title: Her2 alterations in muscle-invasive bladder cancer: Patient selection beyond protein expression for targeted therapy.
abstract: Although the introduction of novel targeted agents has improved patient outcomes in several human cancers, no such advance has been achieved in muscle-invasive bladder cancer (MIBC). However, recent sequencing efforts have begun to dissect the complex genomic landscape of MIBC, revealing distinct molecular subtypes and offering hope for implementation of targeted therapies. Her2 (ERBB2) is one of the most established therapeutic targets in breast and gastric cancer but agents targeting Her2 have not yet demonstrated anti-tumor activity in MIBC. Through an integrated analysis of 127 patients from three centers, we identified alterations of Her2 at the DNA, RNA and protein level, and demonstrate that Her2 relevance as a tumor driver likely may vary even within ERBB2 amplified cases. Importantly, tumors with a luminal molecular subtype have a significantly higher rate of Her2 alterations than those of the basal subtype, suggesting that Her2 activity is also associated with subtype status. Although some of our findings present rare events in bladder cancer, our study suggests that comprehensively assessing Her2 status in the context of tumor molecular subtype may help select MIBC patients most likely to respond to Her2 targeted therapy.
authors.affiliation: Department of Urology, University of Bern, Bern, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kiss
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Wyatt
authors.affiliation: Department of Urology, University Hospital of Southampton, Hampshire SO16 6YD, UK.
authors.forename: James
authors.initials: J
authors.lastname: Douglas
authors.affiliation: Department of Urology, University of Bern, Bern, Switzerland.
authors.forename: Veronika
authors.initials: V
authors.lastname: Skuginna
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Fan
authors.initials: F
authors.lastname: Mo
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Shawn
authors.initials: S
authors.lastname: Anderson
authors.affiliation: Department of Urology, University of Bern, Bern, Switzerland.
authors.forename: Diana
authors.initials: D
authors.lastname: Rotzer
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Achim
authors.initials: A
authors.lastname: Fleischmann
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Vera
authors.initials: V
authors.lastname: Genitsch
authors.affiliation: Department of Urology, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.
authors.forename: Tetsutaro
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Maja
authors.initials: M
authors.lastname: Neuenschwander
authors.affiliation: GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Buerki
authors.affiliation: GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada.
authors.forename: Elai
authors.initials: E
authors.lastname: Davicioni
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Colin
authors.initials: C
authors.lastname: Collins
authors.affiliation: Department of Urology, University of Bern, Bern, Switzerland.
authors.forename: George N
authors.initials: GN
authors.lastname: Thalmann
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Black
authors.affiliation: Department of Urology, University of Bern, Bern, Switzerland.|Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Roland
authors.initials: R
authors.lastname: Seiler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004358:Drug Therapy / Q000379:methods; D005260:Female; D005784:Gene Amplification; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology*; D009361:Neoplasm Invasiveness; D018579:Patient Selection; D011110:Polymorphism, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human