Oncotarget

Research Papers:

Whole-transcriptome analysis links trastuzumab sensitivity of breast tumors to both HER2 dependence and immune cell infiltration

Tiziana Triulzi _, Loris De Cecco, Marco Sandri, Aleix Prat, Marta Giussani, Biagio Paolini, Marialuisa L. Carcangiu, Silvana Canevari, Alberto Bottini, Andrea Balsari, Sylvie Menard, Daniele Generali, Manuela Campiglio, Serena Di Cosimo and Elda Tagliabue

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Oncotarget. 2015; 6:28173-28182. https://doi.org/10.18632/oncotarget.4405

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Abstract

Tiziana Triulzi1,*, Loris De Cecco2,*, Marco Sandri1, Aleix Prat3,4, Marta Giussani1, Biagio Paolini5, Marialuisa L. Carcangiu5, Silvana Canevari2, Alberto Bottini6, Andrea Balsari1,7, Sylvie Menard1, Daniele Generali6, Manuela Campiglio1, Serena Di Cosimo8, Elda Tagliabue1

1Department of Experimental Oncology and Molecular Medicine, Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

2Department of Experimental Oncology and Molecular Medicine, Functional Genomics Core Facility, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

3Translational Genomics Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain

4Medical Oncology Department, Hospital Clínic i Provincial, Barcelona, Spain

5Department of Pathology, Anatomic Pathology A Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

6Dipartimento di Terapia Molecolare e Farmacogenomica, Istituti Ospitalieri di Cremona, Italy

7Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Italy

8Department of Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

*These authors have contributed equally to this work

Correspondence to:

Tagliabue E, e-mail: [email protected]

Keywords: breast cancer, trastuzumab benefit, gene expression profiling, lymphocytes

Received: April 22, 2015     Accepted: June 19, 2015     Published: July 01, 2015

ABSTRACT

While results thus far demonstrate the clinical benefit of trastuzumab, some patients do not respond to this therapy. To identify a molecular predictor of trastuzumab benefit, we conducted whole-transcriptome analysis of primary HER2+ breast carcinomas obtained from patients treated with trastuzumab-containing therapies and correlated the molecular portrait with treatment benefit.

The estimated association between gene expression and relapse-free survival allowed development of a trastuzumab risk model (TRAR), with ERBB2 and ESR1 expression as core elements, able to identify patients with high and low risk of relapse. Application of the TRAR model to 24 HER2+ core biopsies from patients treated with neo-adjuvant trastuzumab indicated that it is predictive of trastuzumab response. Examination of TRAR in available whole-transcriptome datasets indicated that this model stratifies patients according to response to trastuzumab-based neo-adjuvant treatment but not to chemotherapy alone. Pathway analysis revealed that TRAR-low tumors expressed genes of the immune response, with higher numbers of CD8-positive cells detected immunohistochemically compared to TRAR-high tumors.

The TRAR model identifies tumors that benefit from trastuzumab-based treatment as those most enriched in CD8-positive immune infiltrating cells and with high ERBB2 and low ESR1 mRNA levels, indicating the requirement for both features in achieving trastuzumab response.


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