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HER2-HER3 dimer quantification by FLIM-FRET predicts breast cancer metastatic relapse independently of HER2 IHC status
Date Issued
2016-07-07
Date Available
2019-04-01T10:57:44Z
Abstract
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.
Sponsorship
European Commission - Seventh Framework Programme (FP7)
Science Foundation Ireland
Other Sponsorship
Cancer Research UK
King’s College London-UCL Comprehensive Cancer Imaging Centre (CR-UK & EPSRC)
KCL Breast Cancer Now Unit
SynSignal
Primes
Type of Material
Journal Article
Publisher
Impact Journals
Journal
Oncotarget
Volume
7
Issue
32
Start Page
51012
End Page
51026
Copyright (Published Version)
2016 the Authors
Language
English
Status of Item
Peer reviewed
This item is made available under a Creative Commons License
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Name
HER2-HER3 dimer quantification by FLIM-FRET predicts breast.pdf
Size
8.49 MB
Format
Adobe PDF
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