Greater utility of molecular subtype rather than epithelial‐to‐mesenchymal transition (EMT) markers for prognosis in high‐risk non‐muscle‐invasive (HGT1) bladder cancer

Abstract

Approximately 75% of bladder cancers are non-muscle invasive (NMIBC). Of these, up to 53% of cases progress to life-threatening muscle-invasive bladder cancer (MIBC). Patients with high-grade stage T1 (HGT1) NMIBC frequently undergo radical cystectomy (RC), although this represents overtreatment for many. Identification of progressors versus non-progressors could spare unnecessary treatment. Recent studies have confirmed that urothelial carcinoma is composed of two main molecular subtypes, basal and luminal, with 12% of basal tumours exhibiting epithelial-to-mesenchymal transition (EMT). Levels of immune cell infiltration have been shown to be subtype-specific. Here, we performed immunohistochemistry (IHC) for 11 antibodies relating to molecular subtypes or EMT in 26 cases of HGT1 urothelial carcinoma cases with 6 matched samples subsequently obtained at cystectomy (n = 6; 1 muscle-invasive, 5 non-muscle-invasive; 3 = pTis, 1 = pT1, 1 = pTa) and at recurrence (n = 2, pT2). RNAScope was also conducted in a subset. Expression patterns in HGT1 specimens versus MIBC (pT2 +) were examined, and correlated with disease-specific survival (DSS). Levels of stromal tumour-infiltrating lymphocytes (sTILs) were assessed manually to determine whether lymphocyte infiltration was associated with DSS and whether differences existed between HGT1 and MIBC. Molecular subtype markers demonstrated increased prognostic potential compared to the EMT markers assessed. Increased expression of the luminal markers FOXA1 and SCUBE2, were found to be significantly associated with better DFS. No EMT markers were significantly associated with DFS. In areas of non-invasive papillary urothelial carcinoma, but not invasive carcinoma, sTIL levels were found to be significantly associated with DFS. While differences were observed between HGT1 cases that progressed versus those that did not, a larger cohort study is required for validation of these findings. Taken together, an emphasis on molecular subtype markers, rather than EMT markers, may be preferable when studying biomarkers of HGT1 urothelial carcinoma in the future.

Identifying a hypoxia related score to predict the prognosis of bladder cancer: a study with The Cancer Genome Atlas (TCGA) database

“…KLK6 was identified as a prognostic gene for MIBC (39). Increased expression of SCUBE2, as a luminal marker of urothelial carcinoma, was found to be significantly associated with better disease-free survival (40). The expression of SERPINB2 was proved incrementally expressed in cisplatin-resistant bladder cancer cell lines (41).…”

Preoperative Prognostic Nutritional Index and Systemic Immune-Inflammation Index for Predicting the Long-Term Recurrence-Free Survival of Patients with High-Risk Non-Muscle-Invasive Bladder Cancer After Transurethral Resection of a Bladder Tumour: A Cohort Study

“…According to distinct clinical recurrence, progression and prognosis, BC is classi ed into non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). Recently, most patients with BC have been diagnosed with NMIBC [4], and approximately 53% experience progression to life-threatening MIBC [17]. Given the very high recurrence rate, the prediction of recurrence is particularly important in NMIBC.…”

A Robust Immuno-Prognostic Model of Non-Muscle-Invasive Bladder Cancer Indicates Dynamic Interaction in Tumor Immune Microenvironment Contributes to Cancer Progression

“…It is one of the cancers with the most longitudinal costs and consumed resources. Approximately 70-75% of newly diagnosed primary bladder cancers are non-muscle-invasive bladder cancer (NMIBC) (Lenis et al, 2020;Ottley et al, 2020). Up to 21-53% of them eventually progress to life-threatening muscle-invasive bladder cancer (MIBC) (Cookson et al, 1997;van den Bosch and Alfred Witjes, 2011), depending on the stage and grade.…”

“…They found that both stromal tumor-infiltrating lymphocyte (sTIL) levels in noninvasive papillary urothelial carcinoma areas and increased expression of the luminal markers FOXA1 and SCUBE2 are significantly associated with better disease-free survival (DFS), but no EMT markers showed any trend. They suggested that molecular subtype markers, rather than EMT markers, might be preferable to study biomarkers of HGT1 urothelial carcinoma (Ottley et al, 2020). Rouanne et al focused on stromal lymphocyte infiltration by evaluating the percentage of stromal area infiltrated by mononuclear inflammatory cells over the total intratumoral stromal area (Rouanne et al, 2019).…”