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Brief Correspondence

ERBB2 Mutations Characterize a Subgroup of Muscle-invasive Bladder Cancers with Excellent Response to Neoadjuvant Chemotherapy

By: Floris H. Groenendijka, Jeroen de Jongb , Elisabeth E. Fransen van de Puttec , Magali Michauta, Andreas Schlickera, Dennis Petersd, Arno Veldse, Marja Nieuwlande, Michel M. van den Heuvelf, Ron M. Kerkhovene, Lodewijk F. Wesselsa, Annegien Broeksd, Bas W.G. van Rhijnc, René Bernardsa and Michiel S. van der Heijdena g

European Urology, Volume 69 Issue 3, March 2016, Pages 384-388

Published online: 01 March 2016

Keywords: , Muscle-invasive bladder cancer, Neoadjuvant chemotherapy, Response

Abstract Full Text Full Text PDF (1,9 MB) Patient Summary

Abstract

A pathologic complete response to neoadjuvant chemotherapy (NAC) containing platinum is a strong prognostic determinant for patients with muscle-invasive bladder cancer (MIBC). Despite comprehensive molecular characterization of bladder cancer, associations of molecular alterations with treatment response are still largely unknown. We selected pathologic complete responders (ypT0N0; n = 38) and nonresponders (higher than ypT2; n = 33) from a cohort of high-grade MIBC patients treated with NAC. DNA was isolated from prechemotherapy tumor tissue and used for next-generation sequencing of 178 cancer-associated genes (discovery cohort) or targeted sequencing (validation cohort). We found that 9 of 38 complete responders had erb-b2 receptor tyrosine kinase 2 (ERBB2) missense mutations, whereas none of 33 nonresponders had ERBB2 mutations (p = 0.003). ERBB2 missense mutations in complete responders were mostly confirmed activating mutations. ERCC2 missense mutations, recently found associated with response to NAC, were more common in complete responders; however, this association did not reach statistical significance in our cohort. We conclude that ERBB2 missense mutations characterize a subgroup of MIBC patients with an excellent response to NAC.

Patient summary

In this report we looked for genetic alterations that can predict the response to neoadjuvant chemotherapy (NAC) in bladder cancer. We found that mutations in the gene ERBB2 are exclusively present in patients responding to NAC.

Take Home Message

We discovered ERBB2 missense mutation as a novel genomic biomarker of response to neoadjuvant platinum-containing chemotherapy. We also showed that the presence of ERCC2 mutation does not always confer sensitivity to platinum-based chemotherapy.

Keywords: ERBB2, ERCC2, Muscle-invasive bladder cancer, Neoadjuvant chemotherapy, Response.

Footnotes

a Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands

b Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

c Department of Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

d Core Facility for Molecular Pathology and Biobanking, Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

e Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands

f Division of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

g Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

Corresponding author. Department of Medical Oncology, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Tel. +31 20 512 6245; Fax: +31 20 512 2572.

These authors contributed equally.

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