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

Eur Urol. 2015 Jan 27. [Epub ahead of print]

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 hadERBB2mutations (p = 0.003).ERBB2missense mutations in complete responders were mostly confirmed activating mutations.ERCC2missense 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 thatERBB2missense 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 geneERBB2are exclusively present in patients responding to NAC.

Take Home Message

We discoveredERBB2missense mutation as a novel genomic biomarker of response to neoadjuvant platinum-containing chemotherapy. We also showed that the presence ofERCC2mutation 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

lowast 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.