Cargando…

HER2 as a target in invasive urothelial carcinoma

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), D...

Descripción completa

Detalles Bibliográficos
Autores principales: Bellmunt, Joaquim, Werner, Lillian, Bamias, Aristotle, Fay, André P, Park, Rachel S, Riester, Markus, Selvarajah, Shamini, Barletta, Justine A, Berman, David M, de Muga, Silvia, Salido, Marta, Gallardo, Enrique, Rojo, Federico, Guancial, Elizabeth A, Bambury, Richard, Mullane, Stephanie A, Choueiri, Toni K, Loda, Massimo, Stack, Edward, Rosenberg, Jonathan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BlackWell Publishing Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472207/
https://www.ncbi.nlm.nih.gov/pubmed/25720673
http://dx.doi.org/10.1002/cam4.432
_version_ 1782377021537517568
author Bellmunt, Joaquim
Werner, Lillian
Bamias, Aristotle
Fay, André P
Park, Rachel S
Riester, Markus
Selvarajah, Shamini
Barletta, Justine A
Berman, David M
de Muga, Silvia
Salido, Marta
Gallardo, Enrique
Rojo, Federico
Guancial, Elizabeth A
Bambury, Richard
Mullane, Stephanie A
Choueiri, Toni K
Loda, Massimo
Stack, Edward
Rosenberg, Jonathan
author_facet Bellmunt, Joaquim
Werner, Lillian
Bamias, Aristotle
Fay, André P
Park, Rachel S
Riester, Markus
Selvarajah, Shamini
Barletta, Justine A
Berman, David M
de Muga, Silvia
Salido, Marta
Gallardo, Enrique
Rojo, Federico
Guancial, Elizabeth A
Bambury, Richard
Mullane, Stephanie A
Choueiri, Toni K
Loda, Massimo
Stack, Edward
Rosenberg, Jonathan
author_sort Bellmunt, Joaquim
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4472207
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher BlackWell Publishing Ltd
record_format MEDLINE/PubMed
spelling pubmed-44722072015-06-23 HER2 as a target in invasive urothelial carcinoma Bellmunt, Joaquim Werner, Lillian Bamias, Aristotle Fay, André P Park, Rachel S Riester, Markus Selvarajah, Shamini Barletta, Justine A Berman, David M de Muga, Silvia Salido, Marta Gallardo, Enrique Rojo, Federico Guancial, Elizabeth A Bambury, Richard Mullane, Stephanie A Choueiri, Toni K Loda, Massimo Stack, Edward Rosenberg, Jonathan Cancer Med Cancer Research 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. BlackWell Publishing Ltd 2015-06 2015-02-26 /pmc/articles/PMC4472207/ /pubmed/25720673 http://dx.doi.org/10.1002/cam4.432 Text en © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Cancer Research
Bellmunt, Joaquim
Werner, Lillian
Bamias, Aristotle
Fay, André P
Park, Rachel S
Riester, Markus
Selvarajah, Shamini
Barletta, Justine A
Berman, David M
de Muga, Silvia
Salido, Marta
Gallardo, Enrique
Rojo, Federico
Guancial, Elizabeth A
Bambury, Richard
Mullane, Stephanie A
Choueiri, Toni K
Loda, Massimo
Stack, Edward
Rosenberg, Jonathan
HER2 as a target in invasive urothelial carcinoma
title HER2 as a target in invasive urothelial carcinoma
title_full HER2 as a target in invasive urothelial carcinoma
title_fullStr HER2 as a target in invasive urothelial carcinoma
title_full_unstemmed HER2 as a target in invasive urothelial carcinoma
title_short HER2 as a target in invasive urothelial carcinoma
title_sort her2 as a target in invasive urothelial carcinoma
topic Cancer Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472207/
https://www.ncbi.nlm.nih.gov/pubmed/25720673
http://dx.doi.org/10.1002/cam4.432
work_keys_str_mv AT bellmuntjoaquim her2asatargetininvasiveurothelialcarcinoma
AT wernerlillian her2asatargetininvasiveurothelialcarcinoma
AT bamiasaristotle her2asatargetininvasiveurothelialcarcinoma
AT fayandrep her2asatargetininvasiveurothelialcarcinoma
AT parkrachels her2asatargetininvasiveurothelialcarcinoma
AT riestermarkus her2asatargetininvasiveurothelialcarcinoma
AT selvarajahshamini her2asatargetininvasiveurothelialcarcinoma
AT barlettajustinea her2asatargetininvasiveurothelialcarcinoma
AT bermandavidm her2asatargetininvasiveurothelialcarcinoma
AT demugasilvia her2asatargetininvasiveurothelialcarcinoma
AT salidomarta her2asatargetininvasiveurothelialcarcinoma
AT gallardoenrique her2asatargetininvasiveurothelialcarcinoma
AT rojofederico her2asatargetininvasiveurothelialcarcinoma
AT guancialelizabetha her2asatargetininvasiveurothelialcarcinoma
AT bamburyrichard her2asatargetininvasiveurothelialcarcinoma
AT mullanestephaniea her2asatargetininvasiveurothelialcarcinoma
AT choueiritonik her2asatargetininvasiveurothelialcarcinoma
AT lodamassimo her2asatargetininvasiveurothelialcarcinoma
AT stackedward her2asatargetininvasiveurothelialcarcinoma
AT rosenbergjonathan her2asatargetininvasiveurothelialcarcinoma