Her2 amplification distinguishes a subset of non-muscle-invasive bladder cancers with a high risk of progression

Chen, Paul Chih-Hsueh; Yu, Hui-Jung; Chang, Yen-Hwa; Pan, Chin-Chen

doi:10.1136/jclinpath-2012-200944

Cited by 55 publications

(62 citation statements)

References 25 publications

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“…Separate studies have reported ERBB2 amplification predominantly based on FISH analysis in 8% to 9% of primary urothelial carcinomas, and at a higher frequency in lymph node metastases (20). In addition, in a study of non-muscle invasive bladder cancers, ERBB2 amplification has been observed in highgrade urothelial carcinomas (HG-UC) at a similar incidence of 9%, but not in any of the papillary urothelial neoplasms of low malignant potential or low-grade urothelial carcinomas studied, and has been associated with recurrence and progression in high-grade urothelial carcinoma (21). Her2 overexpression has been identified in 19% (22/116) of bladder cancers, with significant enrichment in grade III and muscle invasive tumors (22).…”

Section: Discussionmentioning

confidence: 99%

A High Frequency of Activating Extracellular Domain ERBB2 (HER2) Mutation in Micropapillary Urothelial Carcinoma

Ross

Wang

Al‐Rohil

et al. 2014

Clinical Cancer Research

122

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Purpose: Micropapillary urothelial carcinoma (MPUC) is a rare and aggressive form of bladder cancer. We conducted genomic analyses [next-generation sequencing (NGS)] of MPUC and non-micropapillary urothelial bladder carcinomas (non-MPUC) to characterize the genomic landscape and identify targeted treatment options.Experimental Design: DNA was extracted from 40 mm of formalin-fixed paraffin-embedded sections from 15 MPUC and 64 non-MPUC tumors. Sequencing (NGS) was performed on hybridization-captured, adaptor ligation-based libraries to high coverage for 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. The results were evaluated for all classes of genomic alteration.Results: Mutations in the extracellular domain of ERBB2 were identified in 6 of 15 (40%) of MPUC: S310F (four cases), S310Y (one case), and R157W (one case). All six cases of MPUC with ERBB2 mutation were negative for ERBB2 amplification and Erbb2 overexpression. In contrast, 6 of 64 (9.4%) non-MPUC harbored an ERBB2 alteration, including base substitution (three cases), amplification (two cases), and gene fusion (one case), which is higher than the 2 of 159 (1.3%) protein-changing ERBB2 mutations reported for urinary tract cancer in COSMIC. The enrichment of ERBB2 alterations in MPUC compared with non-MPUC is significant both between this series (P < 0.0084) and for all types of urinary tract cancer in COSMIC (P < 0.001).Conclusions: NGS of MPUC revealed a high incidence of mutation in the extracellular domain of ERBB2, a gene for which there are five approved targeted therapies. NGS can identify genomic alteration, which inform treatment options for the majority of MPUC patients. Clin Cancer Res; 20(1); 68-75. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

A High Frequency of Activating Extracellular Domain ERBB2 (HER2) Mutation in Micropapillary Urothelial Carcinoma

Ross

Wang

Al‐Rohil

et al. 2014

Clinical Cancer Research

122

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“…Twolevel (low and high) [44], 3-level (negative, 1+ and 2+) [44], and 4-level scales (0, 1+, 2+ and 3+) [45] have been used to assess the HER2 status. The cutoff value for IHC overexpression (3 + or strong) also varied from 10 [26] and 30% [28] to 40 [27] and 50% [45] in different studies.…”

Section: Issues In Her2 Assessment Methodsmentioning

confidence: 99%

“…It also pointed out that HER2 status in BC varies from 9% to over 80% in regards to protein overexpression and 0-32% regarding gene amplification (4-76 and 3-9% in NMIBC, respectively, in Table 1); furthermore, conflicting data exist regarding its prognostic relevance in BC [18,24,[26][27][28][29][30][31][32][33][34][35][36]. The reason for such variability of HER2 positivity is multifactorial, resulting from (a) tumor heterogeneity, with case series featuring varying tumor stages and histological grades (and different grading systems), (b) the diversity of methods used to assess HER status (amplification detection versus overexpression detection), (c) the technique used (polymerase chain reaction [PCR], in situ hybridization [ISH] and immunohistochemistry [IHC]) to assess HER2 status, and also (d) the specific definition given to HER2 "positivity" [24,37,38]; ethnic or geographic differences may account for further reasons [39].…”

Section: Her2 and Bcmentioning

confidence: 99%

Human Epidermal Growth Factor Receptor 2 in Non-Muscle Invasive Bladder Cancer: Issues in Assessment Methods and Its Role as Prognostic/Predictive Marker and Putative Therapeutic Target: A Comprehensive Review

et al. 2018

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Although human epidermal growth factor receptor 2 (HER2) plays a prognostic and predictive role in breast and gastric cancer, its function in bladder cancer (BC) is still controversial. A comprehensive review of the literature has been carried out. An electronic search of databases from PubMed, Scopus, Google Scholar was implemented. The search terms were: “BC,” “bladder carcinoma,” “bladder neoplasm,” “human epidermal growth factor 2,” “HER2,” “HER-2,” “c-erbB-2,” “c-erbB2,” “erbB-2,” “erbB2,” “neu,” “marker,” “biomarker,” and “prognosis”. Results of the review consented to (a) summarize the available data on HER2 a predictor of recurrence and/or progression free survival on univariate and multivariate analysis, (b) explore the related issues in assessing HER2 status on these tumor samples, since they may severely impair its predictive function, and (c) report the state-of-the art of HER2 as a putative therapeutic target in BC and especially non-muscle invasive BC. HER2 stands out for being a prognostic factor as well as a therapeutic target in various cancers. Data from the literature concerning its use in BC provide conflicting results, probably due to the inherent complexity of BC biology. Efforts should be made to establish a suitable tumor-specific scoring system, and to assess single drugs’ efficacy in well-designed clinical trials.

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“…Sjödahl et al [12] could not find an association between ERBB2 expression and the stage and grade of bladder cancer. Chen et al [19] could show that ERBB2 amplification could only be found in high-grade NMIBC and goes along with a more aggressive behavior and risk for progression. In this study, the researchers stratified only for low-risk and high-risk tumors.…”

Section: Discussionmentioning

confidence: 99%

ERBB2 Expression as Potential Risk-Stratification for Early Cystectomy in Patients with pT1 Bladder Cancer and Concomitant Carcinoma in situ

Breyer

Otto²,

Wirtz³

et al. 2016

Urol Int

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Background/Aims/Objectives: It is difficult to identify patients with a non-muscle-invasive bladder cancer (NMIBC) at stage pT1 with concomitant carcinoma in situ (Cis) who will benefit from an early cystectomy. Methods: We retrospectively analyzed clinical data and formalin-fixed paraffin-embedded tissues of patients with NMIBC. Messenger ribonucleic acid (mRNA) expression of progesterone receptor (PGR), estrogen receptor (ESR1), ERBB2, and marker of proliferation Ki-67 (MKI67) was measured by single-step reverse transcription quantitative real-time polymerase chain reaction using RNA-specific TaqMan assays. Relative gene expression was determined by the normalization of 2 reference genes (CALM2, B2M) using the 40 ΔΔCT method and relative gene expression was correlated to the histopathological stage and oncological outcome. Results: Of 302 patients with pT1 NMIBC in the initial transurethral resection of the bladder, 65 had a concomitant Cis. Elevated ERBB2 expression (>40.1) significantly correlated with progress in patients with and without concomitant Cis (p = 0.020 and p = 0.049, respectively). For the subgroup of pT1 with concomitant Cis, elevated ERBB2 expression significantly discriminated between a high-risk group of 55% progression-free survival (PFS) and a low-risk group of 90% PFS after a 5-year follow-up (p = 0.020). Cox-regression analysis revealed ERBB2 expression as the only independent prognostic factor for PFS (p = 0.0037). Conclusions: High mRNA expression of ERBB2 can identify patients with pT1 NMIBC with concomitant Cis, who have a high risk of progression and might benefit from an early cystectomy.

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Her2 amplification distinguishes a subset of non-muscle-invasive bladder cancers with a high risk of progression

Abstract: A subset of high-grade NMIBCs contain Her2 amplification and are associated with markedly aggressive behaviour. Her2 diagnostics are valuable for distinguishing patients who require diligent surveillance and would potentially benefit from anti-Her2 therapies.

Cited by 55 publications

References 25 publications

A High Frequency of Activating Extracellular Domain ERBB2 (HER2) Mutation in Micropapillary Urothelial Carcinoma

A High Frequency of Activating Extracellular Domain ERBB2 (HER2) Mutation in Micropapillary Urothelial Carcinoma

Human Epidermal Growth Factor Receptor 2 in Non-Muscle Invasive Bladder Cancer: Issues in Assessment Methods and Its Role as Prognostic/Predictive Marker and Putative Therapeutic Target: A Comprehensive Review

ERBB2 Expression as Potential Risk-Stratification for Early Cystectomy in Patients with pT1 Bladder Cancer and Concomitant Carcinoma in situ

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