特定结构域HER2（ERBB2）表达的测量可能有助于对乳腺癌患者从曲妥珠单抗治疗中获益进行分类。
Measurement of Domain-Specific HER2 (ERBB2) Expression May Classify Benefit From Trastuzumab in Breast Cancer.
作者信息
Carvajal-Hausdorf Daniel E, Schalper Kurt A, Pusztai Lajos, Psyrri Amanda, Kalogeras Konstantine T, Kotoula Vasiliki, Fountzilas George, Rimm David L
机构信息
: Department of Pathology (DECH, KAS, DLR) and Medical Oncology (LP), Yale University School of Medicine, New Haven, CT; Attikon University Hospital, Athens, Greece (AP); Translational Research Section, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece (KTK); Department of Medical Oncology, "Papageorgiou" Hospital (KTK, GF), Department of Pathology (VK), and Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research (VK, GF), Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
出版信息
J Natl Cancer Inst. 2015 May 19;107(8). doi: 10.1093/jnci/djv136. Print 2015 Aug.
BACKGROUND
Studies have shown that antibodies targeting the intracellular (ICD) or extracellular domains (ECD) of human epidermal growth factor receptor 2 (HER2) are equivalent when traditional methods are used. We describe a new method to quantify ICD and ECD expression separately and assess the prognostic value of domain-specific HER2 results in patients who received adjuvant trastuzumab therapy.
METHODS
We measured HER2 protein expression with quantitative immunofluorescence (QIF) in tissue microarrays (TMA) using two different antibodies targeting the ICD (CB11 and A0485) and ECD (SP3 and D8F12). We assessed the prognostic value of ICD and ECD expression in 180 patients from a clinical trial of adjuvant chemotherapy followed by trastuzumab (HeCOG 10/05). We performed an exploratory univariate domain-specific, disease-free survival (DFS) analysis and compared DFS functions with Kaplan-Meier estimates. All statistical tests were two-sided.
RESULTS
HER2 ICD expression by QIF showed slightly higher sensitivity to predict ERBB2 (HER2) gene amplification than ECD expression, which was more specific and had higher positive predictive value. In the HeCOG 10/05 trial specimens, 15% of cases showed discordant results for ICD and ECD expression. High ECD was statistically associated with longer DFS (log-rank P = .049, HR = 0.31, 95% CI = 0.144 to 0.997), while ICD status was not. Among patients with low ECD, there was no difference in DFS by ICD status. However, when ICD was high, high ECD was statistically associated with longer DFS (log-rank P = .027, HR = 0.23, 95% CI = 0.037 to 0.82) compared with low ECD.
CONCLUSION
Quantitative measurements of HER2 ICD and ECD expression in breast cancer suggest a subclassification of HER2-positive tumors. Trastuzumab-treated patients with high ECD showed better DFS than patients with low ECD. This suggests differential benefit from trastuzumab therapy based on HER2 ECD expression.
背景
研究表明，当使用传统方法时，靶向人表皮生长因子受体2（HER2）细胞内结构域（ICD）或细胞外结构域（ECD）的抗体效果相当。我们描述了一种新方法，可分别定量ICD和ECD的表达，并评估结构域特异性HER2检测结果在接受曲妥珠单抗辅助治疗患者中的预后价值。
方法
我们在组织微阵列（TMA）中使用两种靶向ICD（CB11和A0485）和ECD（SP3和D8F12）的不同抗体，通过定量免疫荧光（QIF）测量HER2蛋白表达。我们评估了180例来自辅助化疗后接受曲妥珠单抗治疗的临床试验（HeCOG 10/05）患者中ICD和ECD表达的预后价值。我们进行了探索性单变量结构域特异性无病生存期（DFS）分析，并将DFS函数与Kaplan-Meier估计值进行比较。所有统计检验均为双侧检验。
结果
通过QIF检测的HER2 ICD表达在预测ERBB2（HER2）基因扩增方面显示出比ECD表达略高的敏感性，ECD表达更具特异性且阳性预测值更高。在HeCOG 10/05试验标本中，15%的病例ICD和ECD表达结果不一致。高ECD与更长的DFS在统计学上相关（对数秩检验P = 0.049，HR = 0.31，95%CI = 0.144至0.997），而ICD状态则不然。在ECD低的患者中，ICD状态不同，DFS无差异。然而，当ICD高时，与ECD低相比，高ECD与更长的DFS在统计学上相关（对数秩检验P = 0.027，HR = 0.23，95%CI = 0.037至0.82）。
结论
乳腺癌中HER2 ICD和ECD表达的定量测量提示HER2阳性肿瘤的一种亚分类。曲妥珠单抗治疗的ECD高的患者比ECD低的患者DFS更好。这表明基于HER2 ECD表达，曲妥珠单抗治疗有不同的获益。
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