Introduction
Methodology
Levels of evidence |
(I) Evidence from at least one large randomized, controlled trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomized trials without heterogeneity |
(II) Small randomized trials or large randomized trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneity |
(III) Prospective cohort studies |
(IV) Retrospective cohort studies or case–control studies |
(V) Studies without control group, case reports, expert opinions |
Grades of recommendation |
(A) Strong evidence of efficacy with a substantial clinical benefit; strongly recommended |
(B) Strong or moderate evidence of efficacy but having limited clinical benefit; generally recommended |
(C) Insufficient evidence of efficacy or benefit; does not outweigh risk or disadvantages; optional |
(D) Moderate evidence against efficacy or of adverse outcome; generally not recommended |
(E) Strong evidence against efficacy or of adverse outcome; never recommended |
Molecular biology and classification
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Non-muscle-invasive urothelial carcinomas characterized by activation of the receptor tyrosine kinase-Ras pathway, activating mutations in HRAS or fibroblast growth factor receptor 3 (FGFR3) genes. FGFR3 and HRAS mutations are not generally present within the same cancer.
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Muscle-invasive urothelial carcinoma characterized by alterations in the p53 and retinoblastoma (RB1) pathways. These genes interact with the Ras-mitogen-activated protein kinase (MAPK) signal transduction pathways.
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Fifty-eight genes were significantly mutated; these genes included TP53, KTDM2D, KDM6A, PIK3CA, RB1, and FGFR3. Mutations in the p53/RB tumor suppressor pathway were seen in nearly 90% of tumors and alterations in the PI3K/AKT/mTOR and RTK/RAS signaling pathways were observed in 71%. MIBC exhibits high overall mutation rates, which appears to be associated with mutation signatures for an endogenous mutagenic enzyme, APOBEC cytidine deaminase [6]. Neoantigen load displays a correlation with mutation burden and has been linked survival [7, 8].
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FGFR3-TACC3 was the most common gene fusion reported [9].
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Epigenetic changes were observed in nearly 90% of tumors.
mRNA expression-based molecular subtypes
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The University of North Carolina group reported a classification of high-grade, muscle-invasive bladder tumors, in which they detected two main subtypes:(KRT5/6 and CD44) and luminal (PPARG, GATA3, KRT20, and UPK2). A 47-gene signature (BASE 47) classified high-grade bladder cancer in luminal and basal-like tumors [11].
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The MD Anderson group identified three distinct clusters: basal, luminal, and p53-like tumors [12].
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The Lund group identified two major molecular subtypes, designated MS1 and MS2, displaying differences in the number of genomic alterations, including FGFR3 and TP53 mutations [13].
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The TCGA study identified five expression subtypes [5]:
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Luminal-papillary enriched with FGFR3 alterations; papillary histology.
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Luminal-infiltrated characterized by the presence of lymphocytic infiltrates and chemoresistance. These tumors had increased expression of several immune markers, including PD1/PDL1. The wild-type p53 is also present in this subgroup.
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Luminal highest expression levels of several uroplakins.
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Basal-squamous basal and stem-like markers and squamous differentiation markers. More common in females.
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Neuronal high expression of neuronal differentiation and development genes.
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Clinical prognostic factors
Recommendations
Neoadjuvant and adjuvant treatment
Neoadjuvant treatment
Recommendations
Adjuvant treatment
Recommendations
Bladder-sparing treatments
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5-year and 10-year OS rates of 57 and 36%, respectively.
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Complete response rate following chemoradiotherapy was 69%.
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Of the 205 patients alive at 5 years, 80% had an intact bladder.