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对于HER2阳性早期乳腺癌高风险患者，术前治疗可显著降低风险，现有标准方案是曲妥珠单抗＋帕妥珠单抗＋化疗。不过，现有方案毒性较高，且疗效欠佳。德曲妥珠单抗由1个曲妥珠单抗大分子与7～8个化疗药物德鲁替康小分子通过可分解四肽缀合而成，如同携带多枚核弹头的制导火箭，可靶向癌细胞释放高浓度化疗药物，已被DESTINY-Breast03和DESTINY-Breast09研究先后证实对HER2阳性晚期乳腺癌二线治疗和一线治疗显著优于现有标准方案，那么对HER2阳性早期乳腺癌高风险患者术前治疗是否有效？ 2025年10月21日，欧洲肿瘤内科学会官方期刊《肿瘤学年鉴》在线发表复旦大学附属肿瘤医院吴炅、天津市肿瘤医院曹旭晨、河南省肿瘤医院刘真真、桃园长庚纪念医院陈训彻等来自18个国家和地区147家医院学者的DESTINY-Breast11研究报告，首次对高风险HER2阳性早期乳腺癌术前德曲妥珠单抗单药或联合曲妥珠单抗＋帕妥珠单抗＋紫杉醇或多柔比星＋环磷酰胺联合曲妥珠单抗＋帕妥珠单抗＋紫杉醇的有效性和安全性进行随机分组比较。 DESTINY-Breast11 (NCT05113251): Trastuzumab Deruxtecan (T-DXd) Alone or in Sequence With THP, Versus Standard Treatment (ddAC-THP), in HER2-positive Early Breast Cancer Official Title: A Phase 3 Open-label Trial of Neoadjuvant Trastuzumab Deruxtecan (T-DXd) Monotherapy or T-DXd Followed by THP Compared to ddAC-THP in Participants With High-risk HER2-positive Early-stage Breast Cancer (DESTINY-Breast11)
该国际多中心非盲随机对照三期临床研究于2021年10月25日至2025年3月12日从18个国家和地区147个研究中心入组高风险（术前检查肿瘤≥5厘米但淋巴结阴性或肿瘤任意大小但淋巴结阳性）HER2阳性早期乳腺癌成年女性患者927例，按1比1比1随机为三组：286例单用德曲妥珠单抗8个周期、321例德曲妥珠单抗4个周期继以紫杉醇＋曲妥珠单抗＋帕妥珠单抗4个周期、320例剂量密集多柔比星＋环磷酰胺4个周期继以紫杉醇＋曲妥珠单抗＋帕妥珠单抗4个周期。根据独立数据监测委员会建议，单用德曲妥珠单抗入组于2024年3月13日提前结束。主要终点为全部入组患者的病理完全缓解（术后检查肿瘤消失或未浸润，且淋巴结阴性）。次要终点包括全部入组患者的无事件生存和实际用药患者的安全性。 结果，德、德紫曲帕、多环紫曲帕的病理完全缓解率分别为43.0%、67.3%、56.3%。 德紫曲帕与多环紫曲帕相比，病理完全缓解率高11.2%（95%置信区间：4.0～18.3，P=0.003）亚组分析： 德紫曲帕与多环紫曲帕相比，中位无事件生存（成熟度4.5%）风险比为0.56（95%置信区间：0.26～1.17）。 德、德紫曲帕、多环紫曲帕相比，不良事件发生率： 因此，该研究结果表明，对于HER2阳性早期乳腺癌高风险患者，术前德曲妥珠单抗→紫杉醇＋曲妥珠单抗＋帕妥珠单抗与现有标准方案相比，病理完全缓解有统计学显著性和临床意义，并且安全性较高。 Ann Oncol. 2025 Oct 21. IF: 65.4 Neoadjuvant trastuzumab deruxtecan alone or followed by paclitaxel, trastuzumab, and pertuzumab for high-risk HER2-positive early breast cancer (DESTINY-Breast11): a randomised, open-label, multicentre, phase 3 trial. Nadia Harbeck, Shanu Modi, Lajos Pusztai, Shinji Ohno, Jiong Wu, Sung-Bae Kim, Atsushi Yoshida, Alessandra Fabi, Xuchen Cao, Rona Joseph, Rubi Li, Bogdan Zurawski, Santiago Escrivá-de-Romaní, Renata Meneguetti, Archara Supavavej, Shin-Cheh Chen, Zhenzhen Liu, Catherine Kelly, Giuseppe Curigliano, William F. Symmans, Mohammad Gufran, Jun Ke, Adam Konpa, Pia Herbolsheimer, Jean-Francois Boileau; DESTINY-Breast11 Trial Investigators. LMU University Hospital and CCC Munich, Munich, Germany; Memorial Sloan Kettering Cancer Center, New York, NY, USA; Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA; University of Texas MD Anderson Cancer Center, Houston, TX, USA; AstraZeneca, Waltham, MA, USA; AstraZeneca, Gaithersburg, MD, USA; Sagara Hospital, Kagoshima, Japan; St. Luke's International Hospital, Chuo-ku, Tokyo, Japan; Fudan University Shanghai Cancer Center, Shanghai, China; Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Medical University, Ministry of Education, Tianjin, China; Henan Breast Cancer Centre, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China; Chang Gung Memorial Hospital, Taoyüan, Taiwan, China; Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; European Institute of Oncology, IRCCS, Milano, Italy; University of Milano, Milano, Italy; Regional Cancer Centre, Thiruvananthapuram, India; St Luke's Medical Center, Quezon City, Philippines; Professor Franciszek Lukaszczyk Oncology Center, Bydgoszcz, Poland; AstraZeneca, Warsaw, Poland; Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain; Instituto de Pesquisa Hapvida Notredame, Sao Paulo, Brazil; Chulabhorn Hospital, Chulabhorn Royal Academy, Bangkok, Thailand; Mater Private Hospital, Dublin and Cancer Trials Ireland Breast Group, Dublin, Ireland; AstraZeneca, Luton, UK; Montreal Jewish General Hospital, Segal Cancer Centre, McGill University, Montreal, QC, Canada. HIGHLIGHTS DESTINY-Breast11 is the first phase 3 study to report T-DXd outcomes for high-risk, HER2-positive early breast cancer Neoadjuvant T-DXd-THP led to a statistically significant and clinically meaningful improvement in pCR rate versus ddAC-THP Safety also favoured T-DXd-THP, with lower rates of severe and serious adverse events and haematological toxicities These data support T-DXd-THP as a more effective and less toxic neoadjuvant treatment than anthracycline-based therapy
BACKGROUND: Neoadjuvant standard-of-care for HER2-positive early-stage breast cancer is trastuzumab+pertuzumab with polychemotherapy; however, existing regimens have high toxicity burdens and suboptimal outcomes. DESTINY-Breast11 assessed efficacy and safety of neoadjuvant trastuzumab deruxtecan (T-DXd) alone or followed by paclitaxel+trastuzumab+pertuzumab (THP) versus dose-dense doxorubicin+cyclophosphamide (ddAC) followed by THP for high-risk (≥cT3cN0 or cT0-4cN1-3), HER2-positive disease. PATIENTS AND METHODS: This open-label, phase 3 trial (147 sites, 18 countries) randomised adults 1:1:1 to T-DXd (×8 cycles), T-DXd-THP (4+4 cycles), or ddAC-THP (4+4 cycles). T-DXd-alone arm enrolment closed early following Independent Data Monitoring Committee recommendation. The primary endpoint was pathological complete response (pCR; ypT0/is ypN0; intent-to-treat population). Secondary endpoints included event-free survival (EFS; intent-to-treat population) and safety (safety analysis set). ClinicalTrials.gov: NCT05113251; recruitment closed. RESULTS: Between 25/10/2021 and 12/03/2025, 286 (T-DXd), 321 (T-DXd-THP), and 320 (ddAC-THP) female patients were randomised. pCR rates were 43.0% (T-DXd, n=123), 67.3% (T-DXd-THP, n=216), and 56.3% (ddAC-THP, n=180). T-DXd-THP versus ddAC-THP absolute pCR rate difference was 11.2% (95% CI, 4.0, 18.3; p=0.003), with benefit in hormone receptor-positive (61.4% [n/N=145/236] vs 52.3% [n/N=123/235]; ΔpCR 9.1% [95% CI, 0.2, 17.9]) and -negative (83.1% [n/N=69/83] vs 67.1% [n/N=57/85]; ΔpCR 16.1% [95% CI, 3.0, 28.8]) subgroups. Median EFS (T-DXd-THP vs ddAC-THP, maturity 4.5%) hazard ratio was 0.56 [95% CI, 0.26, 1.17]). Grade ≥3 AE (T-DXd, 22.6% [n=64]; T-DXd-THP, 37.5% [n=120]; ddAC-THP, 55.8% [n=174]), serious AE (T-DXd, 10.2% [n=29]; T-DXd-THP, 10.6% [n=34]; ddAC-THP, 20.2% [n=63]), and all-grade left-ventricular dysfunction (T-DXd, 0.7% [n=2]; T-DXd-THP, 1.3% [n=4]; ddAC-THP, 6.1% [n=19]) rates were lower for T-DXd and T-DXd-THP than ddAC-THP. All-grade adjudicated drug-related interstitial lung disease/pneumonitis rates were low and similar across arms (T-DXd, 4.9% [n=14]; T-DXd-THP, 4.4% [n=14]; ddAC-THP, 5.1% [n=16]). Three treatment-related deaths occurred (T-DXd-THP, 0.3% [n=1]; ddAC-THP, 0.6% [n=2]). CONCLUSIONS: Neoadjuvant T-DXd-THP demonstrated statistically significant and clinically meaningful pCR benefit and improved safety versus ddAC-THP. KEYWORDS: neoadjuvant, early breast cancer, HER2-positive, trastuzumab deruxtecan, pathological complete response DOI: 10.1016/j.annonc.2025.10.019
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