MP98-03 T-DM1, A NOVEL HER2 ANTIBODY-CYTOTOXIC DRUG CONJUGATE, HAS ANTI-METASTATIC POTENTIAL AND IS EFFECTIVE IN BLADDER CANCER WITH HER2 IHC SCORE 2+/3+

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology V1 Apr 2017MP98-03 T-DM1, A NOVEL HER2 ANTIBODY-CYTOTOXIC DRUG CONJUGATE, HAS ANTI-METASTATIC POTENTIAL AND IS EFFECTIVE IN BLADDER CANCER WITH HER2 IHC SCORE 2+/3+ Tetsutaro Hayashi, Htoo Zarni Oo, Wolfgang Jäger, Kohei Kobatake, Akihiro Goriki, Roland Seiler, Tilman Todenhöfer, Na Li, Ladan Fazli, Akio Matsubara, and Peter Black Tetsutaro HayashiTetsutaro Hayashi More articles by this author , Htoo Zarni OoHtoo Zarni Oo More articles by this author , Wolfgang JägerWolfgang Jäger More articles by this author , Kohei KobatakeKohei Kobatake More articles by this author , Akihiro GorikiAkihiro Goriki More articles by this author , Roland SeilerRoland Seiler More articles by this author , Tilman TodenhöferTilman Todenhöfer More articles by this author , Na LiNa Li More articles by this author , Ladan FazliLadan Fazli More articles by this author , Akio MatsubaraAkio Matsubara More articles by this author , and Peter BlackPeter Black More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.3068AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Although prior clinical trials testing trastuzumab in urothelial carcinoma of the bladder (UCB) have failed, recent genomic studies suggest that UCB could potentially respond to HER2-targeted therapy if patients are selected optimally. T-DM1 is an antibody-drug conjugate consisting of trastuzumab linked to the cytotoxic agent DM1. It showed a significant survival advantage in breast cancer patients refractory to trastuzumab. Our previous study demonstrated that T-DM1 has significant anti-tumor effects in pre-clinical models of HER2-overexpressing UCB. These effects were superior to trastuzumab and depended on level of HER2 expression. Here, we studied the potential anti-metastatic function and optimal patients of T-DM1 in UCB. METHODS HER2 expression in bladder cancer treated by radical cystectomy was examined by the same immunohistochemistry (IHC) criteria as for breast cancer. HER2 expression level in UCB cell lines was examined by western blotting (WB), qRT-PCR, FISH and FACS in adherent (AD) and anchorage independent (AI) culture conditions. RESULTS HER2 over-expression (score 2+ or 3+) in IHC was detected in 59 of 159 (37%) bladder cancer patients. HER2 expression was higher in lymph node metastases than in primary tumors. Higher HER2 expression was detected in all cell lines cultured in AI conditions, compared to those in AD conditions. Furthermore, T-DM1 significantly inhibited colony formation in soft agar compared to control IgG or trastuzumab. Since anoikis is a pre-requisite for metastasis, these results suggest that HER2 expression contributes to the establishment of metastasis and T-DM1 could have anti-metastatic potential. The bladder cancer cell line with the highest HER2 expression (BOY) was equivocal HER2 amplification by FISH (HER2/CEP17 ratio: 1.8, HER2 copy number: 4.7), which is known to correspond to HER2 IHC score 2+ in patient tissue. BOY responded most sensitively to T-DM1, and low concentration (10nM) T-DM1 induced apoptosis only in BOY. This suggests T-DM1 could be effective in patients with HER2 over-expression (IHC score 2+/3+). CONCLUSIONS Our pre-clinical results suggest that T-DM1 could have anti-metastatic potential and be a promising targeted therapy for patients with HER2 score 2+/3+ UCB. T-DM1 warrants clinical evaluation in these patients. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1312-e1313 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Tetsutaro Hayashi More articles by this author Htoo Zarni Oo More articles by this author Wolfgang Jäger More articles by this author Kohei Kobatake More articles by this author Akihiro Goriki More articles by this author Roland Seiler More articles by this author Tilman Todenhöfer More articles by this author Na Li More articles by this author Ladan Fazli More articles by this author Akio Matsubara More articles by this author Peter Black More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...