Research Papers:

HER4 expression status correlates with improved outcome in both neoadjuvant and adjuvant Trastuzumab treated invasive breast carcinoma

Bryce P Portier _, Eugen C. Minca, Zhen Wang, Christopher Lanigan, Aaron M. Gruver, Erinn Downs-Kelly, G. Thomas Budd and Raymond R. Tubbs

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Oncotarget. 2013; 4:1662-1672. https://doi.org/10.18632/oncotarget.1232

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Bryce P Portier1, Eugen C Minca2, Zhen Wang2, Christopher Lanigan2, Aaron M Gruver2, Erinn Downs-Kelly2, G Thomas Budd3, and Raymond R Tubbs2

1 Department of Pathology and Genomic Medicine, Houston Methodist, Houston, TX

2 Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH

3 Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH


Bryce P. Portier, email:

Keywords: Breast carcinoma, HER2, HER4, Immunohistochemistry, RT-qPCR, Trastuzumab, H-Score

Received: July 31, 2013 Accepted: August 24, 2013 Published: August 26, 2013


Prognostic and predictive markers utilized in invasive breast carcinoma are limited and include ER, PR, Ki67, and ERBB2 (HER2). In the case of HER2, over-expression or amplification serves as eligibility for anti-HER2 based therapy, including trastuzumab (Herceptin®, Genentech). While clinical trials have shown trastuzumab improves overall survival and time to progression, an individual’s response to anti-HER2 based therapy is highly variable. This suggests that, in a “uniform” HER2 positive population, additional markers could help in predicting patient outcome to therapy. Here we utilized a recently validated high-specificity HER4 antibody (E200) and generated a standard clinical HER4 scoring algorithm (HER4 H-Score) utilizing two breast carcinoma cohorts: 1) patients receiving neoadjuvant trastuzumab (n=47) and 2) patients receiving trastuzumab for metastatic disease (n=33). Our HER4 H-Score showed significant correlation with high sensitivity RT-qPCR performed on matched patients (p=<0.0001). In addition, patients with HER2/HER4 co-over-expression status showed a significant delay in development of metastasis after neo-adjuvant trastuzumab therapy (p= 0.04) and showed a significant improvement in progression free survival after adjuvant trastuzumab therapy (p=0.03). These findings suggest HER4 IHC, used in conjunction with a standard HER2 testing algorithm, could aid in predicting clinical outcome and help identify patients likely to show improved response to trastuzumab therapy.

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