Shami R, Salgado R, Bardia A, Curigliano G, Hu X, Dent R, Pierga J-Y, Tsurutani J, Wildiers H, Ricciardi G, Marchiò C, Penault-Llorca F, Bor-Angelier C, Manoogian M, Lucas S, Olson M T, Liu X, Toro P, Baker A F, Fang Q, Su J, Yoder A, Andrzejuk-Ćwik A, Darilay A, Matsuo T, Jones F, Viale G
Diagnostics and HBS Sciences (DSS), Precision Medicine and Biosamples, Oncology R&D, AstraZeneca, Cambridge, UK.
Division of Research, Peter MacCallum Cancer Centre, Melbourne, Australia; Department of Pathology, ZAS Hospitals, Antwerp, Belgium.
ESMO Open. 2025 Jun;10(6):105310. doi: 10.1016/j.esmoop.2025.105310. Epub 2025 Jun 9.
The DESTINY-Breast06 study demonstrated a statistically significant and clinically meaningful improvement in progression-free survival benefit with trastuzumab deruxtecan (T-DXd) versus chemotherapy treatment of physician's choice in patients with hormone receptor-positive metastatic breast cancer (mBC) whose tumors were scored as human epidermal growth factor receptor 2 (HER2)-low [immunohistochemistry (IHC) 1+, or IHC 2+/in situ hybridization (ISH)-negative] and who had received one or more lines of endocrine therapy and no previous chemotherapy in the metastatic setting. An exploratory analysis consistently showed a benefit for patients with HER2-low and HER2-ultralow (IHC 0 with membrane staining) expression.
Analytical validation of the PATHWAY HER2 (4B5) assay (Roche HER2 4B5 assay; Roche Diagnostic Solutions) at the HER2-ultralow cut-off was carried out, including intermediate precision, inter-reader precision, and inter-laboratory reproducibility. Patients with tumors historically classified as HER2-negative (IHC 0, 1+, and 2+/ISH-negative) based on pre-existing local test results were eligible for screening for DESTINY-Breast06; tumor samples taken in the metastatic setting were assessed centrally to confirm eligibility regarding HER2 status. Additionally, central and pre-existing HER2 test results were compared, and the prevalence of IHC scores based on central test results was assessed.
Intermediate precision met the pre-specified endpoints across all parameters tested; agreement was observed within and between readers and sites, demonstrating that the HER2-ultralow cut-off can be scored accurately and reproducibly using the Roche HER2 4B5 assay (intra- and inter-laboratory and inter-reader agreement ≥95%). A clinically meaningful progression-free survival (hazard ratios 0.43-0.78) and objective response rate (odds ratios 2.5-4.5) improvement for T-DXd over chemotherapy was consistently observed across IHC expression levels. For cases with a pre-existing HER2 IHC 0 result, central testing found 24% with HER2-low, 40% with IHC 0 with membrane staining, and 35% with IHC 0 absent membrane staining.
For patients with HER2 IHC 0 mBC, rescoring and/or retesting with the Roche HER2 4B5 assay is encouraged to determine eligibility for T-DXd.
DESTINY-Breast06研究表明，对于激素受体阳性转移性乳腺癌（mBC）患者，其肿瘤被判定为人类表皮生长因子受体2（HER2）低表达[免疫组织化学（IHC）1+，或IHC 2+/原位杂交（ISH）阴性]，且在转移情况下接受过一线或多线内分泌治疗且未接受过既往化疗，与医生选择的化疗相比，曲妥珠单抗德鲁昔单抗（T-DXd）在无进展生存期方面有统计学显著且具有临床意义的改善。一项探索性分析一致显示，HER2低表达和HER2超低表达（IHC 0伴膜染色）的患者有获益。
对PATHWAY HER2（4B5）检测（罗氏HER2 4B5检测；罗氏诊断解决方案）在HER2超低临界值时进行分析验证，包括中间精密度、阅片者间精密度和实验室间重现性。根据既往当地检测结果，肿瘤既往被分类为HER2阴性（IHC 0、1+和2+/ISH阴性）的患者有资格筛选参加DESTINY-Breast06研究；在转移情况下采集的肿瘤样本进行中心评估，以确认HER2状态的合格性。此外，比较中心和既往的HER2检测结果，并评估基于中心检测结果的IHC评分患病率。
在所有测试参数中，中间精密度均达到预先设定的终点；在阅片者内部和之间以及不同位点之间观察到一致性，表明使用罗氏HER2 4B5检测可以准确且可重复地对HER2超低临界值进行评分（实验室内和实验室间以及阅片者间一致性≥95%）。在所有IHC表达水平上，均一致观察到T-DXd相对于化疗在临床上有意义的无进展生存期改善（风险比0.43 - 0.78）和客观缓解率改善（优势比2.5 - 4.5）。对于既往HER2 IHC 0结果的病例，中心检测发现24%为HER2低表达，40%为IHC 0伴膜染色，35%为IHC 0无膜染色。
对于HER2 IHC 0 mBC患者，鼓励使用罗氏HER2 4B5检测重新评分和/或重新检测，以确定是否符合T-DXd治疗条件。
