Her2 alterations in muscle-invasive bladder cancer: Patient selection beyond protein expression for targeted therapy.

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.

Scientific reports. 2017 Feb 16*** epublish ***

Bernhard Kiss, Alexander W 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 N Thalmann, Peter C Black, Roland Seiler

Department of Urology, University of Bern, Bern, Switzerland., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada., Department of Urology, University Hospital of Southampton, Hampshire SO16 6YD, UK., Institute of Pathology, University of Bern, Bern, Switzerland., Department of Urology, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan., GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada.