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Int J Cancer. 2020 Jan 6. doi: 10.1002/ijc.32859. [Epub ahead of print]

Reactive stroma and trastuzumab resistance in HER2-positive early breast cancer.

Author information

1
Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
2
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
3
Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, Israel.
4
Department of Pathology, GZA-ZNA, Antwerp, Belgium.
5
Division of Research, Peter Mac Callum Cancer Center, Melbourne, Australia.
6
Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
7
Medical Oncology Department, AC Camargo Cancer Center, São Paulo, Brazil.
8
Sharett Institute of Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
9
German Breast Group, Neu-Isenburg and Goethe University Frankfurt and Centre for Haematology and Oncology, Bethanien, Frankfurt, Germany.
10
Institute of Pathology, Philipps-University Marburg and UKGM Marburg, Marburg, Germany.
11
Department of Oncology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
12
Data Management Unit, Institut Jules Bordet, Université Libre de Bruxelles, Belgium.
13
Molecular Immunology Lab, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
14
Department of Oncology, University of Tampere and Tampere University Hospital, Tampere, Finland.
15
Department of Computer Science, Ariel University, Ariel, Israel.
16
Peter MacCallum Cancer Centre, University of Melbourne, Parkville, Victoria, Australia.
17
Service de Biostatistique et d'Epidémiologie, Gustave Roussy, CESP U108, University Paris-Sud, University Paris-Saclay, Villejuif, France.
18
Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium.
19
Institut Jules Bordet, Université Libre de Bruxelles, Belgium.

Abstract

We investigated the value of reactive stroma as a predictor for trastuzumab resistance in patients with early HER2-positive breast cancer receiving adjuvant therapy. The pathological reactive stroma and the mRNA gene signatures that reflect reactive stroma in 209 HER2-positive breast cancer samples from the FinHer adjuvant trial were evaluated. Levels of stromal gene signatures were determined as a continuous parameter, and pathological reactive stromal findings were defined as stromal predominant breast cancer (SPBC; ≥50% stromal) and correlated with distant disease-free survival. Gene signatures associated with reactive stroma in HER2-positive early breast cancer (N = 209) were significantly associated with trastuzumab resistance in estrogen receptor (ER)-negative tumors (hazard ratio [HR] = 1.27 p interaction = 0.014 [DCN], HR = 1.58, p interaction = 0.027 [PLAU], HR = 1.71, p interaction = 0.019 [HER2STROMA, novel HER2 stromal signature]), but not in ER-positive tumors (HR = 0.73 p interaction = 0.47 [DCN], HR = 0.71, p interaction = 0.73 [PLAU], HR = 0.84; p interaction = 0.36 [HER2STROMA]). Pathological evaluation of HER2-positive/ER-negative tumors suggested an association between SPBC and trastuzumab resistance. Reactive stroma did not correlate with tumor-infiltrating lymphocytes (TILs), and the expected benefit from trastuzumab in patients with high levels of TILs was pronounced only in tumors with low stromal reactivity (SPBC <50%). In conclusion, reactive stroma in HER2-positive/ER-negative early breast cancer tumors may predict resistance to adjuvant trastuzumab therapy.

KEYWORDS:

CAF; HER2; TILs; breast cancer; reactive stroma

PMID:
31904863
DOI:
10.1002/ijc.32859

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