title: HER2 as a target in invasive urothelial carcinoma.
abstract: We evaluated primary tumors from two cohorts, Spain (N = 111) and Greece (N = 102), for patients who were treated with platinum-based chemotherapy. Patients were tested for HER2 status (IHC score of 3+ or FISH ratio of ≥ 2.2) by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), DNA copy number, mRNA expression, and mutation status in patients with metastatic urothelial carcinoma (UC), and its impact on survival. ERBB2 mutation was determined by hotspot sequencing. mRNA expression was assessed using NanoString counting. Association of overall survival (OS) and HER2 status was assessed by a Cox regression model. NIH-3T3 cells containing HER2 V777L were assessed for growth, invasion, and HER2 kinase activation. In all, 22% of Spanish and 4% of Greek cohorts had 3+ HER2 staining by IHC. FISH amplification was identified in 20% of Spanish and 4% of Greek cohorts. Kappa coefficient between FISH and IHC was 0.47. HER2 status was not associated with OS in univariate (Spanish P = 0.34; Greek P = 0.11) or multivariate (Spanish P = 0.49; Greek P = 0.12) analysis. HER2-positive tumors expressed higher levels of HER2 mRNA than HER2-negative tumors (P < 0.001). HER2 mutations (V777L and L755S) were identified in two (2%) patients. In vitro analysis of V777L results in transformation of NIH-3T3 cells, leading to increased growth, invasion on soft agar, and HER2 kinase constitutive activation. In summary, HER2 overexpression or amplification in the primary tumor did not predict OS in patients with metastatic UC. HER2 positivity rates can differ between different populations. Further trials in genomically screened patients are needed to assess HER2-targeted therapies in UC.
authors.affiliation: Bladder Cancer Center, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Medical Oncology, University Hospital de Mar-IMIM, Barcelona, Spain.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bellmunt
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Lillian
authors.initials: L
authors.lastname: Werner
authors.affiliation: University of Athens and Hellenic Co-operative Oncology Group, Athens, Greece.
authors.forename: Aristotle
authors.initials: A
authors.lastname: Bamias
authors.affiliation: Bladder Cancer Center, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: André P
authors.initials: AP
authors.lastname: Fay
authors.affiliation: Bladder Cancer Center, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Park
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Markus
authors.initials: M
authors.lastname: Riester
authors.affiliation: Center for Molecular Oncologic Pathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Shamini
authors.initials: S
authors.lastname: Selvarajah
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Justine A
authors.initials: JA
authors.lastname: Barletta
authors.affiliation: The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: David M
authors.initials: DM
authors.lastname: Berman
authors.affiliation: Hospital de Mar Research Institute-IMIM, Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: de Muga
authors.affiliation: Hospital de Mar Research Institute-IMIM, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Salido
authors.affiliation: Hospital Parc Tauli, Sabadell, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Gallardo
authors.affiliation: Hospital de Mar Research Institute-IMIM, Barcelona, Spain.|IIS-Fundacion Jimenez Diaz, Madrid, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Rojo
authors.affiliation: Bladder Cancer Center, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Elizabeth A
authors.identifier: http://orcid.org/0000-0002-6518-5179
authors.initials: EA
authors.lastname: Guancial
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York City, New York.
authors.forename: Richard
authors.initials: R
authors.lastname: Bambury
authors.affiliation: Bladder Cancer Center, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Mullane
authors.affiliation: Bladder Cancer Center, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.affiliation: Center for Molecular Oncologic Pathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Edward
authors.initials: E
authors.lastname: Stack
authors.affiliation: Bladder Cancer Center, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Memorial Sloan Kettering Cancer Center, New York City, New York.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rosenberg
mesh_terms: D017326:Clinical Trials, Phase III as Topic; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D009154:Mutation / Q000235:genetics*; D009362:Neoplasm Metastasis; D015588:Observer Variation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: ERBB2; HER2; genomic alterations; prognosis; urothelial carcinomas