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Oncotarget. 2018 Sep 28;9(76):34229-34239. doi: 10.18632/oncotarget.26026. eCollection 2018 Sep 28.

Inactive immune pathways in triple negative breast cancers that showed resistance to neoadjuvant chemotherapy as inferred from kinase activity profiles.

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Shien-Lab, National Cancer Center Hospital, Tokyo, Japan.
Division of Clinical Research Support, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
PamGene International BV, 's-Hertogenbosch, The Netherlands.
Department of Breast Surgery, National Cancer Center Hospital, Tokyo, Japan.
Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
Department of Basic Pathology, National Defense Medical College, Saitama, Japan.


About 5% of Triple negative breast cancer patients (TNBCs) who receive neoadjuvant chemotherapy (NAC) experience progressive disease (PD). Few reports are published on TNBCs with PD during NAC, whereas TNBCs that respond to NAC have been well-studied. We investigated kinase activity profiles of TNBCs to explore the biological differences underlying the lack of response to NAC. Among 740 TNBCs, 20 non-responders were identified. Seven non-responders and 10 TNBCs that did not receive NAC (control group) were evaluated. No correlation was observed between NAC response and age, menopausal status, tumor size and axillary lymph node status. Tyrosine kinase activity profiles of TNBC primary tissues from NAC non-responders and the controls were determined with a peptide microarray system. Kinase activity measurements showed that 35 peptides had significantly (p < 0.05) lower phosphorylation in non-responders. ZAP70, LCK, SYK and JAK2 were identified as differentially active upstream kinases. Pathway analysis suggested lower activity in immune-related pathways in non-responders. The number of tumor infiltrating lymphocytes (TILs) was significantly lower (p = 0.0053) in non-responders. Kinases related to the immune system are less activated in non-responders. TILs evaluation suggested that the immune system is hardly active in non-responders and is not activated by NAC treatment.


neoadjuvant chemotherapy; peptide micro array; triple negative breast cancer; tumor infiltrating lymphocytes; tyrosine kinase activity

Conflict of interest statement

CONFLICTS OF INTEREST Riet Hilhorst, Savithri Rangarajan, Rinie van Beuningen and Rob Ruijtenbeek are employees of PamGene International BV and have no other financial interests. The other authors have declared no conflicts of interest.

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