大约70%的晚期乳腺癌为激素受体阳性HER2阴性，主要依靠内分泌治疗和化疗。对于内分泌治疗耐药患者，虽然细胞周期蛋白依赖性激酶CDK4/6抑制剂有效，但是仍然可能发生耐药。乳腺癌命运第四交响曲（DESTINY-Breast04）研究已经证实，德曲妥珠单抗与标准化疗方案相比，对HER2低表达晚期乳腺癌化疗失败患者显著有效，尤其对于激素受体阳性肿瘤。由于HER2低表达被归入HER2阴性，对曲妥珠单抗无效，那么德曲妥珠单抗对激素受体阳性HER2低表达或超低表达晚期乳腺癌内分泌治疗耐药尚未化疗患者是否有效？

　　2024年9月15日，国际四大医学期刊之一、创刊212年的美国麻省医学会《新英格兰医学杂志》以及欧洲肿瘤内科学会（ESMO）第49届大会同时公布复旦大学附属肿瘤医院胡夕春、哈尔滨医科大学附属肿瘤医院张清媛等19位国际学者的乳腺癌命运第六交响曲（DESTINY-Breast06）研究报告，首次对德曲妥珠单抗或标准化疗方案治疗激素受体阳性HER2低表达或超低表达晚期乳腺癌内分泌治疗耐药尚未化疗患者的有效性和安全性进行了比较。

  • DESTINY-Breast06 (NCT04494425): Study of Trastuzumab Deruxtecan (T-DXd) vs Investigator’s Choice Chemotherapy in HER2-low, Hormone Receptor Positive, Metastatic Breast Cancer (DB-06)
  • Official Title: A Phase 3, Randomized, Multi-center, Open-label Study of Trastuzumab Deruxtecan (T-DXd) Versus Investigator’s Choice Chemotherapy in HER2-Low, Hormone Receptor Positive Breast Cancer Patients Whose Disease Has Progressed on Endocrine Therapy in the Metastatic Setting (DESTINY-Breast06)
　　该国际多中心非盲随机对照三期临床研究于2020年8月20日至2024年3月18日从全球324个研究中心入组激素受体阳性HER2低表达（免疫组化1+或2+且原位杂交阴性）或超低表达（膜染色免疫组化0～1+）晚期乳腺癌内分泌治疗耐药（晚期至少二线内分泌治疗失败、早期术后内分泌治疗24个月内复发、晚期一线内分泌治疗＋CDK4/6抑制剂6个月内进展）尚未化疗患者866例（HER2低表达713例、超低表达153例）按1∶1随机分为两组：其中436例给予德曲妥珠单抗、其余430例给予医师选择化疗（卡培他滨、白蛋白紫杉醇或紫杉醇三选一）。主要终点为根据盲法独立集中复核的HER2低表达患者无进展生存。次要终点包括全部随机分组患者的无进展生存、总生存和安全性。
　　结果，德曲妥珠单抗与医师选择化疗相比：
  • HER2低表达患者
  • 中位无进展生存：13.2个月比8.1个月（95%置信区间：11.4～15.2、7.0～9.0）
  • 进展或死亡风险：降低38%（风险比：0.62，95%置信区间：0.51～0.74；P<0.001）
  • 全部随机分组患者
  • 中位无进展生存：13.2个月比8.1个月（95%置信区间：12.0～15.2、7.0～9.0）
  • 进展或死亡风险：降低37%（风险比：0.63，95%置信区间：0.53～0.75；P<0.001）
  • HER2超低表达患者
  • 中位无进展生存：13.2个月比8.3个月（95%置信区间：9.8～17.3、5.8～15.2）
  • 进展或死亡风险：降低22%（风险比：0.78；95%置信区间：0.50～1.21）
　　根据亚组分析，无论年龄、HER2表达水平、用过CDK4/6抑制剂、早期术前或术后是否用过紫杉类、晚期几线内分泌治疗耐药、内分泌治疗耐药为原发或继发、医师选择化疗为卡培他滨或紫杉醇、是否肝转移，德曲妥珠单抗组与医师选择化疗组相比，进展或死亡风险都显著降低，除了未用过CDK4/6抑制剂、医师选择化疗为白蛋白紫杉醇的患者进展或死亡风险降低不显著。
　　由于总死亡率尚未达到50%，故总生存尚未达到中位。
　　德曲妥珠单抗与医师选择化疗相比：
  • ≥3级不良事件发生率：52.8%比44.4%。
  • 确诊间质性肺病或实质性肺炎发生率：11.3%（49例，其中3例5级）比0.2%（1例2级）
　　因此，该研究结果表明，对于激素受体阳性HER2低表达或超低表达晚期乳腺癌内分泌治疗耐药尚未化疗患者，德曲妥珠单抗与医师选择化疗相比，无进展生存显著延长，未发现新的安全问题。该研究结果将扭转此类患者的命运，并将德曲妥珠单抗的治疗时机进一步前移至化疗之前。
　　对此，《新英格兰医学杂志》总编、循证医学副主编、执行主编发表锵锵三人行。

相关链接

N Engl J Med. 2024 Sep 15. IF: 96.2

Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer.

Bardia A, Hu X, Dent R, Yonemori K, Barrios CH, O’Shaughnessy JA, Wildiers H, Pierga JY, Zhang Q, Saura C, Biganzoli L, Sohn J, Im SA, Lévy C, Jacot W, Begbie N, Ke J, Patel G, Curigliano G; DESTINY-Breast06 Trial Investigators.

Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, and Massachusetts General Hospital, Boston, MA; Fudan University Shanghai Cancer Center, and the Department of Oncology, Shanghai Medical College, Fudan University, Shanghai; Harbin Medical University Cancer Hospital, Harbin, China; National Cancer Center Singapore, Singapore; National Cancer Center Hospital, Tokyo; Latin American Cooperative Oncology Group, Porto Alegre, Brazil; Texas Oncology and US Oncology, Baylor University Medical Center, Dallas; University Hospitals Leuven, Leuven, Belgium; Institut Curie and Université Paris Cité, Paris; Centre Francois Baclesse, Caen; Institut du Cancer de Montpellier, Université de Montpellier, INSERM Unité 1194, Montpellier, France; Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona; Santo Stefano Hospital, Azienda Unità Sanitaria Locale Toscana Centro, Prato; European Institute of Oncology, University of Milan, Milan, Italy; Yonsei Cancer Center, Seoul National University Hospital, Seoul, Korea; AstraZeneca, Cambridge, United Kingdom; AstraZeneca, Waltham, MA.

BACKGROUND: Outcomes in patients with hormone receptor-positive metastatic breast cancer worsen after one or more lines of endocrine-based therapy. Trastuzumab deruxtecan has shown efficacy in patients with metastatic breast cancer with low expression of human epidermal growth factor receptor 2 (HER2) after previous chemotherapy.

METHODS: We conducted a phase 3, multicenter, open-label trial involving patients with hormone receptor-positive metastatic breast cancer with low HER2 expression (a score of 1+ or 2+ on immunohistochemical [IHC] analysis and negative results on in situ hybridization) or ultralow HER2 expression (IHC 0 with membrane staining) who had received one or more lines of endocrine-based therapy and no previous chemotherapy for metastatic breast cancer. Patients were randomly assigned in a 1:1 ratio to receive trastuzumab deruxtecan or the physician’s choice of chemotherapy. The primary end point was progression-free survival (according to blinded independent central review) among the patients with HER2-low disease. Secondary end points included progression-free survival among all the patients who had undergone randomization, overall survival, and safety.

RESULTS: Of the 866 patients who underwent randomization, 713 had HER2-low disease, and 153 had HER2-ultralow disease. Among the patients with HER2-low disease, the median progression-free survival was 13.2 months (95% confidence interval [CI], 11.4 to 15.2) in the trastuzumab deruxtecan group and 8.1 months (95% CI, 7.0 to 9.0) in the chemotherapy group (hazard ratio for disease progression or death, 0.62; 95% CI, 0.51 to 0.74; P<0.001); the results were consistent in the exploratory HER2-ultralow population. Data for overall survival were immature. Adverse events of grade 3 or higher occurred in 52.8% of the patients in the trastuzumab deruxtecan group and in 44.4% of those in the chemotherapy group. Adjudicated interstitial lung disease or pneumonitis occurred in 49 patients (11.3%; three events were grade 5 in severity) and in 1 patient (0.2%; grade 2), respectively.

CONCLUSIONS: Among patients with hormone receptor-positive, HER2-low or HER2-ultralow metastatic breast cancer who had received one or more lines of endocrine-based therapy, treatment with trastuzumab deruxtecan resulted in longer progression-free survival than chemotherapy. No new safety signals were identified.

Funded by AstraZeneca and Daiichi Sankyo

DESTINY-Breast06 ClinicalTrials.gov number: NCT04494425

PMID: 39282896

DOI: 10.1056/NEJMoa2407086

N Engl J Med. 2024 Sep 14. IF: 96.2

NEJM at ESMO – Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer.

Rubin EJ, Yeku OO, Morrissey S.

Editor-in-Chief of NEJM; Associate Editor of NEJM Evidence; Executive Managing Editor of NEJM.

In this audio interview, Editor-in-Chief Eric Rubin and NEJM Evidence Associate Editor Oladapo Yeku discuss research being presented at the 2024 European Society of Medical Oncology annual meeting.

PMID: 39282916

DOI: 10.1056/NEJMe2411488