Precision oncology in urothelial cancer

Liow, Elizabeth

doi:10.1136/esmoopen-2019-000616

Cited by 6 publications

(8 citation statements)

References 87 publications

(156 reference statements)

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“…Altered receptor tyrosine kinases such as EGFR and ERBB2 can also stimulate oncogenic activation of the PI3K/AKT/mTOR pathway, which interplays with the Ras/Raf/MAPK cascade in regulation of critical cellular processes. Disruption of the RTK/Ras/PI3K pathway occurs in ~72% of human high grade invasive UC [ 18 ]; however in many cases this is due to aberrant PI3K [ 18 , 38 , 49 ]. PIK3CA is the most commonly mutated of the PI3K subunit genes across all human cancers, and while infrequent in UC (5–10% of all UC cases and 20% of high-grade invasive cases), mutations of PIK3CA are associated with a poor prognosis [ 18 , 38 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

“…Disruption of the RTK/Ras/PI3K pathway occurs in ~72% of human high grade invasive UC [ 18 ]; however in many cases this is due to aberrant PI3K [ 18 , 38 , 49 ]. PIK3CA is the most commonly mutated of the PI3K subunit genes across all human cancers, and while infrequent in UC (5–10% of all UC cases and 20% of high-grade invasive cases), mutations of PIK3CA are associated with a poor prognosis [ 18 , 38 , 49 ]. The vast majority of PIK3CA somatic alterations occur within two hotspots located in exon 9 (codons E542K and E545H) and one in exon 20 (H1047R/L).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies note a high prevalence of mutations of chromatin modifiers in human UC, including histone demethylases and methyltransferases [ 18 , 38 , 49 , 53 ]. Similarly, the present study highlights several epigenetic factors as targets of recurrent mutation in canine UC, particularly histone demethylase and methyltransferase genes and the chromatin remodeling gene ARID1A .…”

Section: Discussionmentioning

confidence: 99%

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Whole exome sequencing analysis of canine urothelial carcinomas without BRAF V595E mutation: Short in-frame deletions in BRAF and MAP2K1 suggest alternative mechanisms for MAPK pathway disruption

et al. 2023

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Molecular profiling studies have shown that 85% of canine urothelial carcinomas (UC) harbor an activating BRAF V595E mutation, which is orthologous to the V600E variant found in several human cancer subtypes. In dogs, this mutation provides both a powerful diagnostic marker and a potential therapeutic target; however, due to their relative infrequency, the remaining 15% of cases remain understudied at the molecular level. We performed whole exome sequencing analysis of 28 canine urine sediments exhibiting the characteristic DNA copy number signatures of canine UC, in which the BRAF V595E mutation was undetected (UDV595E specimens). Among these we identified 13 specimens (46%) harboring short in-frame deletions within either BRAF exon 12 (7/28 cases) or MAP2K1 exons 2 or 3 (6/28 cases). Orthologous variants occur in several human cancer subtypes and confer structural changes to the protein product that are predictive of response to different classes of small molecule MAPK pathway inhibitors. DNA damage response and repair genes, and chromatin modifiers were also recurrently mutated in UDV595E specimens, as were genes that are positive predictors of immunotherapy response in human cancers. Our findings suggest that short in-frame deletions within BRAF exon 12 and MAP2K1 exons 2 and 3 in UDV595E cases are alternative MAPK-pathway activating events that may have significant therapeutic implications for selecting first-line treatment for canine UC. We developed a simple, cost-effective capillary electrophoresis genotyping assay for detection of these deletions in parallel with the BRAF V595E mutation. The identification of these deletion events in dogs offers a compelling cross-species platform in which to study the relationship between somatic alteration, protein conformation, and therapeutic sensitivity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Whole exome sequencing analysis of canine urothelial carcinomas without BRAF V595E mutation: Short in-frame deletions in BRAF and MAP2K1 suggest alternative mechanisms for MAPK pathway disruption

et al. 2023

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“…Mutations in members of the fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) family have been associated with reduced tumor infiltration by immune cells and poor outcome from ICI therapy in UC. [24][25][26][27][28][29] Mutations in FGFR3, present in 19.4% (118/607) of evaluable patients, were associated with reduced OS in the avelumab/BSC arm (HR [mutant vs wild-type] = 1.76; 95% CI 1.160, 2.658; P = 0.0078; n = 310) but not in the BSC arm (HR for [mutant vs wild-type] = 1.03; 95% CI 0.694, 1.517; P = 0.898; n = 297); interaction term P = 0.0847. Mutations in FGFR1, present in 4.6% (28/607) of patients, did not show different association with OS in the avelumab/BSC arm compared with the BSC arm (interaction term P = 0.7487).…”

Section: Mutations In Specific Pathwaysmentioning

confidence: 99%

Avelumab maintenance in advanced urothelial carcinoma: biomarker analysis of the phase 3 JAVELIN Bladder 100 trial

Powles

Sridhar

Loriot

et al. 2021

Nat Med

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In a recent phase 3 randomized trial of 700 patients with advanced urothelial cancer (JAVELIN Bladder 100; NCT02603432), avelumab/best supportive care (BSC) significantly prolonged overall survival (OS) relative to BSC alone as maintenance therapy following first-line chemotherapy. Tumor molecular profiling revealed that avelumab survival benefit was positively associated with PD-L1 expression by tumor cells, tumor mutational burden, APOBEC mutation signatures, expression of genes underlying innate and adaptive immune activity, and the number of alleles encoding high-affinity variants of activating Fc receptors. Gene expression signatures connected to tissue growth were potentially associated with reduced OS in avelumab/BSC. Individual biomarkers did not comprehensively identify patients who could benefit from therapy. These results characterize the complex biologic pathways underlying survival benefit from immune checkpoint inhibition in advanced urothelial carcinoma and suggest that multiple biomarkers may be needed to identify patients that would benefit from treatment.

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“…Molecular research on UC has improved the understanding of tumor progression and metastasis [2]. Systemic targeted treatment alone or as part of multimodal strategies is increasingly used for patients with advanced UC [3]. Comprehensive molecular profiling with cellular and functional analyses of the tumor is important to determine specific targeted abnormalities or biomarkers that lead to better risk stratification and identification of appropriate treatments for individual patients.…”

Section: Introductionmentioning

confidence: 99%

Increasing Biomarker Guidance in the Treatment of Urothelial Carcinoma: Systematic Review of International Clinical Trials

Bolenz¹,

Kunath²,

Zengerling³

et al. 2023

Urol Int

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Purpose: Precision oncology requires biomarker testing from tumor tissue for clinical decision-making and selection of targeted therapies. We systematically evaluated the role of tissue biomarker testing within interventional clinical trials for locally advanced and metastatic urothelial carcinoma (UC). Methods: A systematic search within the publicly available ClinicalTrials.gov database was performed for the period 1995 to January 2020. We searched for all interventional studies on systemic treatments for advanced UC. Two investigators independently screened the records and extracted the data for statistical analyses. Results: We included 356 studies out of 827 initial records in the final analysis. The overall number of interventional trials in UC patients significantly increased during the past 25 years. Forty-three studies (12.1%) required specific biomarker testing as a prerequisite for inclusion. Of the remaining 313 trials, explorative biomarkers of interest were studied in 83 studies (23.3%). In trials with obligate biomarker testing as a precondition for study inclusion, only 3 studies (7%) required an actual fresh pretreatment biopsy, while the majority of studies did not state any tissue requirements (55.8%) or accepted archival tissue samples (37.3%). Among studies without biomarker prerequisites, freshly obtained tissue samples were required in 16.3% of studies evaluating immune checkpoint inhibition and 5.7% evaluating targeted therapy. The collection of archival tissue was allowed in 67.4% and 20% of studies evaluating immune checkpoint inhibitors and targeted therapies, respectively. Conclusion: There has been an increase in the number of studies using biomarker-guided interventions for the treatment of advanced UC over the past 25 years. Studies investigating druggable targets in actual UC biopsies immediately before treatment are still rare. Standardized criteria for tissue-based biomarker testing may further accelerate personalized treatment of patients with advanced UC.

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Precision oncology in urothelial cancer

Cited by 6 publications

References 87 publications

Whole exome sequencing analysis of canine urothelial carcinomas without BRAF V595E mutation: Short in-frame deletions in BRAF and MAP2K1 suggest alternative mechanisms for MAPK pathway disruption

Whole exome sequencing analysis of canine urothelial carcinomas without BRAF V595E mutation: Short in-frame deletions in BRAF and MAP2K1 suggest alternative mechanisms for MAPK pathway disruption

Avelumab maintenance in advanced urothelial carcinoma: biomarker analysis of the phase 3 JAVELIN Bladder 100 trial

Increasing Biomarker Guidance in the Treatment of Urothelial Carcinoma: Systematic Review of International Clinical Trials

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