Constitutive phosphorylated STAT3-associated gene signature is predictive for trastuzumab resistance in primary HER2-positive breast cancer

BMC Medicine

Christos Sotiriou^1,10  Martine Piccart^1,10  Pirkko-Liisa Kellokumpu-Lehtinen¹  Nicolas Sirtaine⁹  Sherene Loi⁵  Heikki Joensuu²  Carsten Denkert⁴  Sibylle Loibl⁷  Patrick Neven⁸  Christine Desmedt³  Françoise Rothé³  Gert Van den Eynden⁶  Roberto Salgado³  Michail Ignatiadis^1,10  David Venet³  Delphine Vincent³  Debora Fumagalli³  Sylvain Brohée³  Amir Sonnenblick³ 

[1] Department of Oncology, University of Tampere and Tampere University Hospital, PO Box 607, Tampere, FIN 33101, Finland;Department of Oncology, Helsinki University, Hospital and Helsinki University, Helsinki, Finland;Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Bld de Waterloo, Université Libre de Bruxelles, Brussels, 1000, Belgium;Institute of Pathology, Charité Hospital Campus Mitte, and German Cancer Consortium (DKTK), Berlin, Germany;Division of Cancer Medicine and Research, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia;Molecular Immunology Lab, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, 1000, Belgium;German Breast Group, Neu-Isenburg and Sana-Klinikum, Offenbach, Germany;Multidisciplinary Breast Center, KULeuven, University Hospitals, Leuven, Belgium;Pathology Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium;Medical Oncology Unit, Institut Jules Bordet, Université Libre de Bruxelles, Bld de Waterloo, 1000, Brussels, Belgium

关键词: Trastuzumab resistance;    Randomised trial;    Phosphorylated STAT3;    HER2;    FinHer;    Breast cancer;   

Others  :  1222069
DOI  :  10.1186/s12916-015-0416-2

 received in 2015-04-22, accepted in 2015-07-01,  发布年份 2015

【 摘 要 】

Background

The likelihood of recurrence in patients with breast cancer who have HER2-positive tumors is relatively high, although trastuzumab is a remarkably effective drug in this setting. Signal transducer and activator of transcription 3 protein (STAT3), a transcription factor that is persistently tyrosine-705 phosphorylated (pSTAT3) in response to numerous oncogenic signaling pathways, activates downstream proliferative and anti-apoptotic pathways. We hypothesized that pSTAT3 expression in HER2-positive breast cancer will confer trastuzumab resistance.

Methods

We integrated reverse phase protein array (RPPA) and gene expression data from patients with HER2-positive breast cancer treated with trastuzumab in the adjuvant setting.

Results

We show that a pSTAT3-associated gene signature (pSTAT3-GS) is able to predict pSTAT3 status in an independent dataset (TCGA; AUC = 0.77, P = 0.02). This suggests that STAT3 induces a characteristic set of gene expression changes in HER2-positive cancers. Tumors characterized as high pSTAT3-GS were associated with trastuzumab resistance (log rank P = 0.049). These results were confirmed using data from the prospective, randomized controlled FinHer study, where the effect was especially prominent in HER2-positive estrogen receptor (ER)-negative tumors (interaction test P = 0.02). Of interest, constitutively activated pSTAT3 tumors were associated with loss of PTEN, elevated IL6, and stromal reactivation.

Conclusions

This study provides compelling evidence for a link between pSTAT3 and trastuzumab resistance in HER2-positive primary breast cancers. Our results suggest that it may be valuable to add agents targeting the STAT3 pathway to trastuzumab for treatment of HER2-positive breast cancer.

【 授权许可】

   
2015 Sonnenblick et al.

【 图 表 】

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