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Cancers arising from the bladder urothelium often exhibit lineage plasticity with regions of urothelial carcinoma adjacent to or admixed with regions of divergent histomorphology, most commonly squamous differentiation. To define the biologic basis for and clinical significance of this morphologic heterogeneity, here we perform integrated genomic analyses of mixed histology bladder cancers with separable regions of urothelial and squamous differentiation. We find that squamous differentiation is a marker of intratumoral genomic and immunologic heterogeneity in patients with bladder cancer and a biomarker of intrinsic immunotherapy resistance. Phylogenetic analysis confirms that in all cases the urothelial and squamous regions are derived from a common shared precursor. Despite the presence of marked genomic heterogeneity between co-existent urothelial and squamous differentiated regions, no recurrent genomic alteration exclusive to the urothelial or squamous morphologies is identified. Rather, lineage plasticity in bladder cancers with squamous differentiation is associated with loss of expression of FOXA1, GATA3, and PPARG, transcription factors critical for maintenance of urothelial cell identity. Of clinical significance, lineage plasticity and PD-L1 expression is coordinately dysregulated via FOXA1, with patients exhibiting morphologic heterogeneity pre-treatment significantly less likely to respond to immune checkpoint inhibitors. Bladder cancer can often exhibit genomic and morphological heterogeneity. Here, the authors use genomics analysis to show lineage plasticity of bladder cancers with squamous differentiation, and identify key transcription factors related to this morphological and immune heterogeneity. [ABSTRACT FROM AUTHOR]

Objectives: The PI3k/Akt pathway has been associated with the development and progression of bladder tumors, with most studies focused on papillary or muscle-invasive tumors. We sought to characterize the expression patterns of the PI3K/Akt pathway in a large cohort of high-risk preinvasive carcinoma in situ (CIS) tumors of the bladder. Our goal was to understand whether PI3K/Akt pathway alterations associated with CIS resemble early- or late-stage bladder cancers.Material and Methods: We evaluated tissue specimens from 97 patients with CIS of the bladder, of which 14 had a concomitant papillary tumor. All patients were treated with intravesical bacillus Calmette-Guerin. All specimens were evaluated for PTEN, p-AKT, and p-S6 immunoreactivity. Markers were evaluated for percentage and intensity of staining and were scored using a 0 to 3+grading system.Results: PTEN staining was noted as least intense in 67% of tumor specimens and 22% of normal urothelium. P-Akt and p-S6 had intense staining in 77% and 90% of tumor specimens vs. 44% and 68% in normal tissue, respectively. Low-intensity staining for PTEN at 12 months correlated with higher recurrence risk (P = 0.026).Conclusion: We describe a large cohort of CIS bladder tumors with decreased staining intensity of PTEN and increased staining intensity of p-AKT and p-S6, similar to high-grade and high-stage papillary tumors. Low-intensity staining of PTEN at 12 months was associated with an increased risk of recurrence. [ABSTRACT FROM AUTHOR]

What's known on the subject? and What does the study add? No recent advances have been made in the treatment of patients with advanced bladder cancer and, to date, targeted therapies have not resulted in an improvement in outcome. The mammalian target of rapamycin pathway has been shown to be up-regulated in bladder cancer and represents a rational target for therapeutic intervention., In the present phase II study of everolimus, one near-complete response, one partial response and several minor responses suggest that everolimus possesses biological activity in a subset of patients with bladder cancer. To maximize benefit from targeted agents such as everolimus, the preselection of patients based on molecular phenotype is required., Objective To assess the efficacy and tolerability of everolimus in advanced urothelial carcimoma ( UC)., Patients and Methods The present study comprised a single-arm, non-randomized study in which all patients received everolimus 10 mg orally once daily continuously (one cycle = 4 weeks)., In total, 45 patients with metastatic UC progressing after one to four cytotoxic agents were enrolled between February 2009 and November 2010 at the Memorial Sloan- Kettering Cancer Center., The primary endpoints were 2-month progression-free survival ( PFS) and the safety of everolimus, with the secondary endpoint being the response rate., A Simon minimax two-stage design tested the null hypothesis that the true two month PFS rate was ≤50%, as opposed to the alternative hypothesis of ≥70%., Results The most common grade 3/4 toxicities were fatigue, infection, anaemia, lymphopaenia, hyperglycaemia and hypophosphataemia., There were two partial responses in nodal metastases, with one patient achieving a 94% decrease in target lesions and remaining on drug at 26 months., An additional 12 patients exhibited minor tumour regression., There were 23 of 45 (51%) patients who were progression-free at 2 months with a median (95% CI) PFS of 2.6 (1.8-3.5) months and a median (95% CI) overall survival of 8.3 (5.5-12.1) months., No clear association was observed between mammalian target of rapamycin pathway marker expression and 2-month PFS., Conclusions Although everolimus did not meet its primary endpoint, one partial response, one near-complete response and twelve minor regressions were observed., Everolimus possesses meaningful anti-tumour activity in a subset of patients with advanced UC., Studies aiming to define the genetic basis of everolimus activity in individual responders are ongoing. [ABSTRACT FROM AUTHOR]