Clinical Research Papers:

Integrative proteomic and gene expression analysis identify potential biomarkers for adjuvant trastuzumab resistance: analysis from the Fin-her phase III randomized trial

Amir Sonnenblick _, Sylvain Brohée, Debora Fumagalli, Françoise Rothé, Delphine Vincent, Michael Ignatiadis, Christine Desmedt, Roberto Salgado, Nicolas Sirtaine, Sherene Loi, Patrick Neven, Sibylle Loibl, Carsten Denkert, Heikki Joensuu, Martine Piccart and Christos Sotiriou

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Oncotarget. 2015; 6:30306-30316. https://doi.org/10.18632/oncotarget.5080

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Amir Sonnenblick1,*, Sylvain Brohée1,*, Debora Fumagalli1, Françoise Rothé1, Delphine Vincent1, Michael Ignatiadis1, Christine Desmedt1, Roberto Salgado1, Nicolas Sirtaine2, Sherene Loi3, Patrick Neven4, Sibylle Loibl5, Carsten Denkert6, Heikki Joensuu7, Martine Piccart1, Christos Sotiriou1

1Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium

2Pathology Dept, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium

3Division of Cancer Medicine and Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia

4Multidisciplinary Breast Center, KULeuven, University Hospitals, Belgium

5German Breast Group, Neu-Isenburg and Sana-Klinikum, Offenbach, Germany

6Institute of Pathology, Charité Hospital, Campus Mitte, German Cancer Consortium (DKTK), Berlin, Germany

7Department of Oncology, Helsinki University Central Hospital and Helsinki University, Helsinki, Finland

*These authors have contributed equally to this work

Correspondence to:

Christos Sotiriou, e-mail: [email protected]

Keywords: trastuzumab resistance, AnnexinA1 (ANXA1), Fin-her, randomized trial

Received: June 08, 2015     Accepted: August 21, 2015     Published: September 03, 2015


Trastuzumab is a remarkably effective therapy for patients with human epidermal growth factor receptor 2 (HER2) - positive breast cancer (BC). However, not all women with high levels of HER2 benefit from trastuzumab.

By integrating mRNA and protein expression data from Reverse-Phase Protein Array Analysis (RPPA) in HER2-positive BC, we developed gene expression metagenes that reflect pathway activation levels. Next we assessed the ability of these metagenes to predict resistance to adjuvant trastuzumab using gene expression data from two independent datasets.

10 metagenes passed external validation (false discovery rate [fdr] < 0.05) and showed biological relevance with their pathway of origin. These metagenes were further screened for their association with trastuzumab resistance. An association with trastuzumab resistance was observed and validated only for the AnnexinA1 metagene (ANXA1). In the randomised phase III Fin-her study, tumours with low levels of the ANXA1 metagene showed a benefit from trastuzumab (multivariate: hazard ratio [HR] for distant recurrence = 0.16[95%CI 0.05–0.5]; p = 0.002; fdr = 0.03), while high expression levels of the ANXA1 metagene were associated with a lack of benefit to trastuzmab (HR = 1.29[95%CI 0.55–3.02]; p = 0.56). The association of ANXA1 with trastuzumab resistance was successfully validated in an independent series of subjects who had received trastuzumab with chemotherapy (Log Rank; p = 0.01).

In conclusion, in HER2-positive BC, some proteins are associated with distinct gene expression profiles. Our findings identify the ANXA1metagene as a novel biomarker for trastuzumab resistance.

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