣嘉勒医院、萨萨里大学圣母领报医院、卡利亚里大学布辛科医院、萨萨里大学医院、维罗纳大学卡拉布里亚医院、那不勒斯腓特烈二世大学、库内奥圣十字卡尔教学医院、埃莱娜王后国家癌症研究所、都灵大学圣洛伦佐医院、阿维亚诺肿瘤学参考中心的LEAD（GIM4）研究报告，对于完成术后2～3年他莫昔芬内分泌治疗的激素受体阳性早期乳腺癌绝经后女性，比较了来曲唑延长内分泌治疗5年与2～3年的有效性和安全性。该研究由诺华和意大利卫生部资助。
Letrozole Adjuvant Therapy Duration (LEAD) Study (NCT01064635): Standard Versus Long Treatment. A Phase III Trial in Post-Menopausal Women With Early Breast Cancer (GIM4: Letrozole in Treating Breast Cancer in Postmenopausal Women With Stage I, II, or III Breast Cancer Previously Treated With Tamoxifen)
该多中心非盲随机对照三期临床研究于2005年8月1日～2010年10月24日从意大利69家医院入组经组织学证实I～III期激素受体阳性乳腺浸润癌术后完成至少2年但不超过3年零3个月他莫昔芬治疗未见复发迹象且根据美国东部肿瘤学协作组体力状态评分≤2的绝经后女性2056例（奥地利阿那曲唑研究入组3484例）按1∶1随机分为两组：
对照组（1030例）每天口服来曲唑2.5毫克连续2～3年
延长组（1026例）每天口服来曲唑2.5毫克连续5年
被研究者和研究者对治疗分配非盲。主要研究终点为意向治疗患者的无浸润病变生存（奥地利阿那曲唑研究主要终点为无病生存）。对接受至少1个月研究治疗的1960例患者进行安全性分析。
结果，中位随访11.7年（奥地利阿那曲唑研究为8.3年）后，对照组1030例与延长组1026例意向治疗患者相比：
浸润病变或死亡发生率：25.4%比20.7%（262比212例）
12年无浸润病变生存率：62%比67%（95%置信区间：57～66、62～71；风险比：0.78，95%置信区间：0.65～0.93；P=0.0064）
总死亡发生率：14.3%比11.3%（147比116例）
12年总生存率：84%比88%（95%置信区间：82～87、86～90；风险比：0.77，95%置信区间：0.60～0.98，P=0.036）
对照组983例与延长组977例实际治疗患者相比：
3～4级关节疼痛发生率：2.2%比3.0%（22比29例）
3～4级肌肉疼痛发生率：0.7%比0.9%（7比9例）
治疗相关严重不良事件：0.3%比0.8%（3比8例）
毒性反应相关死亡事件：未见
因此，该研究结果表明，对于术后完成2～3年他莫昔芬内分泌治疗的绝经后早期乳腺癌患者，来曲唑延长内分泌治疗5年与2～3年相比，生存率显著较高。术后内分泌治疗用他莫昔芬2～3年，随后用来曲唑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案之一。
对此，美国西雅图抗癌协会、西雅图华盛顿大学、弗雷德·哈钦森癌症研究中心发表同期评论：乳腺癌术后内分泌治疗最佳方案。
相关链接
Lancet Oncol. 2021 Sep 17. Online ahead of print.
Extended therapy with letrozole as adjuvant treatment of postmenopausal patients with early-stage breast cancer: a multicentre, open-label, randomised, phase 3 trial.
Lucia Del Mastro, Mauro Mansutti, Giancarlo Bisagni, Riccardo Ponzone, Antonio Durando, Laura Amaducci, Enrico Campadelli, Francesco Cognetti, Antonio Frassoldati, Andrea Michelotti, Silvia Mura, Ylenia Urracci, Giovanni Sanna, Stefania Gori, Sabino De Placido, Ornella Garrone, Alessandra Fabi, Carla Barone, Stefano Tamberi, Claudia Bighin, Fabio Puglisi, Gabriella Moretti, Grazia Arpino, Alberto Ballestrero, Francesca Poggio, Matteo Lambertini, Filippo Montemurro, Paolo Bruzzion; Gruppo Italiano Mammella investigators.
IRCCS Ospedale Policlinico San Martino, Genoa, Italy; University of Genoa, Genoa, Italy; ASUFC Santa Maria Della Misericordia, Udine, Italy; Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy; Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy; Citta' della Salute e della Scienza di Torino, Turin, Italy; Faenza Hospital, Faenza, Italy; Istituto Regina Elena per lo Studio e la Cura dei Tumori, Rome, Italy; S Anna University Hospital, Ferrara, Italy; S Chiara Hospital, Pisa, Italy; Ospedale Civile Santissima Annunziata, Sassari, Italy; Hospital Businco, Cagliari, Italy; University-Hospital of Sassari, Sassari, Italy; IRCCS Ospedale Sacro Cuore-Don Calabria, Verona, Italy; University of Naples Federico II, Naples, Italy; AO S Croce e Carle Ospedale di Insegnamento, Cuneo, Italy; IRCCS Regina Elena National Cancer Institute, Rome, Italy; S Lorenzo Hospital, Turin, Italy; Centro di Riferimento Oncologico di Aviano IRCCS, Aviano, Aviano, Italy.
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
DOI: 10.1016/S1470-2045(21)00352-1
Lancet Oncol. 2021 Sep 17. Online ahead of print.
Optimal adjuvant endocrine therapy for breast cancer.
Rachel L Yung, Nancy E Davidson.
Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle Cancer Care Alliance, Seattle, WA, USA.
DOI: 10.1016/S1470-2045(21)00420-4