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

// Takeshi Sawada 1, 5 , Riet Hilhorst 6 , Savithri Rangarajan 6 , Masayuki Yoshida 4 , Yuko Tanabe 3 , Kenji Tamura 3 , Takayuki Kinoshita 4 , Tatsu Shimoyama 5 , Rinie van Beuningen 6 , Rob Ruijtenbeek 6 , Hitoshi Tsuda 2, 7 and Fumiaki Koizumi 1, 5 1 Shien-Lab, National Cancer Center Hospital, Tokyo, Japan 2 Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan 3 Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan 4 Department of Breast Surgery, National Cancer Center Hospital, Tokyo, Japan 5 Division of Clinical Research Support, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan 6 PamGene International BV, 's-Hertogenbosch, The Netherlands 7 Department of Basic Pathology, National Defense Medical College, Saitama, Japan Correspondence to: Fumiaki Koizumi, email: fkoizumi@cick.jp Keywords: triple negative breast cancer; neoadjuvant chemotherapy; tyrosine kinase activity; tumor infiltrating lymphocytes; peptide micro array Received: June 08, 2017      Accepted: August 02, 2018      Published: September 28, 2018 ABSTRACT 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.