Weitsman Gregory, Barber Paul R, Nguyen Lan K, Lawler Katherine, Patel Gargi, Woodman Natalie, Kelleher Muireann T, Pinder Sarah E, Rowley Mark, Ellis Paul A, Purushotham Anand D, Coolen Anthonius C, Kholodenko Boris N, Vojnovic Borivoj, Gillett Cheryl, Ng Tony
Richard Dimbleby Department of Cancer Research, Randall Division and Division of Cancer Studies, King's College London, Guy's Medical School Campus, London, UK.
Department of Oncology, Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
Oncotarget. 2016 Aug 9;7(32):51012-51026. doi: 10.18632/oncotarget.9963.
Overexpression of HER2 is an important prognostic marker, and the only predictive biomarker of response to HER2-targeted therapies in invasive breast cancer. HER2-HER3 dimer has been shown to drive proliferation and tumor progression, and targeting of this dimer with pertuzumab alongside chemotherapy and trastuzumab, has shown significant clinical utility. The purpose of this study was to accurately quantify HER2-HER3 dimerisation in formalin fixed paraffin embedded (FFPE) breast cancer tissue as a novel prognostic biomarker.FFPE tissues were obtained from patients included in the METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) study. HER2-HER3 dimerisation was quantified using an improved fluorescence lifetime imaging microscopy (FLIM) histology-based analysis. Analysis of 131 tissue microarray cores demonstrated that the extent of HER2-HER3 dimer formation as measured by Förster Resonance Energy Transfer (FRET) determined through FLIM predicts the likelihood of metastatic relapse up to 10 years after surgery (hazard ratio 3.91 (1.61-9.5), p = 0.003) independently of HER2 expression, in a multivariate model. Interestingly there was no correlation between the level of HER2 protein expressed and HER2-HER3 heterodimer formation. We used a mathematical model that takes into account the complex interactions in a network of all four HER proteins to explain this counterintuitive finding.Future utility of this technique may highlight a group of patients who do not overexpress HER2 protein but are nevertheless dependent on the HER2-HER3 heterodimer as driver of proliferation. This assay could, if validated in a group of patients treated with, for instance pertuzumab, be used as a predictive biomarker to predict for response to such targeted therapies.
HER2过表达是一种重要的预后标志物，也是浸润性乳腺癌中对HER2靶向治疗反应的唯一预测生物标志物。已证实HER2-HER3二聚体可驱动细胞增殖和肿瘤进展，在化疗和曲妥珠单抗基础上加用帕妥珠单抗靶向该二聚体已显示出显著的临床应用价值。本研究的目的是在福尔马林固定石蜡包埋（FFPE）乳腺癌组织中准确量化HER2-HER3二聚化，作为一种新的预后生物标志物。FFPE组织取自METABRIC（国际乳腺癌分子分类联盟）研究中的患者。使用基于组织学的改进荧光寿命成像显微镜（FLIM）分析对HER2-HER3二聚化进行量化。对131个组织微阵列核心的分析表明，通过FLIM测定的Förster共振能量转移（FRET）所测量的HER2-HER3二聚体形成程度可预测术后长达10年发生转移复发的可能性（风险比3.91（1.61-9.5），p = 0.003），在多变量模型中独立于HER2表达。有趣的是，HER2蛋白表达水平与HER2-HER3异二聚体形成之间没有相关性。我们使用了一个数学模型，该模型考虑了所有四种HER蛋白网络中的复杂相互作用来解释这一违反直觉的发现。该技术未来的应用可能会凸显出一组未过表达HER2蛋白但仍依赖HER2-HER3异二聚体作为增殖驱动因素的患者。如果在一组接受例如帕妥珠单抗治疗的患者中得到验证，该检测方法可作为预测生物标志物来预测对此类靶向治疗的反应。
