对于HER2阳性早期乳腺癌，术前化疗＋HER2抗体曲妥珠单抗治疗后，仍残留与未残留浸润癌患者相比，预后显著较差。7年前，KATHERINE研究首次证实第一代HER2抗体缀合化疗药物恩美曲妥珠单抗与曲妥珠单抗相比，可以显著减少HER2阳性早期乳腺癌术前治疗后仍残留浸润癌患者复发或死亡风险。4年前，乳腺癌命运第四交响曲DESTINY-Breast04研究首次证实第二代HER2抗体缀合化疗药物德曲妥珠单抗与恩美曲妥珠单抗相比，可以显著减少HER2阳性晚期乳腺癌化疗失败患者进展或死亡风险。那么，德曲妥珠单抗与恩美曲妥珠单抗相比，能否改变HER2阳性早期乳腺癌术前治疗后仍残留浸润癌患者命运？
2025年12月10日，国际四大医学期刊之一、创刊于1812年的美国麻省医学会官方期刊《新英格兰医学杂志》在线发表复旦大学附属肿瘤医院邵志敏、台湾大学医学院附设医院黄俊升、吉林大学第一医院李薇、北京肿瘤医院李惠平、山东第一医科大学附属肿瘤医院王永胜、中山大学孙逸仙纪念医院姚和瑞、河北医科大学第四医院耿翠芝、福建省肿瘤医院宋传贵、台北马偕纪念医院张源清、桃园长庚纪念医院陈训彻、哈尔滨医科大学附属肿瘤医院李志高以及德国、韩国、巴西、美国、西班牙、日本、秘鲁、墨西哥、波兰、新加坡、法国学者的乳腺癌命运第五交响曲DESTINY-Breast05研究中期分析报告，首次对德曲妥珠单抗与恩美曲妥珠单抗治疗HER2阳性早期乳腺癌术前治疗后仍残留浸润癌患者的有效性和安全性进行头对头随机分组比较。
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DESTINY-Breast05 (NCT04622319): A Study of Trastuzumab Deruxtecan (T-DXd) Versus Trastuzumab Emtansine (T-DM1) in High-risk HER2-positive Participants With Residual Invasive Breast Cancer Following Neoadjuvant Therapy
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Official Title: A Phase 3, Multicenter, Randomized, Open-Label, Active-Controlled Study of Trastuzumab Deruxtecan (T-DXd) Versus Trastuzumab Emtansine (T-DM1) in Participants With High-Risk HER2-Positive Primary Breast Cancer Who Have Residual Invasive Disease in Breast or Axillary Lymph Nodes Following Neoadjuvant Therapy (DESTINY-Breast05)
该国际多中心非盲随机对照三期临床研究于2020年12月4日至2024年1月23日从全球481家医院入组HER2阳性早期乳腺癌术前治疗后仍残留浸润癌和淋巴结阳性或诊断时已无法手术患者1635例，根据治疗前初诊时病灶可手术切除或不可手术切除、激素受体阳性或阴性、术前治疗后病理淋巴结阳性或阴性以及术前HER2靶向治疗单药或双药进行分层，再按1比1随机分为两组，其中818例给予德曲妥珠单抗每公斤体重5.4毫克，其余817例给予恩美曲妥珠单抗每公斤体重3.6毫克，每个21天静脉给药1次，共14次。主要终点为无浸润癌生存，关键次要终点为无癌生存（包括无乳腺非浸润癌和非乳腺第二原发癌生存），其他终点包括总生存、无远处复发生存、无脑转移生存和安全性。
截至2025年7月2日中期分析，德曲妥珠单抗组与恩美曲妥珠单抗组相比：
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中位随访：29.9个月比29.7个月
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浸润癌或死亡发生率：6.2%比12.5%
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浸润癌或死亡风险：减少53%（风险比：0.47，95%置信区间：0.34～0.66，P<0.001）
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3年无浸润癌生存率：92.4%比83.7%
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浸润癌发生率：6.4%比12.6%
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非浸润癌或死亡风险：减少53%（风险比：0.47，95%置信区间：0.34～0.66，P<0.001）
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3年无癌生存率：92.3%比83.5%
德曲妥珠单抗组最常见不良事件发生率：
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恶心：71.3%
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便秘：32.0%
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中性粒细胞计数减少：31.6%
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呕吐：31.0%
恩美曲妥珠单抗组最常见不良事件发生率：
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谷草转氨酶升高：50.2%
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谷丙转氨酶升高：45.3%
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血小板计数减少：49.8%
经裁定，德曲妥珠单抗组与恩美曲妥珠单抗组相比，药物相关肺间质病发生率为9.6%比1.6%，德曲妥珠单抗组肺间质病患者死亡2例。
因此，该研究结果表明，对于高风险HER2阳性乳腺癌术前治疗后仍残留浸润癌患者，德曲妥珠单抗与恩美曲妥珠单抗相比，3年无浸润癌生存率显著提高，毒性反应主要发生于胃肠和血液系统，重要风险为肺间质病，需要进行密切监测和管理。
相关链接
N Engl J Med. 2025 Dec 10. IF: 78.5
Trastuzumab Deruxtecan in Residual HER2-Positive Early Breast Cancer.
Loibl S, Park YH, Shao Z, Huang CS, Barrios C, Abraham J, Prat A, Niikura N, Im SA, Li W, Li H, Wang Y, Yao H, Kim SB, Geng CZ, Rodriguez Pantigoso W, Ramírez Godinez FJ, Song C, Ching Chang Y, Antoniazzi A, Chen SC, Li Z, Nowecki Z, Lim J, Mathias E, Sato Y, Lu W, Abdel-Monem H, Untch M, Geyer CE Jr; DESTINY-Breast05 Trial Investigators.
German Breast Group, Neu-Isenburg, Germany; Goethe University Frankfurt, Frankfurt am Main, Germany; Health and Medical University, Breast Cancer Center, Helios Hospital Berlin-Buch, Berlin, Germany; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Seoul National University Hospital, Seoul, Korea; Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; Fudan University Cancer Hospital, Shanghai, China; National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan, China; First Hospital of Jilin University, Changchun, China; Peking University Cancer Hospital and Institute, Beijing, China; Cancer Hospital of Shandong First Medical University, Jinan, China; Sun Yat-Sen Memorial Hospital, Guangzhou, China; Fourth Hospital of Heibei Medical University, Shijiazhuang, China; Union Hospital of Fujian Medical University, Fuzhou, China; MacKay Memorial Hospital, Taipei, Taiwan, China; Chang Gung Memorial Hospital, Taoyuan City, Taiwan, China; Harbin Medical University Cancer Hospital, Harbin, China; Hospital Sao Lucas, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil; Fundacao Pio XII-Hospital do Cancer de Barretos, Sao Paulo, Brazil; Cleveland Clinic, Cleveland, USA; Daiichi Sankyo, Basking Ridge, NJ, USA; National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation, Pittsburgh, USA; University of Pittsburgh School of Medicine-UPMC Hillman Cancer Center, Pittsburgh, USA; Hospital Clínic de Barcelona, Barcelona, Spain; University of Barcelona, Barcelona, Spain; Tokai University School of Medicine, Isehara, Japan; Instituto Peruano de Oncología y Radioterapia, Lima, Peru; Hospital Civil de Guadalajara, Guadalajara, Mexico; Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland; National University Cancer Institute, Singapore; Daiichi Sankyo, Rueil-Malmaison, France.
BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer and residual disease after neoadjuvant therapy are at high risk for recurrence.
METHODS: In a phase 3, open-label, international, randomized trial, we investigated postneoadjuvant trastuzumab deruxtecan (T-DXd; 5.4 mg per kilogram of body weight) as compared with trastuzumab emtansine (T-DM1; 3.6 mg per kilogram), the current standard treatment, in patients with HER2-positive breast cancer with residual invasive disease and node-positive disease at surgery or inoperable disease at diagnosis. The primary end point was invasive disease-free survival, and the key secondary end point was disease-free survival (including survival free from noninvasive breast cancers and second primary nonbreast cancers). Other end points included overall survival, distant recurrence-free interval, brain metastasis-free interval, and safety.
RESULTS: A total of 1635 patients were randomly assigned (in a 1:1 ratio) to receive T-DXd (818 patients) or T-DM1 (817 patients). At the data-cutoff date, the median duration of follow-up was approximately 30 months in each group. Invasive-disease events or deaths were reported in 51 patients (6.2%) in the T-DXd group and 102 patients (12.5%) in the T-DM1 group (hazard ratio, 0.47; 95% confidence interval [CI], 0.34 to 0.66; P<0.001); 3-year invasive disease-free survival was 92.4% and 83.7%, respectively. Invasive-disease events, noninvasive-disease events, or deaths were reported in 52 patients (6.4%) in the T-DXd group and 103 patients (12.6%) in the T-DM1 group (hazard ratio, 0.47; 95% CI, 0.34 to 0.66; P<0.001); 3-year disease-free survival was 92.3% and 83.5%, respectively. The most common adverse events were nausea (71.3% of patients), constipation (32.0%), decreased neutrophil count (31.6%), and vomiting (31.0%) with T-DXd and increased liver-enzyme levels (aspartate aminotransferase [50.2%] and alanine aminotransferase [45.3%]) and decreased platelet count (49.8%) with T-DM1. The incidence of adjudicated drug-related interstitial lung disease was higher with T-DXd than with T-DM1 (9.6% vs. 1.6%). Two patients with interstitial lung disease in the T-DXd group died.
CONCLUSIONS: In patients with high-risk, residual invasive HER2-positive breast cancer, postneoadjuvant T-DXd resulted in a significantly higher likelihood of invasive disease-free survival than T-DM1; toxic effects were mainly gastrointestinal and hematologic. An important identified risk of T-DXd is interstitial lung disease, which requires appropriate monitoring and management.
Funded by Daiichi Sankyo and AstraZeneca
DESTINY-Breast05 ClinicalTrials.gov number: NCT04622319
PMID: 41370739
DOI: 10.1056/NEJMoa2514661