Intratumoral Heterogeneity of Molecular Subtypes in Muscle-invasive Bladder Cancer—An Extensive Multiregional Immunohistochemical Analysis

A broad panel of therapies is available for bladder cancer (BC) patients of all disease stages. However, the challenge for the clinician remains regarding which option is the best match for which patient. In the past few years, therapeutic strategies for BC patients have been experiencing a shift from “fit for all” to individual approaches, taking advantage of the specific cancer biology. Prominent examples, which are already available in the clinics, are fibroblast growth factor receptor (FGFR)-targeting biologicals [1] and PD1 checkpoint inhibitors [2] in the metastatic and adjuvant settings of urothelial carcinoma, respectively. Compared with single genetic alterations, molecular subtypes give a more comprehensive picture of what mechanisms lie behind an individual tumor. The investigation of molecular subtypes and, more importantly, consensus classifications revolutionized our understanding of non–muscle-invasive [3], localized [4], and metastatic stages of BC [5]. Although several classifications exist, most of them differentiate between luminal and basal subtypes. While molecular subtyping was initially based on RNA sequencing, several investigations established protein-based markers and successfully correlated RNA- with immunohistochemistry (IHC)-based subtypes (surrogate molecular classification of BC) [6], [7], [8]. Several studies underlined the clinical impact of subtyping, as specific subtypes were associated with the likelihood of therapy response [9], especially in the neoadjuvant setting [9], [10], [11]. However, results are partially inconclusive, as it is still under debate whether luminal or nonluminal tumors gain the greatest benefit from neoadjuvant chemotherapy [10], [11], [12]. One reason for this observation might be intratumoral heterogeneity (ITH). Spatial ITH, defined by the existence of genetically distinct tumor clones and consequently distinct proteomic profiles (IHC profiles) within the same tumor at the same time, might also contribute to tumor recurrences or mixed responses. Clonal evolution as well as sporadic mutations is seen as major drivers for ITH [13]. The prevalence of ITH was shown in several cancer entities, including lung cancer [14], prostate cancer [15], [16], and glioblastoma [17]. In BC, there are only limited data on the extent and relevance of ITH. In a study, comparing BC subtypes between the primary tumor and synchronous lymph node metastases, 18% of matched samples showed discordant subtypes [18]. A study focusing on the basal/squamous BC subtype also demonstrated significant ITH [19], which was confirmed by others [20]. On the other side, a low frequency of ITH in BC was proposed by an IHC-based study comparing two tissue cores of 948 cases [21]. ITH might have a significant impact on molecular subtype–guided personalized treatment concepts and our understanding of BC biology. According to our hypothesis, the extent of ITH of molecular subtypes might be under-rated. The aims of our study were to (1) investigate spatial ITH of molecular subtypes in muscle-invasive BC (MIBC) based on IHC, (2) compare molecular subtypes between the invasive tumor front and tumor center, and (3) study the association of subtype ITH with staging variables, specific subtypes, and oncological outcome.

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