HER3, p95HER2, and HER2 protein expression levels define multiple subtypes of HER2-positive metastatic breast cancer.
HER3, p95HER2, and HER2 protein expression levels define multiple subtypes of HER2-positive metastatic breast cancer.
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HER3、p95HER2 和 HER2 蛋白表达水平定义了 HER2 阳性转移性乳腺癌的多种亚型。
DOI：
10.1007/s10549-013-2665-0
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发表时间：
2013-08
影响因子：
3.8
通讯作者：
Bates, Michael
中科院分区：
文献类型：
--
作者：
Lipton, Allan;Goodman, Laurie;Leitzel, Kim;Cook, Jennifer;Sperinde, Jeff;Haddad, Mojgan;Koestler, Wolfgang J.;Huang, Weidong;Weidler, Jodi M.;Ali, Suhail;Newton, Alicia;Fuchs, Eva-Marie;Paquet, Agnes;Singer, Christian F.;Horvat, Reinhard;Jin, Xueguang;Banerjee, Joyee;Mukherjee, Ali;Tan, Yuping;Shi, Yining;Chenna, Ahmed;Larson, Jeff;Lie, Yolanda;Sherwood, Thomas;Petropoulos, Christos J.;Williams, Stephen;Winslow, John;Parry, Gordon;Bates, Michael
曲妥珠单抗在治疗HER2/neu过表达乳腺癌中是有效的，但并非所有患者都能从中受益。体外数据表明HER3在AKT-mTOR通路信号活性启动中的作用，导致曲妥珠单抗不敏感。我们试图研究HER3单独和p95HER2 (p95)（曲妥珠单抗耐药标记物）作为曲妥珠单抗逃逸的生物标志物的潜力。利用VeraTag®检测平台，我们开发了一种基于双抗体接近度的检测方法，用于精确定量福尔马林固定石蜡包埋（FFPE）乳腺肿瘤中HER3总蛋白（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和决策树分析将结果与无进展生存期和总生存期相关联，该分析还包括HER2总（H2T）和p95表达水平。在HER2过表达的患者亚群中，HER3和/或p95蛋白的高水平表达与曲妥珠单抗治疗的不良临床结果显著相关。基于定量的H3T， p95和H2T测量，确定了her2阳性乳腺癌的多种亚型，这些亚型在曲妥珠单抗治疗后的结果不同。这些数据表明，HER3和p95是曲妥珠单抗治疗临床结果的信息性生物标志物，并且her2阳性乳腺癌的多种亚型可以通过H3T、p95和H2T的定量测量来确定。本文的在线版本（doi:10.1007/s10549-013-2665-0）包含补充材料，仅供授权用户使用。
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. The online version of this article (doi:10.1007/s10549-013-2665-0) contains supplementary material, which is available to authorized users.
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影响因子：
158.5
作者：
Joensuu, H;Kellokumpu-Lehtinen, P;Isola, J
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