HER2 as a target in invasive urothelial carcinoma

Joaquim Bellmunt; Lillian Werner; Aristotle Bamias; André P. Fay; Rachel S. Park; Markus Riester; Shamini Selvarajah; Justine A. Barletta; David M. Berman; Silvia de Muga; Marta Salido; Enrique Gallardo; Federico Rojo; Elizabeth A. Guancial; Richard Bambury; Stephanie A. Mullane; Toni K. Choueiri; Massimo Loda; Edward Stack; Jonathan Rosenberg

doi:10.1002/cam4.432

HER2 as a target in invasive urothelial carcinoma

Joaquim Bellmunt, Lillian Werner, Aristotle Bamias, André P. Fay, Rachel S. Park, Markus Riester, Shamini Selvarajah, Justine A. Barletta, David M. Berman, Silvia de Muga, Marta Salido, Enrique Gallardo, Federico Rojo, Elizabeth A. Guancial, Richard Bambury, Stephanie A. Mullane, Toni K. Choueiri, Massimo Loda, Edward Stack, Jonathan Rosenberg

School of Medicine

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

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. The association between HER2 status and overall survival (OS) in UC remains unclear. HER2 positivity may not only be a biomarker for more aggressive disease but also a potential therapeutic target. We report that HER2 overexpression or amplification in the primary tumor did not predict OS in patients with metastatic UC. Further trials in genomically screened patients are needed to assess HER2-targeted therapies in UC.

Original language	English (US)
Pages (from-to)	844-852
Number of pages	9
Journal	Cancer Medicine
Volume	4
Issue number	6
DOIs	https://doi.org/10.1002/cam4.432
State	Published - Jun 1 2015

Keywords

ERBB2
Genomic alterations
HER2
Prognosis
Urothelial carcinomas

ASJC Scopus subject areas

Oncology
Radiology Nuclear Medicine and imaging
Cancer Research

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10.1002/cam4.432

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Bellmunt, J., Werner, L., Bamias, A., Fay, A. P., Park, R. S., Riester, M., Selvarajah, S., Barletta, J. A., Berman, D. M., de Muga, S., Salido, M., Gallardo, E., Rojo, F., Guancial, E. A., Bambury, R., Mullane, S. A., Choueiri, T. K., Loda, M., Stack, E., & Rosenberg, J. (2015). HER2 as a target in invasive urothelial carcinoma. Cancer Medicine, 4(6), 844-852. https://doi.org/10.1002/cam4.432

Bellmunt, J, Werner, L, Bamias, A, Fay, AP, Park, RS, Riester, M, Selvarajah, S, Barletta, JA, Berman, DM, de Muga, S, Salido, M, Gallardo, E, Rojo, F, Guancial, EA, Bambury, R, Mullane, SA, Choueiri, TK, Loda, M, Stack, E & Rosenberg, J 2015, 'HER2 as a target in invasive urothelial carcinoma', Cancer Medicine, vol. 4, no. 6, pp. 844-852. https://doi.org/10.1002/cam4.432

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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. The association between HER2 status and overall survival (OS) in UC remains unclear. HER2 positivity may not only be a biomarker for more aggressive disease but also a potential therapeutic target. We report that HER2 overexpression or amplification in the primary tumor did not predict OS in patients with metastatic UC. Further trials in genomically screened patients are needed to assess HER2-targeted therapies in UC.",

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author = "Joaquim Bellmunt and Lillian Werner and Aristotle Bamias and Fay, {Andr{\'e} P.} and Park, {Rachel S.} and Markus Riester and Shamini Selvarajah and Barletta, {Justine A.} and Berman, {David M.} and {de Muga}, Silvia and Marta Salido and Enrique Gallardo and Federico Rojo and Guancial, {Elizabeth A.} and Richard Bambury and Mullane, {Stephanie A.} and Choueiri, {Toni K.} and Massimo Loda and Edward Stack and Jonathan Rosenberg",

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doi = "10.1002/cam4.432",

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T1 - HER2 as a target in invasive urothelial carcinoma

AU - Bellmunt, Joaquim

AU - Werner, Lillian

AU - Bamias, Aristotle

AU - Fay, André P.

AU - Park, Rachel S.

AU - Riester, Markus

AU - Selvarajah, Shamini

AU - Barletta, Justine A.

AU - Berman, David M.

AU - de Muga, Silvia

AU - Salido, Marta

AU - Gallardo, Enrique

AU - Rojo, Federico

AU - Guancial, Elizabeth A.

AU - Bambury, Richard

AU - Mullane, Stephanie A.

AU - Choueiri, Toni K.

AU - Loda, Massimo

AU - Stack, Edward

AU - Rosenberg, Jonathan

PY - 2015/6/1

Y1 - 2015/6/1

N2 - 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. The association between HER2 status and overall survival (OS) in UC remains unclear. HER2 positivity may not only be a biomarker for more aggressive disease but also a potential therapeutic target. We report that HER2 overexpression or amplification in the primary tumor did not predict OS in patients with metastatic UC. Further trials in genomically screened patients are needed to assess HER2-targeted therapies in UC.

AB - 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. The association between HER2 status and overall survival (OS) in UC remains unclear. HER2 positivity may not only be a biomarker for more aggressive disease but also a potential therapeutic target. We report that HER2 overexpression or amplification in the primary tumor did not predict OS in patients with metastatic UC. Further trials in genomically screened patients are needed to assess HER2-targeted therapies in UC.

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KW - HER2

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HER2 as a target in invasive urothelial carcinoma

Abstract

Keywords

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