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Reactive stroma and trastuzumab resistance in HER2-positive early breast cancer |
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| Authors: | Amir Sonnenblick Mali Salmon-Divon Roberto Salgado Efrat Dvash Noam Pondé Tamar Zahavi Asher Salmon Sibylle Loibl Carsten Denkert Heikki Joensuu Lieveke Ameye Gert Van den Eynden Pirkko-Liisa Kellokumpu-Lehtinen Amos Azaria Sherene Loi Stefan Michiels François Richard Christos Sotiriou |
| Institution: | 1. Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel;2. Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;3. Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium Medical Oncology Department, AC Camargo Cancer Center, São Paulo, Brazil;4. Sharett Institute of Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel;5. German Breast Group, Neu-Isenburg and Goethe University Frankfurt and Centre for Haematology and Oncology, Bethanien, Frankfurt, Germany;6. Institute of Pathology, Philipps-University Marburg and UKGM Marburg, Marburg, Germany;7. Department of Oncology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland;8. Data Management Unit, Institut Jules Bordet, Université Libre de Bruxelles, Belgium;9. Molecular Immunology Lab, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium;10. Department of Oncology, University of Tampere and Tampere University Hospital, Tampere, Finland;11. Department of Computer Science, Ariel University, Ariel, Israel;12. Peter MacCallum Cancer Centre, University of Melbourne, Parkville, Victoria, Australia;13. Service de Biostatistique et d'Epidémiologie, Gustave Roussy, CESP U108, University Paris-Sud, University Paris-Saclay, Villejuif, France;14. Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium;15. 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: | HER2 breast cancer reactive stroma CAF TILs |