title: ERBB2 Mutations Characterize a Subgroup of Muscle-invasive Bladder Cancers with Excellent Response to Neoadjuvant Chemotherapy.
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.
  
  
  RESULTS
  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.
authors: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Floris H
authors: FH
authors: Groenendijk
authors: Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Jeroen
authors: J
authors: de Jong
authors: Department of Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Elisabeth E
authors: EE
authors: Fransen van de Putte
authors: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Magali
authors: M
authors: Michaut
authors: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Andreas
authors: A
authors: Schlicker
authors: Core Facility for Molecular Pathology and Biobanking, Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Dennis
authors: D
authors: Peters
authors: Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Arno
authors: A
authors: Velds
authors: Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Marja
authors: M
authors: Nieuwland
authors: Division of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Michel M
authors: MM
authors: van den Heuvel
authors: Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Ron M
authors: RM
authors: Kerkhoven
authors: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Lodewijk F
authors: LF
authors: Wessels
authors: Core Facility for Molecular Pathology and Biobanking, Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Annegien
authors: A
authors: Broeks
authors: Department of Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Bas W G
authors: BW
authors: van Rhijn
authors: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: René
authors: R
authors: Bernards
authors: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address: ms.vd.heijden@nki.nl.
authors: Michiel S
authors: MS
authors: van der Heijden
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D017024:Chemotherapy, Adjuvant; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D018579:Patient Selection; D010641:Phenotype; D057285:Precision Medicine; D011237:Predictive Value of Tests; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D013997:Time Factors; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: ERBB2; ERCC2; Muscle-invasive bladder cancer; Neoadjuvant chemotherapy; Response