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• W2604752435 abstract "You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology I1 Apr 2017MP44-08 THE LANDSCAPE OF HER2 ALTERATIONS IN MUSCLE-INVASIVE BLADDER CANCER: IMPACT ON PATIENT SELECTION FOR TARGETED THERAPIES? Bernhard Kiss, Alexander Wyatt, James Douglas, Veronika Skuginna, Fan Mo, Shawn Anderson, Diana Rotzer, Achim Fleischmann, Vera Genitsch, Tetsutaro Hayashi, Maja Neuenschwander, Christine Buerki, Elai Davicioni, Colin Collins, George Thalmann, Peter Black, and Roland Seiler Bernhard KissBernhard Kiss More articles by this author , Alexander WyattAlexander Wyatt More articles by this author , James DouglasJames Douglas More articles by this author , Veronika SkuginnaVeronika Skuginna More articles by this author , Fan MoFan Mo More articles by this author , Shawn AndersonShawn Anderson More articles by this author , Diana RotzerDiana Rotzer More articles by this author , Achim FleischmannAchim Fleischmann More articles by this author , Vera GenitschVera Genitsch More articles by this author , Tetsutaro HayashiTetsutaro Hayashi More articles by this author , Maja NeuenschwanderMaja Neuenschwander More articles by this author , Christine BuerkiChristine Buerki More articles by this author , Elai DavicioniElai Davicioni More articles by this author , Colin CollinsColin Collins More articles by this author , George ThalmannGeorge Thalmann More articles by this author , Peter BlackPeter Black More articles by this author , and Roland SeilerRoland Seiler More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1339AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In contrast to cancers of the breast and stomach, targeting Her2 has not yet demonstrated anti-tumor activity in muscle-invasive bladder cancer (MIBC). We hypothesized that an integrated approach to Her2 characterization in MIBC may better guide patient prioritization for targeted therapy. METHODS We investigated Her2 alterations on different biological levels (DNA, RNA and protein) in pre-chemotherapy MIBC of 127 patients who recieved at least 3 cycles of neoadjuvant chemotherapy prior to radical cystectomy (NAC cohort). The findings were underlined in the The Cancer Genome Atlas (TCGA) bladder dataset (n=407). Moreover, the signifcance of Her2 was analysed between the recently identified molecular subtypes (TCGA clusters). RESULTS In the NAC cohort, FISH revealed that 16/83 tumors harbored ERBB2 amplification, while 24/127 had high Her2 protein expression by IHC (i.e. IHC score = 3). Samples with ERBB2 amplification had higher mRNA (p<0.001) and protein expression (p<0.001). However, 6/16 amplified samples had mRNA expression in the 1st tertile, and 10/16 had IHC scores of either 1 (n=5) or 2 (n=5). Interestingly, epigenetic regulation may downregulate Her2 expression. ERBB2 amplified tumors with low mRNA and protein expression showed a high ERBB2 methylation rate (R=-0.62, p<0.001). While the vast majority of ERBB2 amplified tumors (37/41), showed amplification of other known oncogenes (e.g. CCND1, CCDE1), 4 tumors showed ‘exclusively’ ERBB2 amplification.In both datasets, Her2 alterations were most frequent in TCGA cluster I. None of the Her2 alterations harbored prognostic information in the TCGA dataset. In the NAC dataset, Her2 was a marker of unfavourable outcome in tumors assigned to TCGA cluster I. CONCLUSIONS Assessment of Her2 alterations on all biological levels provides a more comprehensive insight into Her2, than FISH or/and IHC alone. Failure of previous clinical trials may have confounded by this complex molecular landscape of Her2 alterations in MIBC. Our findings could help to improve patient selection for future clinical trials. Finally, Her2 activity is associated with molecular subtypes and therefore, future biomarker studies should take molecular subtypes into account. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e566-e567 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Bernhard Kiss More articles by this author Alexander Wyatt More articles by this author James Douglas More articles by this author Veronika Skuginna More articles by this author Fan Mo More articles by this author Shawn Anderson More articles by this author Diana Rotzer More articles by this author Achim Fleischmann More articles by this author Vera Genitsch More articles by this author Tetsutaro Hayashi More articles by this author Maja Neuenschwander More articles by this author Christine Buerki More articles by this author Elai Davicioni More articles by this author Colin Collins More articles by this author George Thalmann More articles by this author Peter Black More articles by this author Roland Seiler More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ..." @default.
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