Breast Oncology Research, Division of Hematology/Oncology, Department of Medicine, Penn State Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA.
Breast Cancer Res Treat. 2013 Aug;141(1):43-53. doi: 10.1007/s10549-013-2665-0.
Trastuzumab is effective in the treatment of HER2/neu over-expressing breast cancer, but not all patients benefit from it. In vitro data suggest a role for HER3 in the initiation of signaling activity involving the AKT–mTOR pathway leading to trastuzumab insensitivity. We sought to investigate the potential of HER3 alone and in the context of p95HER2 (p95), a trastuzumab resistance marker, as biomarkers of trastuzumab escape. Using the VeraTag® assay platform, we developed a dual antibody proximity-based assay for the precise quantitation of HER3 total protein (H3T) from formalin-fixed paraffin-embedded (FFPE) breast tumors. We then measured H3T in 89 patients with metastatic breast cancer treated with trastuzumab-based therapy, and correlated the results with progression-free survival and overall survival using Kaplan–Meier and decision tree analyses that also included HER2 total (H2T) and p95 expression levels. Within the sub-population of patients that over-expressed HER2, high levels of HER3 and/or p95 protein expression were significantly associated with poor clinical outcomes on trastuzumab-based therapy. Based on quantitative H3T, p95, and H2T measurements, multiple subtypes of HER2-positive breast cancer were identified that differ in their outcome following trastuzumab therapy. These data suggest that HER3 and p95 are informative biomarkers of clinical outcomes on trastuzumab therapy, and that multiple subtypes of HER2-positive breast cancer may be defined by quantitative measurements of H3T, p95, and H2T.
曲妥珠单抗在治疗 HER2/neu 过表达的乳腺癌方面有效,但并非所有患者都从中获益。体外数据表明,HER3 在启动涉及 AKT-mTOR 通路的信号活性中发挥作用,导致曲妥珠单抗不敏感。我们试图研究 HER3 本身以及作为曲妥珠单抗逃逸生物标志物的 p95HER2(p95)在 context 中的潜力。我们使用 VeraTag® assay 平台,开发了一种双抗体邻近测定法,用于从福尔马林固定石蜡包埋(FFPE)乳腺癌肿瘤中精确定量总 HER3 蛋白(H3T)。然后,我们测量了 89 例接受曲妥珠单抗治疗的转移性乳腺癌患者的 H3T,并使用 Kaplan-Meier 和决策树分析(包括 HER2 总蛋白(H2T)和 p95 表达水平)将结果与无进展生存期和总生存期相关联。在 HER2 过表达的患者亚群中,高水平的 HER3 和/或 p95 蛋白表达与曲妥珠单抗治疗的不良临床结局显著相关。基于定量 H3T、p95 和 H2T 测量,鉴定了多种不同曲妥珠单抗治疗后结局的 HER2 阳性乳腺癌亚型。这些数据表明,HER3 和 p95 是曲妥珠单抗治疗临床结局的信息生物标志物,并且可以通过定量测量 H3T、p95 和 H2T 来定义多种 HER2 阳性乳腺癌亚型。