Abstract
PurposeNon-invasive high-grade (HG) bladder cancer is a heterogeneous disease that is characterized insufficiently. First-line Bacillus Calmette-Guérin instillation fails in a substantial amount of cases and alternative bladder-preserving treatments are limited, underlining the need to promote a further molecular understanding of non-invasive HG lesions. Here, we characterized pure HG papillary urothelial bladder cancer (pure pTa HG), a potential subgroup of non-invasive HG bladder carcinomas, with regard to molecular subtype affiliation and potential for targeted therapy.MethodsAn immunohistochemistry panel comprising luminal (KRT20, ERBB2, ESR2, GATA3) and basal (KRT5/6, KRT14) markers as well as p53 and FGFR3 was used to analyze molecular subtype affiliations of 78 pure pTa HG/papillary pT1(a) HG samples. In 66 of these, ERBB2 fluorescence in situ hybridization was performed. Additionally, targeted sequencing (31 genes) of 19 pTa HG cases was conducted, focusing on known therapeutic targets or those described to predict response to targeted therapies noted in registered clinical trials or that are already approved.ResultsWe found that pure pTa HG/papillary pT1(a) HG lesions were characterized by a luminal-like phenotype associated with frequent (58% of samples) moderate to high ERBB2 protein expression, rare FGFR3 alterations on genomic and protein levels, and a high frequency (89% of samples) of chromatin-modifying gene alterations. Of note, 95% of pTa HG/papillary pT1 HG cases harbored at least one potential druggable genomic alteration.ConclusionsOur data should help guiding the selection of targeted therapies for investigation in future clinical trials and, additionally, may provide a basis for prospective mechanistic studies of pTa HG pathogenesis.
Highlights
Bladder cancer (BC) is the most common malignancy of the urinary tract with an estimated number of 380,000 new cases and 150,000 deaths per year worldwide [1]
muscle-invasive bladder cancer (MIBC) mainly arises via carcinoma in situ (CIS), a flat highgrade (HG) lesion characterized by TP53 mutations, and papillary lesions of HG [2, 3]
To study the presence of genetic alterations (GAs) with potential impact on targeted therapy response, targeted sequencing was conducted in 23 samples from 23 patients, comprising 16 pTa HG/papillary pT1 HG tumor specimens without a history of pTa LG/MIBC lesions, three papillary pT1 HG samples with a history of pTa LG or muscle-invasive disease (Online Resource 3) and four normal smooth muscle specimens as controls
Summary
Bladder cancer (BC) is the most common malignancy of the urinary tract with an estimated number of 380,000 new cases and 150,000 deaths per year worldwide [1]. The majority of BC patients present with non-invasive, low-grade papillary carcinomas (pTa LG), characterized by frequent FGFR3 gene alterations and a good prognosis (5-year survival of ~ 90%). Frequently recurring, these tumors only infrequently progress to muscle-invasive disease. Muscle-invasive bladder cancer (MIBC) has an unfavorable prognosis (5-year survival < 50%) and a high risk of progression to metastasis [2]. Based on our observations and those made by others [4], we hypothesize that a subgroup of non-invasive pTa HG lesions arises de novo (i.e., without a LG history).
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