Mocetinostat for patients with previously treated, locally advanced/metastatic urothelial carcinoma and inactivating alterations of acetyltransferase genes

BackgroundThe authors evaluated mocetinostat (a class I/IV histone deacetylase inhibitor) in patients with urothelial carcinoma harboring inactivating mutations or deletions in CREB binding protein [CREBBP] and/or E1A binding protein p300 [EP300] histone acetyltransferase genes in a singleâ arm, openâ label phase 2 study.MethodsEligible patients with platinumâ treated, advanced/metastatic disease received oral mocetinostat (at a dose of 70 mg 3 times per week [TIW] escalating to 90 mg TIW) in 28â day cycles in a 3â stage study (ClinicalTrials.gov identifier NCT02236195). The primary endpoint was the objective response rate.ResultsGenomic testing was feasible in 155 of 175 patients (89%). Qualifying tumor mutations were CREBBP (15%), EP300 (8%), and both CREBBP and EP300 (1%). A total of 17 patients were enrolled into stage 1 (the intentâ toâ treat population); no patients were enrolled in subsequent stages. One partial response was observed (11% [1 of 9 patients; the population that was evaluable for efficacy comprised 9 of the 15 planned patients]); activity was deemed insufficient to progress to stage 2 (null hypothesis: objective response rate of â ¤15%). All patients experienced â ¥1 adverse event, most commonly nausea (13 of 17 patients; 77%) and fatigue (12 of 17 patients; 71%). The median duration of treatment was 46 days; treatment interruptions (14 of 17 patients; 82%) and dose reductions (5 of 17 patients; 29%) were common. Mocetinostat exposure was lower than anticipated (doseâ normalized maximum serum concentration [Cmax] after TIW dosing of 0.2 ng/mL/mg).ConclusionsTo the authorsâ knowledge, the current study represents the first clinical trial using genomicâ based selection to identify patients with urothelial cancer who are likely to benefit from selective histone deacetylase inhibition. Mocetinostat was associated with significant toxicities that impacted drug exposure and may have contributed to modest clinical activity in these pretreated patients. The efficacy observed was considered insufficient to warrant further investigation of mocetinostat as a single agent in this setting.After the genomicâ based selection of patients with urothelial cancer with inactivating mutations/deletions in the histone acetyltransferase genes CREBBP and/or EP300, singleâ agent mocetinostat appears to be associated with significant toxicities that limit drug exposure. This may have contributed to the limited activity noted in the current phase 2 study (response rate of 11%) among heavily pretreated patients with platinumâ refractory disease.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147860/1/cncr31817_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147860/2/cncr31817.pd

Advanced urothelial cancer: a radiology update

The recent genomic characterization of urothelial carcinoma by the Cancer Genome Atlas Project, made possible by the introduction of high throughput, reduced cost, and sequence analysis, has shed new insights on the biology of advanced disease. In addition, studies on imaging of advanced urothelial carcinoma have widened the knowledge on disease presentation and on pattern of metastatic spread and their correlation with the underlying biology of urothelial carcinoma. The wide range of treatments for advanced urothelial cancer, including combined chemotherapy regimens and immune checkpoint inhibitors, each result in treatment class-specific patterns of response and adverse events. Results of studies point to the need for a reliable biomarker, perhaps with imaging, that predicts prognosis and treatment response to systemic treatment, and can be used to select the most effective treatment while minimizing toxicity. This review of advanced urothelial cancer introduces the latest advances in genetic profiling, the current role of imaging, the radiographic appearance of treatment response and their toxicities, and details potential future areas of imaging research

Muscle-invasive Urothelial Cancer: Association of Mutational Status with with Metastatic Pattern and Survival

Background: Muscle-invasive urothelial cancer (MIUC) is characterized by substantial genetic heterogeneity and high mutational frequency. Correlation between frequently mutated genes with clinical behavior has been recently demonstrated. Nonetheless, correlation between mutational status of MIUC and metastatic pattern is unknown. Purpose: To investigate the association of mutational status of MIUC with metastatic pattern, metastasis-free survival (MFS), and overall survival (OS). Materials and Methods: This single-center retrospective study evaluated consecutive patients with biopsy-proven MIUC who under-wentserial cross-sectional imaging (CT, MRI, or fluorine 18 fluorodeoxyglucose PET/CT) between April 2010 and December 2018. Mutational status was correlated with location of meta-stases using the chi(2) or Fisher exact test. Mutational status and metastatic pattern were correlated with MFS and OS using univariable Cox proportional hazard models. High-risk (presence of TP53, RB1, or KDM6A mutation) and low-risk (presence of ARID1A, FGFR3, PIK3CA, STAG2, and/or TSC1 mutation and absence of TP53, RB1, or KDM6A mutation) groups were determined according to existing literature and were correlated with MFS and OS by using multivariable Cox proportional hazard models. Results: One hundred three patients (mean age, 72 years 6 11 [standard deviation]; 81 men) were evaluated. Seventeen of 103 (16%) patients had metastatic disease at diagnosis; 38 of 103 (37%) developed metastatic disease at a median of 5.9 months (interquartile range, 0.8-28 months). TP53 mutation (seen in 58 of 103 patients, 56%) was associated with lymphadenopathy (relative risk [RR]: 1.7; 95% confidence interval [CI]: 1.2, 2.4; P =.002) and osseous metastases (RR: 1.9; 95% CI: 1.6, 2.3; P =.02); RB1 mutation (seen in 19 of 103 patients, 18.4%) was associated with peritoneal carcinomatosis (RR: 5.9; 95% CI: 3.8, 9.2; P =.03). ARID1A mutation was associated with greater OS (hazard ratio [HR]: 3.1; 95% CI: 1.2, 10; P =.01). At multivariable Cox analysis, the high-risk group (TP53, RB1, and/or KDM6A mutations) was independently associated with shorter MFS (HR: 3.5, 95%CI: 1.3, 12; P =.009) and shorter OS (HR: 3.1; 95% CI: 1.2, 10; P =.02). Conclusion: Mutational status of muscle-invasive urothelial cancer has implications on metastatic pattern, metastasis-free survival, and overall survival. (C) RSNA, 202

Use of Quantitative T2-Weighted and Apparent Diffusion Coefficient Texture Features of Bladder Cancer and Extravesical Fat for Local Tumor Staging After Transurethral Resection

OBJECTIVE. The purpose of this study was to determine whether quantitative T2-weighted imaging and apparent diffusion coefficient (ADC) texture features of bladder cancer and extravesical fat are predictive of muscle invasive bladder cancer (category >= T2) and extravesical (category >= T3) disease after transurethral resection of a bladder tumor (TURBT). MATERIALS AND METHODS. In this retrospective study, 36 patients (27 men, nine women; mean age, 71 years) were identified who underwent post-TURBT MRI followed by cystectomy without intervening treatment from August 2011 through October 2016. Texture features of bladder cancer and extravesical fat adjacent to the tumor on T2-weighted and ADC images were extracted and compared between category = T3 and category T1 versus >= T2 tumors by means of Kruskal-Wallis or Mann-Whitney U test. Multivariate logistic regression analysis was performed, and ROC curves were calculated. RESULTS. Twenty-six of the 36 (72%) tumors were >= T2, and 53% (19/36) were >= T3. In multivariate analysis, bladder cancer entropy on T2-weighted images (p = 0.006; odds ratio [OR], 4.56; 95% CI, L49-20.41; AUC, 0.85) and ADC maps (p = 0.019; OR, 2.24; 95% CI, 1.13-5.31; AUC, 0.80) and extravesical fat entropy on T2-weighted images (p = 0.005; OR, 17.50; 95% CI, 3.01-200.80; AUC, 0.84) and ADC maps (p = 0.002; OR, 6.54; 95% CI, 1.9032.40; AUC, 0.82) remained greater for z T3 than for s T2 tumors. In multivariate analysis, bladder cancer entropy on ADC maps (p = 0.027; OR, 2.11; 95% CI, 1.08-5.03; AUC, 0.76) and extravesical fat entropy on T2-weighted images (p = 0.010; OR, 5.33; 95% CI, 1.25-3.79; AUC, 0.78) and ADC maps (p = 0.029; OR, 3.80; 95% CI, 1.25-16.97; AUC, 0.74) remained greater for category >= T2 compared with category T1 tumors. CONCLUSION. Greater entropy of primary bladder cancers and extravesicular fat was observed in category >= T3 than in category = T2 than in category T1 tumors. MRI texture analysis can help with local bladder cancer staging in patients who have undergone TURBT and may serve as a biomarker for higher local category bladder cancers