HER2 as a target in invasive urothelial carcinoma

• Published in: Cancer medicine (Malden, MA) MA), 2015-06, Vol.4 (6), p.844-852
• Main Authors: Bellmunt, Joaquim, Werner, Lillian, Bamias, Aristotle, Fay, André P., Park, Rachel S., Riester, Markus, Selvarajah, Shamini, Barletta, Justine A., Berman, David M., 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
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.432

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