Grade Progression and Regression in Recurrent Urothelial Cancer

Borhan, Ali; Reeder, Jay E.; O’Connell, Mary J.; Wright, Kate O.; Wheeless, Leon L.; Sant'Agnese, Paul A. di; McNALLY, Melanie L.; Messing, Edward M.

doi:10.1097/01.ju.0000067160.09881.45

Cited by 24 publications

(11 citation statements)

References 15 publications

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“…The suggested lack of correlation between the chronological appearance of tumors and genetic progression is also supported by the fact that recurring tumors may be of lower grade than the preceding ones [29] and that TP53 and to acute myeloid leukemia (AML). The chronic phase would include the induction of selfrenewal capacity and ultimately in a field-defect, and the acute phase a local transformation of preneoplastic cells to overt tumors.…”

Section: Premalignant Lesions and Morphologically Normal Urothelium Imentioning

confidence: 96%

On the Origin of Syn- and Metachronous Urothelial Carcinomas

Höglund

2007

European Urology

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Word count: 3 994Take home message: An alternative model for the origin of syn-and metachronous tumors that better explain the existing genetic data is described. 2 AbstractObjective: To evaluate existing models for the origin of meta-and synchronous urothelial carcinomas in light of the accumulated genetic data. Methods Conclusion:The proposed model can better account for the existing genetic and histological data on syn-and metachronous urothelial carcinomas.3

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Section: Premalignant Lesions and Morphologically Normal Urothelium Imentioning

confidence: 96%

On the Origin of Syn- and Metachronous Urothelial Carcinomas

Höglund

2007

European Urology

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“…Interestingly, tumours with the highest genomic complexity are not necessarily the last to appear 156,158,159 , explaining the observation that recurrent tumours may be of lower grade than preceding tumours 160 . These observations provide further evidence for widespread 'field change' in the diseased bladder.…”

Section: Molecular Biomarkersmentioning

confidence: 99%

Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity

2014

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Correspondence to M.A.K. m.a.knowles@leeds.ac.uk 2 Preface Urothelial carcinoma of the bladder comprises two long-recognised disease entities with distinct molecular features and clinical outcome. Low-grade, non-muscle-invasive tumours recur frequently but rarely progress to muscle invasion, whereas muscle invasive tumours are usually diagnosed de novo and frequently metastasize. Recent genome-wide expression and sequencing studies identify genes and pathways that are key drivers of urothelial cancer and reveal a more complex picture with multiple molecular subclasses that cut across conventional grade and stage groupings. This improved understanding of molecular features, disease pathogenesis and heterogeneity provides new opportunities for prognostic application, disease monitoring and personalised therapy.Bladder cancer is the most common cancer of the urinary tract with approximately 380,000 new cases and 150,000 deaths per year worldwide 1 . It ranks fifth among cancers in men in Western countries.Epidemiological studies identify a range of environmental risk factors, many of which reflect exposure to excreted carcinogenic molecules (BOX 1). Recent genome-wide association studies have also identified germline variants that contribute to risk 2 .In Europe and North America, more than 90% of bladder cancers are urothelial carcinoma. These tumours are staged using the Tumour Nodes Metastasis (TNM) system 3 , which describes the extent of invasion (Tis-T4), and graded according to their cellular characteristics. Two classification systems are in current use 4, 5 .At diagnosis the majority of bladder cancers (~ 60%) are non-muscle-invasive (NMIBC) (stage Ta) NMIBCs frequently recur (50-70%) but infrequently progress to invasion (10-15%) 6 and five-year survival is ~90%. These patients are monitored by cystoscopy and may have multiple resections over many years.Improved monitoring is needed, ideally via urine analysis, which could reduce the morbidity and costs associated with cystoscopy. Although risk tables provide a prognostic tool 7 , no molecular biomarkers accurately predict disease progression. For these patients, localised therapies to remove residual neoplastic and preneoplastic cells post-resection may have major impacts on both quality of life and in health economic terms. MIBCs (>stage T2) have less favourable prognosis with five-year survival <50% and common progression to metastasis (BOX1). Treatment has not advanced for several decades and new approaches to systemic therapy are needed 8 .Improved treatment requires detailed understanding of urothelial carcinoma pathogenesis and molecular biology. A model has evolved, taking into account both histopathological and molecular features. This socalled 'two-pathway' model proposes that papillary NMIBC develops via epithelial hyperplasia and recruitment of a branching vasculature. MIBCs are proposed to develop via flat dysplasia and carcinoma in situ (CIS). The molecular characteristics of MIBC and NMIBC are highly distinct (Tables 1 and 2). Whilst 3 m...

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“…Urothelial cancer is dichotomized by tumor grade; low grade represents slightly more than 50% of all newly diagnosed malignancies and high grade slightly less than 50% (5) (2) . Many molecular changes characterize low- and high-grade disease, but in reality, patients often develop low- and high-grade lesions simultaneously and recurrences often differ in grade from prior tumors (6). Although more commonly associated with high-grade disease, altered expression of epidermal growth factor receptor (EGFR) is found in both low- and high-grade bladder cancer (7).…”

Section: Introductionmentioning

confidence: 99%

A Phase 2 Cancer Chemoprevention Biomarker Trial of Isoflavone G-2535 (Genistein) in Presurgical Bladder Cancer Patients

Messing

Gee

Saltzstein

et al. 2012

Cancer Prevention Research

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The soy compound genistein has been observed preclinically to inhibit bladder cancer growth with one potential mechanism being inhibition of epidermal growth factor receptor phosphorylation (p-EGFR). A phase 2 randomized, placebo-controlled trial investigated whether daily, oral genistein (300 or 600 mg/day as the purified soy extract G-2535) for 14–21 days before surgery alters molecular pathways in bladder epithelial tissue in 59 subjects diagnosed with urothelial bladder cancer (median age 71). G-2535 treatment was well tolerated; observed toxicities were primarily mild to moderate gastrointestinal or metabolic and usually not attributed to study drug. Genistein was detected in plasma and urine of subjects receiving G-2535 at concentrations greater than placebo subjects’ but were not dose-dependent. Reduction in bladder cancer tissue p-EGFR staining between the placebo arm and the combined genistein arms was significant at the protocol-specified significance level of 0.10 (p=0.07). This difference was most prominent when comparing the 300 mg group vs placebo (p=0.015), but there was no significant reduction in p-EGFR staining between the 600 mg group and placebo. No difference in normal bladder epithelium p-EGFR staining was observed between treatment groups. No significant differences in tumor tissue staining between treatment groups was observed for COX-2, Ki-67, activated caspase 3, Akt, p-Akt, MAPK, or p-MAPK. No significant differences in urinary Survivin or BLCA-4 levels between treatment groups were observed. Genistein displayed a possible bimodal effect (more effective at the lower dose) on bladder cancer tissue EGFR phosphorylation that should be evaluated further, possibly in combination with other agents.

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Grade Progression and Regression in Recurrent Urothelial Cancer

Abstract: While progression from low to high grade occurred in less than 15% of patients, grade regression was observed in almost 50%. The loss of p53 positivity in regressing tumors indicates that these recurrences are molecularly distinct from the corresponding initial tumor.

Cited by 24 publications

References 15 publications

On the Origin of Syn- and Metachronous Urothelial Carcinomas

On the Origin of Syn- and Metachronous Urothelial Carcinomas

Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity

A Phase 2 Cancer Chemoprevention Biomarker Trial of Isoflavone G-2535 (Genistein) in Presurgical Bladder Cancer Patients

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