Journal Article

HER2 as a target in invasive urothelial carcinoma

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

2015

Overview

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.

• Publisher: John Wiley & Sons, Inc,BlackWell Publishing Ltd
• Subject: Biomarkers / Bladder cancer / Breast cancer / Cancer Research / Chemotherapy / Clinical trials / Clinical Trials, Phase III as Topic / Cohort Studies / Copy number / Cytotoxicity / Deoxyribonucleic acid / DNA / DNA Copy Number Variations - genetics / Epidermal growth factor / ErbB-2 protein / ERBB2 / Fluorescence in situ hybridization / Gene amplification / Gene expression / Genetic transformation / genomic alterations / HER2 / Humans / Immunohistochemistry / In Situ Hybridization, Fluorescence / Invasiveness / Laboratories / Medical prognosis / Metastases / Metastasis / Mutation / Mutation - genetics / Neoplasm Metastasis / Observer Variation / Platinum / prognosis / Proteins / Ratios / Receptor, ErbB-2 - genetics / Receptor, ErbB-2 - metabolism / RNA, Messenger - genetics / RNA, Messenger - metabolism / Software / Studies / Survival Analysis / Tumors / Urinary Bladder Neoplasms - drug therapy / Urinary Bladder Neoplasms - genetics / Urothelial carcinoma / urothelial carcinomas