Genomic landscape of locally advanced or metastatic urothelial carcinoma with squamous differentiation compared to pure urothelial carcinoma

BackgroundUrothelial carcinoma with squamous differentiation (UCS) is the most common variant differentiation of urothelial carcinoma (UC). Although treatment is usually similar to pure UC, there is paucity of data regarding its genomic landscape and putative molecular drivers. In this study, we compared the mutational profile of tumors with UCS and UC histology.MethodsIn this IRB-approved retrospective study, patients with advanced UCS and UC undergoing tumor based comprehensive genomic profiling from a CLIA-certified laboratory were included. An independent genitourinary pathologist reviewed all cases. Patients were determined to have UCS based on presence of any component of squamous differentiation. Patients with UC having any other secondary histology variant were excluded. Genes with alterations (GA) in less than 5% of patients and variants of unknown significance were excluded from the analysis. Chi-square test was used to compare gene aberration frequency and the p-values were adjusted for false using Benjamini-Hochberg (BH) correction.ResultsAmong the 87 eligible patients with UCS (n=31) and UC (n=56), patients with UCS were more likely to be female (32.3% vs. 14.3%, p=0.047) with no significant differences in other clinicopathological features. Most common genomic alterations seen in UCS were TP53 (67.7%), KMT2D (48.4%) and ARID1A (32.3%). KMT2D mutations were significantly enriched in UCS (48.4% vs. 0%, FDR adj p <0.001, p = <0.001) compared to UC. Prevalence of CUL4A mutations was numerically higher in UCS vs. UC (12.9% vs. 1.8%, FDR adj p = 0.43, p = 0.03). Tumor mutation burden and the number of genomic aberrations per patient were not significantly different between the two groups.ConclusionThese findings highlight significant enrichment of KMT2D mutations in UCS and potential role of chromatin remodeling genes as drivers and potential therapeutic targets.     

A multi-institutional phase II trial of gemcitabine plus paclitaxel in patients with locally advanced or metastatic urothelial cancer

The purpose of the study was to evaluate response and survival in patients with metastatic urothelial cancer treated with combination gemcitabine and paclitaxel administered on a biweekly schedule at doses of 3000 mg/m2 and 150 mg/m2, respectively. Patients with adequate organ function and performance status were accrued through 7 institutions, stratified by prior therapy status, and treated as noted. Response was evaluated by 1979 bi-dimensional World Health Organization (WHO) criteria. Of 55 eligible patients, 17 had a partial and 5 had a complete response rate for an overall response rate of 40% (27-54%). One complete response and one partial response were observed in the 6 previously treated patients. Overall median survival was 11.8 months (11.9 months in the chemonaive cohort). Grade 3 or 4 myelosuppression occurred in 56%, but only 4 serious infections were observed. We conclude that because of a lower than expected complete response rate, even when corrected for prognostic groupings, this regimen is not recommended for routine use in patients with metastatic urothelial cancer. Insufficient patients with poor renal function or prior therapy were accrued to reach conclusions regarding its utility in these subgroups.     

A retrospective review of combination chemohormonal therapy as initial treatment for locally advanced or metastatic adenocarcinoma of the prostate

ObjectiveChemotherapy for hormone-refractory prostate cancer reduces PSA levels and enhances overall survival (OS), suggesting that administration in earlier disease stages may be beneficial. If expansion of an androgen-independent clone present during androgen deprivation mediates the transformation from an androgen-dependent to an androgen-independent phenotype, combination chemohormonal therapy would be effective initial treatment for locally advanced or metastatic prostate cancers. A retrospective review was conducted to evaluate results.Materials and methodsChemohormonal therapy outcomes were retrospectively evaluated in men with locally advanced or metastatic prostate cancer seen at our institution between January 2001 and February 2003. Chemotherapy consisted of three 8-week cycles (once weekly intravenous doxorubicin 20 mg/m² and thrice daily oral ketoconazole 400 mg in weeks 1, 3, and 5; once weekly intravenous docetaxel 35 mg/m² and thrice daily oral estramustine 280 mg in weeks 2, 4, and 6; and no therapy in weeks 7 and 8). Hormone therapy consisted of hormonal ablation during and after antiandrogen therapy after chemotherapy.ResultsData for 31 men (median age, 63 years [range, 41–74 years]; white, 97% [30/31]) were reviewed. At 1 year, median PSA level had fallen 99.3% (range, 91.7%–99.9%) from a baseline value of 14.3 ng/ml (range, 1.9–497.9 ng/mL). Median time to progression was 34+ months (range, 14–68+ months). Median OS was 56+ months (range, 17–73+ months).ConclusionsCombination chemohormonal therapy for locally advanced or metastatic prostate cancer safely and effectively reduces PSA levels and increases OS. We are now testing this approach in a prospective, Phase II randomized clinical trial.     

Use of radical cystectomy as initial therapy for the treatment of high-grade T1 urothelial carcinoma of the bladder: A SEER database analysis

ObjectivesHigh-grade T1 (HGT1) bladder cancer represents a heterogeneous disease with an aggressive phenotype. Despite prior reports demonstrating improved cancer-specific mortality (CSM) in patients who receive an early/immediate radical cystectomy (RC), the role of early surgery remains ill-defined. We analyzed the Surveillance Epidemiology and End Results (SEER) database to ascertain the use of RC as an initial therapy for clinical HGT1 bladder cancer.Materials and methodsUsing the SEER database from 2004 through 2007, we identified and stratified patients with clinical HGT1 bladder cancer who underwent RC as initial therapy within 1 year of diagnosis. We used χ² tests and t-tests to compare characteristics of surgical vs. nonsurgical patients. Cumulative incidence functions and Gray's test for inferences were employed to assess cause-specific mortality outcomes.ResultsFrom 2004 to 2007, 8,467 patients were diagnosed with clinical HGT1 bladder cancer, and 397 (4.7%) patients underwent RC. Patients who underwent RC for clinical HGT1 disease were significantly younger (P < 0.0001) and married (P < 0.0001). Surgical patients also had a significantly improved overall (P = 0.004) and other cause of death (P = 0.0053) survival probabilities yet CSM at 1, 2, and 3 years was not statistically different between the surgical and nonsurgical groups (P = 0.134).ConclusionsIn contrast to the clinically early stage renal and prostate cancers, HGT1 bladder cancer exhibits a higher degree of early progression and potential lethality. Despite routine use of extirpative surgery for T1 lesions of the kidney and prostate, our analysis of the SEER database reveals that definitive surgical therapy is uncommonly employed for HGT1 bladder cancer.     

Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Michaelson MD,McKay RR,Werner L,Atkins MB,Van Allen EM,Olivier KM,Song J,Signoretti S,McDermott DF,Choueiri TK.Cancer. 2015 Oct 1;121(19):3435-43. [Epub 2015 Jun 8]. doi: 10.1002/cncr.29503.

Background

Sarcomatoid renal cell carcinoma (RCC) is associated with an aggressive biology and a poor prognosis. Poor-risk RCC is defined by clinical prognostic factors and demonstrates similarly aggressive behavior. No standard treatment exists for patients with sarcomatoid RCC, and treatment options for patients with poor-risk disease are of limited benefit. The objective of this study was to investigate the efficacy of antiangiogenic therapy in combination with cytotoxic chemotherapy in clinically aggressive RCC.