Advanced Urothelial Bladder Cancer Research Articles

PD1/PDL1 inhibitors for the treatment of advanced urothelial bladder cancer.

IntroductionUntil recently, systemic chemotherapy was the only option for treating bladder cancer and outcomes remained dismal. After a long gap of no progress for 40 years, immuno-therapy with checkpoint inhibitors (PDL1 and PD1) has revolutionized the treatment paradigm of bladder cancer, with five approved agents to treat platinum-refractory bladder cancer since the first approval of atezolizumab in May 2016.MethodsThis review summarizes the most recent data on approved checkpoint inhibitors currently used in management of advanced bladder cancer. Early- and late-phase trials of the five checkpoint inhibitors (pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab) in advanced bladder cancer are reviewed in detail. This review also describes the potential application of PD1/PDL1 inhibitors in adjuvant and neoadjuvant settings and non-muscle-invasive bladder cancer, as well as with radiation in muscle-invasive bladder cancer treatment. The role of PDL1 and tumor-mutation burden and clinical considerations in choosing a particular immunotherapy are also discussed.ResultsThe approved checkpoint inhibitors (PD1 and PDL1 inhibitors) have similar efficacy and safety profiles in metastatic platinum-refractory bladder cancer, but they vary in dose and frequency and cost burden. However, only pembrolizumab has shown superiority over standard chemotherapy in a randomized Phase III setting so far. In addition, in the first-line setting for cisplatin-ineligible patients, both pembrolizumab and atezolizumab are US Food and Drug Administration-approved and well tolerated. There is a lack of consensus on the utility of testing for PDL1 as a predictive biomarker, as patients with no PDL1 expression also derive some clinical benefit. Tumor-mutation burden is another predictive biomarker, but needs further validation.ConclusionImmunotherapy has offered a glimmer of hope to patients with bladder cancer. The current landscape is rapidly evolving, with novel immunotherapy-combination trials to improve outcomes further and evaluate predictive biomarkers to help identify patients most likely to benefit from such therapies.

High CDKN2A/p16 and Low FGFR3 Expression Predict Progressive Potential of Stage pT1 Urothelial Bladder Carcinoma.

A recent study on the comprehensive genomic profile of advanced urothelial bladder cancer (UBC) showed cyclin-dependent kinase inhibitor 2A (CDKN2A) and fibroblast growth factor receptor 3 (FGFR3) as the most often clinically relevant genomic alterations. Therefore, the prognostic role of FGFR3 and CDKN2A/p16 for pT1 UBC was studied. Clinical data and formalin-fixed paraffin-embedded tissues of pT1 UBC treated with an organ-preserving approach was analyzed retrospectively. Total RNA was isolated using commercial RNA extraction kits and mRNA expression of CDKN2A/p16 and FGFR3 was measured using single step reverse transcription quantitative real time polymerase chain reaction using RNA-specific TaqMan assays. Data from 296 patients (79.4% male; median age: 72 years) could be used for the final evaluation. Spearman correlation revealed a statistically significant negative correlation between mRNA expression of CDKN2A/p16 and FGFR3. There was a positive correlation between CDKN2A/p16 and G3 tumors (ρ= 0.1875; P= .0012) and associated carcinoma in situ (ρ= 0.1703, P=.0033) and a negative correlation between FGFR3 and these factors (ρ=-0.2791, P< .0001 and ρ=-0.2182, P=.0002). High CDKN2A/p16 expression (≥38.04) and low FGFR3 expression (<39.14) were statistically significantly associated with worse progression-free survival (PFS; P= .0194 and P= .0089). Multivariate Cox regression analysis could identify patients with low FGFR3 and high CDKN2A/p16 expression (log rank (LR) χ2= 10.69; P=.0048) as well as tumor size≥3 cm (LR χ2= 6.03; P= .0141) as independent predictors for PFS. High expression of CDKN2A/p16 and low expression of FGFR3 show a correlation with established prognostic features for non-muscle-invasive bladder cancer and can predict progression of stage pT1 UBC.

Unwrapping the genomic characteristics of urothelial bladder cancer and successes with immune checkpoint blockade therapy

Urothelial bladder cancer (UBC) is one of the most common lethal cancer worldwide and the 5-year survival rate has not improved significantly with current treatment protocols during the last decade. Intravesical immunotherapy with Bacillus Calmette-Guérin is currently the standard care for non-muscle invasive UBC. Recently, a subset of patients with locally advanced or metastatic UBC have responded to checkpoint blockade immunotherapy against the programmed cell death 1 protein (PD-1) or its ligand (PD-L1) or the cytotoxic T-lymphocyte antigen 4 that releases the inhibition of T cells, the remarkable clinical efficacy on UBC has brought total five checkpoint inhibitors approved by the FDA in the last 2 years, and this is revolutionizing treatment of advanced UBC. We discuss the rationale for immunotherapy in bladder cancer, progress with blocking the PD-1/PD-L1 pathway for UBC treatment, and ongoing clinical trials. We highlight the complexity of the interactions between cancer cells and the immune system, the genomic basis for response to checkpoint blockade immunotherapy, and potential biomarkers for predicting immunotherapeutic response.

Reply by Authors

No AccessJournal of UrologyLetter to the Editor/Errata1 Mar 2018Reply by Authors View All Author Informationhttps://doi.org/10.1016/j.juro.2017.09.159AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Reply by Authors." The Journal of Urology, 199(3), pp. 855–856 References 1 : Association of PD-L1 expression on tumor-infiltrating mononuclear cells and overall survival in patients with urothelial carcinoma. Ann Oncol2015; 26: 812. Google Scholar 2 : Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol2016; 34: 3119. Google Scholar 3 : Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet2016; 387: 1909. Google Scholar 4 : Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol2016; 17: 1590. Google Scholar 5 : PD-L1 expression in melanoma: a quantitative immunohistochemical antibody comparison. Clin Cancer Res2017; 23: 4938. Google Scholar 6 : Comparison of different antibody clones for immunohistochemistry detection of programmed cell death ligand 1 (PD-L1) on non-small cell lung carcinoma. Appl Immunohistochem Mol Morphol2017; 10.1097/PAI.0000000000000531. Crossref, Google Scholar 7 : PD-L1 immunohistochemistry assays for lung cancer: results from phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project. J Thorac Oncol2017; 12: 208. Google Scholar © 2018 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 199Issue 3March 2018Page: 855-856 Advertisement Copyright & Permissions© 2018 by American Urological Association Education and Research, Inc.MetricsAuthor Information Expand All Advertisement PDF downloadLoading ...

Precision medicine for urothelial bladder cancer: update on tumour genomics and immunotherapy.

Effective management of advanced urothelial bladder cancer is challenging. New discoveries that improve our understanding of molecular bladder cancer subtypes have revealed numerous potentially targetable genomic alterations and demonstrated the efficacy of treatments that harness the immune system. These findings have begun to change paradigms of bladder cancer therapy. For example, DNA repair pathway mutations in genes such as ERCC2, FANCC, ATM, RB1, and others can predict responses to neoadjuvant platinum-based chemotherapies and to targeted therapies on the basis of mutation status. Furthermore, an increasing number of pan-cancer clinical trials (commonly referred to as basket or umbrella trials) are enrolling patients on the basis of molecular and genetic predictors of response. These studies promise to provide improved insight into the true utility of personalized medicine in the treatment of bladder cancer and many other cancer types. Finally, therapies that modulate immune responses have shown great benefit in many cancer types. Several immune checkpoint inhibitors that target programmed cell death protein 1 (PD1), its ligand PDL1, and cytotoxic T lymphocyte-associated protein 4 (CTLA4) have already been approved for use in bladder cancer, representing the most important change to the urological oncologist's tool-kit in over a decade. These advances also provide opportunities for personalization of bladder cancer therapy.

Emerging targeted therapies in advanced bladder cancer

The prognosis of advanced urothelial bladder cancer (UBC) is dismal despite conventional platinum-based chemotherapy and, as such, new therapeutic agents are urgently needed. Recently, many novel molecular-targeted agents inhibiting immune checkpoints, VEGF/R, FGF/R, or EGF/R are being developed in clinical trials. Among them, immune checkpoint inhibitors (ICI) targeting the PD-1/PDL1 pathway have shown the most promising outcomes with durable clinical response and favorable safety profile. Agents targeting VEGF/R, FGF/R, or EGF/R pathways are still being investigated and are not providing clear clinical benefit yet. An appropriate selection of fit patients may be necessary for further clinical development of these agents. While we are still in the beginning of targeted therapy for advanced UBC, recent breakthroughs in ICI treatment and accumulating knowledge in molecular biology of UBC will provide a new horizon in the future treatment of UBC.

Association of early reduction in circulating tumor DNA (ctDNA) with improved progression-free survival (PFS) and overall survival (OS) of patients (pts) with urothelial bladder cancer (UBC) treated with durvalumab (D).

11538 Background: Mutation variant allele frequencies (VAFs) in ctDNA indicate the frequency of cancer clones harboring the specific variant in the primary lesion and metastases, thus providing a surrogate for tumor burden. We previously reported that early reduction in VAF in ctDNA was associated with improved survival on durvalumab in NSCLC subjects. Here we replicated this association in UBC pts treated with durvalumab. Methods: CP1108/NCT01693562 was a nonrandomized phase 1/2 trial evaluating D in pts with advanced UBC or other solid tumors. By 24OCT2016, 103 UBC pts received 10 mg/kg Q2W of D with median 8.4 mos follow up. A panel of 70 genes was assayed for DNA variants using the Guardant360 cancer panel in plasma ctDNA from 33 UBC pts pre-treatment and 29 pts pre and 6 wks on-treatment. The mean VAF pre or on treatment of patient single nucleotide variants (SNVs) and insertion/deletions was correlated with clinical outcomes. Objective response rate (ORR) was calculated according to RECIST v1.1 and a Cox proportional hazard ratio (HR) was calculated adjusting for baseline ECOG, sex, age, and smoking status. Results: Complete and partial responders (CR/PRs) showed a significant decrease (Δ = -2.4%, p = 0.02) in ctDNA mean VAF post-treatment with D (i.e. reduction in tumor burden) compared to an increase in mean VAF (i.e. increase in tumor burden) in progressive disease (PD) pts (Δ = +2.7%, p = 0.31). This correlation was also observed in total mutation count in CR/PR (Δ = -4.6, p = 0.003) compared to PD pts (Δ = +2.8, p = 0.44). Pts with a decrease in ctDNA VAF at week 6 had longer median PFS (9.3 mos, 95%CI = [3.0, not reached(NR)] and OS (median NR, 95% CI = [20.3,NR]) compared to those with an increase in VAF (median PFS = 1.4 mos, 95%CI = [1.3,NR];HR = 0.29; p = 0.05 and median OS = 8.2 mos, 95% CI = [2.3,NR]; HR = 0.12; adjusted p = 0.04). DCR was 85%/14% for pts with a decrease/increase in VAF (p = 0.002). Conclusions: CtDNA VAFs were reduced in responders but not non-responders after six wks of D. A decrease in VAFs 6 wks following treatment with D correlated with longer PFS and OS, suggesting utility as an early indicator of clinical benefit. Clinical trial information: NCT01693562.

Advances in urothelial bladder cancer immunotherapy, dawn of a new age of treatment.

Urothelial bladder cancer displays a high number of somatic mutations that render these tumors more responsive to immunotherapy. Several immunotherapeutic agents were examined in patients with advanced stage urothelial bladder cancer and recently atezolizumab - an (PDL-1) immune checkpoint inhibitor antibody - was approved for the treatment of patients with metastatic disease progressing after platinum combination therapy. Despite the great success, there are still some unanswered questions and ongoing trials that are in progress to define the role of combination therapy and sequencing strategies. The objective of our manuscript is to summarize the most recent data on immunotherapy in advanced urothelial cancer. Current challenges and future perspectives of immunotherapy as a monotherapy or in combination strategies will also be analyzed.

Spotlight on atezolizumab and its potential in the treatment of advanced urothelial bladder cancer.

Metastatic urothelial carcinoma of the bladder is an aggressive malignancy with poor prognosis, reflecting a lack of effective systemic therapies. The current standard of care includes multiagent platinum-based chemotherapy; however a majority of patients do not respond to treatment and most eventually succumb to disease. Recently, renewed interest in immunotherapy in the form of immune-checkpoint inhibition has gained widespread attention for a number of malignancies. Atezolizumab, an anti-PDL1 antibody, has been shown to be effective in a subset of patients previously treated with or unfit for platinum-based chemotherapy, and has shown durable responses with a good tolerability profile. We review the mechanism of action and clinical evidence of atezolizumab for metastatic urothelial bladder cancer, and discuss this drug within the context of ongoing developments in this dynamic field of immunooncology.

Durvalumab (MEDI4736; anti-PD-L1 inhibitor): to shed light on the treatment of advanced urothelial bladder cancer patients refractory to systemic chemotherapy

For several decades, chemotherapy regimens for advanced urothelial cancer of the urinary bladder have not changed, and they include methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) and gemcitabine and cisplatin (GC) with similar efficacy and relatively less toxicity (1). Moreover, there are a few second-line chemotherapeutic agents demonstrating substantial therapeutic responses in patients who are resistant to platinum-based treatments (2). Although the novel targeted agents may offer alternative therapeutic options, their efficacies are still limited and further investigations are needed (3). Recently, many researchers have shown great interest in the role of local and systemic immune responses, which interplay with cancer cells, as a novel therapeutic target (4).

Durvalumab (MEDI4736; anti-PD-L1 inhibitor): to shed light on the treatment of advanced urothelial bladder cancer patients refractory to systemic chemotherapy

Durvalumab (MEDI4736; anti-PD-L1 inhibitor): to shed light on the treatment of advanced urothelial bladder cancer patients refractory to systemic chemotherapy

Management Considerations After Cystectomy for Bladder Cancer

TO THE EDITOR: We write about the Grand Rounds case discussion by Sonpavde et al in a recent issue of Journal of Clinical Oncology. The discussion illustrates the twin challenges presented by locally advanced urothelial bladder cancer. The first challenge, which was covered well in the detailed review, is the risk of distant metastases. This risk is mitigated by a 5% survival gain with neoadjuvant chemotherapy and a disease-free survival gain with adjuvant chemotherapy. What is missing from the discussion is the second oncologic challenge of pelvic recurrence. In the presented patient case, the eventual pT3N1 stage gave the patient a 15% to 30% risk of pelvic recurrence either in isolation or, more likely, together with distant relapse. This pelvic failure rate has been demonstrated in multi-institutional case series, individual institutional series, and the two large randomized trials of neoadjuvant chemotherapy, which all demonstrated that chemotherapy unfortunately does not reduce the pelvic recurrence rate. This pelvic failure is an absolute ceiling on potential curability and also can be a source of significant clinical morbidity. Bladder cancer remains the one cancer for which optimization of locoregional control with multimodality therapy has not been studied rigorously. That is now set to change with the currently accruing NRG GU001 trial, which is a phase II randomized study of postoperative adjuvant radiotherapy in this setting. If all other solid tumors can be taken as an example, it is likely that bladder cancer too will benefit from the best of surgery, adjuvant radiotherapy, and systemic treatment. It is by offering patients the possibility of enrollment into this and other trials that we will improve the outlook for this disease. To finish by returning to the presented patient case: It so happens that, in the interest of safety, the NRG trial currently excludes patients with a neo bladder, so systemic treatment is the sole active, treatment option. If the patient did not have a neoadjuvant bladder, he would have been eligible for the radiation trial even if he received systemic adjuvant treatment postoperatively.

AB063. Comparisons of prognosis between urothelial carcinoma of the upper urinary tract and bladder with pT3-4 diseases

ObjectiveTo compare the prognosis of locally advanced upper tract urothelial carcinoma (UTUC) and bladder cancer (BC) in patients treated with radical surgeries.MethodsA retrospective analysis of the clinicopathological data of 228 consecutive UTUC patients and 174 BC patients treated by radical surgeries from 2000 to 2012 at a high-volume center in China was conducted. Kaplan-Meier method and Cox regression were used to compare overall survival (OS) and cancer-specific survival (CSS) and to find prognostic factors.ResultsBC were associated with male sex (P<0.001), high grade (P=0.002), multifocality (P<0.001), positive lymph node (P=0.002), no hydronephrosis (P<0.001) and open surgical approach (P<0.001). UTUC have statistically significant better 5-year CSS rate (61.0% vs. 49.8%, P=0.008) and OS rate (58.3% vs. 37.4%, P<0.001) than BC. Bladder tumor location [UTCU vs. BC: hazard ratio (HR) =0.703 and HR =0.462] and positive lymph node status (HR =1.919 and HR =1.667) were independent risk factors of cancer-specific death and overall mortality, respectively.ConclusionsOur data suggest that locally invasive urothelial carcinomas (UC) behave differently in the upper and lower urinary tracts. UTUC has a better prognosis than BC when stage and grade are considered simultaneously and lymph node involvement has significant influences on clinical outcomes of urothelial carcinoma.

Standard or accelerated methotrexate, vinblastine, doxorubicin and cisplatin as neoadjuvant chemotherapy for locally advanced urothelial bladder cancer: Does dose intensity matter?

BackgroundThere is continuing controversy regarding the optimal regimen for neoadjuvant chemotherapy (NAC) in bladder cancer. Patients and methodsWe performed a retrospective analysis of 241 consecutive bladder cancer patients who received a combination of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) using a standard (52 patients) or an accelerated schedule (189 patients) as NAC before radical cystectomy in 17 centres of the French GEnito-urinary TUmour Group from March 2004–May 2013. ResultsThe median age was 62 years. As expected, the median number of cycles, the median total dose of cisplatin and the median cisplatin dose intensity were higher in patients treated with the accelerated regimen. Conversely, the median duration of chemotherapy was shorter. Regarding toxicity, grade III/IV neutropenia, grade III thrombocytopenia and grade III anaemia as well were more frequently observed in patients treated with the standard regimen. Among 211 (88%) patients who proceeded to cystectomy, 75 (35%) patients achieved an ypT0 pN0 status (no pathologic residual tumour cells) with no significant difference according to the MVAC schedule. Three-year overall survival rates were 66.5% (95% confidence interval [CI], 56–79) and 72% (95% CI, 59.5–88) in the standard and accelerated cohorts, respectively. In the multivariate analysis, two independent prognostic parameters were retained: the ypT0 stage and the ypN0 stage. Heterogeneity test did not show any interaction with NAC regimens. ConclusionSimilar pathological response and survival rates were observed whatever the chemotherapy regimen used. Haematological toxicity was greater in patients who received standard MVAC.

Immune biomarkers associated with clinical benefit from atezolizumab (MPDL3280a; anti-PD-L1) in advanced urothelial bladder cancer (UBC)

Meeting abstracts Atezolizumab (anti-PD-L1) has demonstrated robust clinical activity in UBC [[1][1]]. Elevated PD-L1 expression on tumor-infiltrating immune cells (IC) is associated with increased clinical efficacy; however, the contribution of other immune biomarkers is unknown. In this study, we

Impact of ERBB2 mutations on in vitro sensitivity of bladder cancer to lapatinib

Lapatinib, a dual tyrosine kinase inhibitor of ErbB1 and ErbB2, shows a clinical benefit in a subset of patients with advanced urothelial bladder cancer (UBC). We hypothesized that the corresponding gene, ERBB2, is affected by mutations in a subset of UBC and that these mutations impact ErbB2 function, signaling, UBC proliferation, gene expression, and predict response to lapatinib. We found ERBB2 mutations in 5 of 33 UBC cell lines (15%), all of which were derived from invasive or high grade tumors. Phosphorylation and activation of ErbB2 and its downstream pathways were markedly enhanced in mutated cell lines compared with the ERBB2 wild-type. In addition, the gene expression profile was distinct, specifically for genes encoding for proteins of the extracellular matrix. RT112 cells infected with ERBB2 mutants showed a particular growth pattern (“mini-foci”). Upon treatment with lapatinib, 93% of these “mini-foci” were reversed. The sensitivity to lapatinib was greatest among cell lines with ERBB2 mutations. In conclusion, ERBB2 mutations occur in a subset of UBC and impact proliferation, signaling, gene expression and predict a greater response to lapatinib. If confirmed in the clinical setting, this may lead the way toward personalized treatment of a subset of UBC.

116 Chemoinduced downstaging as a potential surrogate marker of efficacy and of increased survival following neoadjuvant chemotherapy of locally advanced urothelial urinary bladder cancer

116 Chemoinduced downstaging as a potential surrogate marker of efficacy and of increased survival following neoadjuvant chemotherapy of locally advanced urothelial urinary bladder cancer

Tumor Regression Grade of Urothelial Bladder Cancer After Neoadjuvant Chemotherapy

Histopathologic tumor regression grades (TRGs) after neoadjuvant chemotherapy predict survival in different cancers. In bladder cancer, corresponding studies have not been conducted. Fifty-six patients with advanced invasive urothelial bladder cancer received neoadjuvant chemotherapy before cystectomy and lymphadenectomy. TRGs were defined as follows: TRG1: complete tumor regression; TRG2: >50% tumor regression; TRG3: 50% or less tumor regression. Separate TRGs were assigned for primary tumors and corresponding lymph nodes. The prognostic impact of these 2 TRGs, the highest (dominant) TRG per patient, and competing tumor features reflecting tumor regression (ypT/ypN stage, maximum diameter of the residual tumor) were determined. Tumor characteristics in initial transurethral resection of the bladder specimens were tested for response prediction. The frequency of TRGs 1, 2, and 3 in the primary tumors were n=16, n=19, and n=21; corresponding data from the lymph nodes were n=31, n=9, and n=16. Interobserver agreement in determination of the TRG was strong (κ=0.8). Univariately, all evaluated parameters were significantly (P ≤ 0.001) related to overall survival; however, the segregation of the Kaplan-Meier curves was best for the dominant TRG. In multivariate analysis, only dominant TRG predicted overall survival independently (P=0.035). In transurethral resection specimens of the chemotherapy-naive bladder cancer, the only tumor feature with significant (P<0.03) predictive value for therapy response was a high proliferation rate. In conclusion, among all parameters reflecting tumor regression, the dominant TRG was the only independent risk factor. A favorable chemotherapy response is associated with a high proliferation rate in the initial chemotherapy-naive bladder cancer. This feature might help personalize neoadjuvant chemotherapy.

Larotaxel with Cisplatin in the First-Line Treatment of Locally Advanced/Metastatic Urothelial Tract or Bladder Cancer: A Randomized, Active-Controlled, Phase III Trial (CILAB)

Background: This open-label, randomized phase III trial evaluated larotaxel/cisplatin versus gemcitabine/cisplatin as first-line treatment for locally advanced (T4b) or metastatic urothelial tract or bladder cancer. Methods: Patients were randomized to larotaxel 50 mg/m² with cisplatin 75 mg/m² every 3 weeks (larotaxel/cisplatin) or gemcitabine 1,000 mg/m² on days 1, 8, and 15 with cisplatin 70 mg/m² on day 1 every 4 weeks (gemcitabine/cisplatin). The primary endpoint was overall survival (OS). Results: The trial was prematurely closed following the sponsor's decision to stop clinical development of larotaxel (n = 337 randomized). The larotaxel dose was reduced to 40 mg/m² and cisplatin to 60 mg/m² following a data monitoring committee safety review of the first 97 patients. At the time of analysis, the median OS was 13.7 months [95% confidence interval (CI) 11.2-17.1] with larotaxel/cisplatin and 14.3 months (95% CI 10.5 to not reached) with gemcitabine/cisplatin [hazard ratio (HR) 1.21; 95% CI 0.83-1.76; p = 0.33]. The median progression-free survival (PFS) was 5.6 months (95% CI 4.1-6.2) with larotaxel/cisplatin and 7.6 months (95% CI 6.6-9.1) with gemcitabine/cisplatin (HR 1.67; 95% CI 1.24-2.25). More myelosuppression was observed with gemcitabine/cisplatin. Conclusion: There was no difference in OS. Although the trial was closed prematurely, PFS appeared worse with larotaxel/cisplatin, suggesting that larotaxel/cisplatin does not improve outcomes versus cisplatin/gemcitabine.

Abstract 784: Plasmacytoid urothelial carcinoma: Molecular and histopathological characterization of a rare variant of bladder cancer

Abstract AIM: The plasmaycytoid urothelial carcinoma (PUC) is a rare variant of urothelial carcinoma. To date only few cases have been reported and molecular data are not published yet. Therefore, we analysed clinical, histopathological and molecular features in a series of 32 PUC. METHODS: Expression of CK7, CK20, PAN-CK, p53, Ki67, CD138, E-cadherin and beta-catenin was analysed immunohistochemically on a tissue microarray. UroVysion FISH was performed to asses ploidy status. After microdissection and DNA isolation, FGFR3 and PIK3CA mutation status were determined using SNaPshot analysis. P53 mutation analysis was performed by direct sequencing of exons 5-9. Clinical data available from 16 PUC were compared to 269 patients with conventional locally advanced urothelial bladder cancer within a randomized multicenter trial (AUO-AB 05/95). RESULTS: PUC were usually diagnosed in advanced pathologic stage (64% pT3, 23% pT4) with 60% metastatic disease. Overall survival of PUC treated with cystectomy and adjuvant chemotherapy was lower than of patients with conventional locally advanced bladder cancer (23.3 vs. 49.9 months, p=0.051). 87% of PUCs showed loss or strongly reduced expression of E-cadherin. Beta-catenin was completely absent in 22.5% and associated with loss of E-cadherin (p=0.033). 16.7% of PUC showed a nuclear staining for beta-catenin, which was more frequent in E-cadherin negative PUC. CK20 expression was abnormal in all cases. 22.6% of PUCs were negative for CK7. 97% of PUC displayed a positive PAN-CK staining. 78% coexpressed CD138. Nuclear accumulation of P53 was found in 68.4% of E-cadherin negative PUC, but only in 27.2% of E-cadherin positive ones. p53 mutations were found in 9/31 cases. 69% of PUC showed increased Ki67 labelling index (&amp;gt;15%). FISH displayed PUC as highly aneuploid tumors. Relative deletion of 9p21 was found in 70%. No mutations were found in FGFR3 and PIK3CA. CCONCLUSIONS: PUC showed molecular and histopathologic features of aggressive bladder cancer. Prognosis in locally advanced PUC treated with adjuvant chemotherapy seems to be unfavourable in comparison to conventional bladder cancer. Loss of E-Cadherin is present in the majority of PUC and is associated with a higher degree of p53 and beta-catenin accumulation, which is in line with the high metastatic potential of PUC. CD 138 is not suitable for differential diagnosis to plasmocytoma. PAN CK is an important diagnostic tool for clarification of the epithelial origin of PUC as there are cases negative for CK7 and CK20. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 784.