Andres J. Schrader

Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone.

BACKGROUND Abiraterone, an androgen synthesis inhibitor, has been successfully used in the treatment of castration-resistant prostate cancer (CRPC) for 2 yr. Enzalutamide is a second-generation nonsteroidal antiandrogen that has recently been approved for the same indication. OBJECTIVE This is the first study to evaluate the effectiveness of enzalutamide after failure of abiraterone. DESIGN, SETTING, AND PARTICIPANTS Thirty-five patients were identified as having received sequential therapy with abiraterone followed by enzalutamide. All patients had undergone prior docetaxel chemotherapy, and no patient had received ketoconazole. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Posttreatment changes in prostate-specific antigen (PSA) were used to determine the activity of enzalutamide in patients who had received prior abiraterone. RESULTS AND LIMITATIONS The median duration of abiraterone treatment was 9.0 mo (range: 2.0-19.0 mo). Of the 35 patients, 16 (45.7%) achieved a >50% decline in PSA, and 14 (40%) had a rising PSA as the best response. The median duration of subsequent enzalutamide treatment was 4.9 mo (Kaplan-Meier estimate; 95% confidence interval [CI], 2.4-7.4). Seven of 16 CRPC patients who were initially abiraterone-sensitive (43.8%) and 3 of 19 CRPC patients who were initially abiraterone-insensitive (15.8%) showed a >50% PSA decline while taking enzalutamide. Of the 35 patients, 17 (48.6%) were primarily enzalutamide-resistant and showed a rising PSA as the best response. Median time to progression was 4.0 mo (95% CI, 2.0-6.0) for 18 of 35 patients with at least one declining PSA value while taking enzalutamide (51.4%). Of the 17 patients who were assessable radiologically, only 1 (2.9%) attained a confirmed partial response. Small sample size was the major limitation. CONCLUSIONS Enzalutamide treatment achieved only a modest response rate in patients progressing after abiraterone. Although cross-resistance between abiraterone and enzalutamide was a common phenomenon, it was not inevitable, and a small but significant number of patients showed significant benefit from sequential treatment.

Clinical significance of epithelial-mesenchymal transition

The concept of epithelial-mesenchymal transition (EMT), a process where cells change their epithelial towards a mesenchymal phenotype, has gained overwhelming attention especially in the cancer research community. Thousands of scientific reports investigated changes in gene, mRNA and protein expression compatible with EMT and their possible correlation with tumor invasion, metastatic spread or patient prognosis; however, up to now, a proof of clinical significance of the concept is still missing. This review, with a main focus on the role of EMT in tumors, will summarize the basic molecular events underlying EMT including the signaling pathways capable of its induction as well as changes in EMT-associated protein expression and will very briefly touch the role of microRNAs in EMT. We then outline protein markers that are used most frequently for the assessment of EMT in research and diagnostic evaluation of tumor specimens and depict the link between EMT, a cancer stem cell (CSC) phenotype and resistance to conventional antineoplastic therapies. Furthermore, we evaluate a possible correlation between EMT marker expression and patient prognosis as well as current therapeutic concepts targeting the EMT process to slow down or prevent metastatic spread of malignant tumors.

Enzalutamide Antitumour Activity Against Metastatic Castration-resistant Prostate Cancer Previously Treated with Docetaxel and Abiraterone: A Multicentre Analysis

BACKGROUND The degree of antitumour activity of enzalutamide following disease progression on docetaxel and abiraterone remains controversial. OBJECTIVE To examine the effect of enzalutamide in patients progressing following taxane-based chemotherapy and abiraterone. DESIGN, SETTING, AND PARTICIPANTS Metastatic castration-resistant prostate cancer patients entering one of four European compassionate use programmes of enzalutamide. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point was overall survival (OS). Secondary end points were association between OS and posttreatment prostate-specific antigen (PSA) kinetics, patient characteristics, and progression-free survival, respectively. Kaplan-Meier survival analysis and Cox proportional hazard analysis were performed. RESULTS AND LIMITATIONS We identified 137 patients who prior to enzalutamide had progressed following a median of eight cycles of docetaxel and seven courses of abiraterone. The median time on enzalutamide was 3.2 mo; median OS from the time patients started enzalutamide was 8.3 mo (95% confidence interval, 6.8-9.8). Only 45 (38%) and 22 (18%) patients had PSA declines (unconfirmed) >30% and 50%, respectively. Patients who had more than 30% or 50% falls in PSA had improved survival compared with patients who had no such PSA fall (11.4 mo vs 7.1 mo; p=0.001 and 12.6 vs 7.4 mo; p=0.007, respectively). Poor performance status and low haemoglobin was negatively associated with OS. CONCLUSIONS Median OS on enzalutamide following disease progression on taxane-based chemotherapy and abiraterone was modest, but patients who experience a PSA decline >30% or 50%, respectively, with enzalutamide in this setting had longer survival. PATIENT SUMMARY Enzalutamide produces modest prostate-specific antigen (PSA) responses in patients progressing following chemotherapy and abiraterone. Despite a modest PSA response, survival may still be improved.

Incidence and long-term prognosis of papillary compared to clear cell renal cell carcinoma – A multicentre study

AIM OF THE STUDY Papillary renal cell carcinoma (pRCC) is the second most common subtype of RCC after the conventional clear cell type (cRCC). However, its characteristics and prognosis have been less intensively investigated. The aim of our study was to examine the tumour characteristics and long-term prognosis of pRCC compared to clear cell RCC (cRCC). METHODS In total, 4941 evaluable patients were subjected to either radical nephrectomy or nephron-sparing surgery for pRCC or cRCC at five centres in Germany (University Hospitals of Hannover, Homburg/Saar, Mainz, Ulm and Marburg) between 1990 and 2010. RESULTS pRCC (n=565) and cRCC (n=4376) patients were comparable with regard to mean age, clinical symptoms, tumour differentiation and regional lymph node metastases. Patients with pRCC had a significantly higher rate of organ confined tumours (pT1-2, N/M0; 74.9% versus 62.9%), less synchronic visceral metastases (9.6% versus 15.2%), and a higher 5-year CSS rate than those with cRCC (85.1% versus 76.9%). Multivariate analysis identified the papillary subtype as a significant positive prognostic factor in localised (HR, 0.45) but as a negative prognostic factor in metastatic tumour stages (HR, 1.37). CONCLUSION pRCC can apparently be differentiated into two subgroups: an organ-confined/localised subgroup with a significantly better prognosis and an advanced/metastatic subgroup with a worse prognosis compared to cRCC.

Fibronectin 1 mRNA expression correlates with advanced disease in renal cancer

BackgroundFibronectin 1 (FN1) is a glycoprotein involved in cellular adhesion and migration processes. The aim of this study was to elucidate the role of FN1 in development of renal cell cancer (RCC) and to determine a prognostic relevance for optimal clinical management.Methods212 renal tissue samples (109 RCC, 86 corresponding tissues from adjacent normal renal tissue and 17 oncocytomas) were collected from patients undergoing surgery for renal tumors and subjected to total RNA extraction. Detection of FN1 mRNA expression was performed using quantitative real time PCR, three endogenous controls, renal proximal tubular epithelial cells (RPTEC) as biological control and the ΔΔCt method for calculation of relative quantities.ResultsMean tissue specific FN1 mRNA expression was found to be increased approximately seven fold comparing RCC and corresponding kidney control tissues (p < 0.001; ANOVA). Furthermore, tissue specific mean FN1 expression was increased approx. 11 fold in clear cell compared to papillary RCC (p = 9×10-5; Wilcoxon rank sum test). Patients with advanced disease had higher FN1 expression when compared to organ-confined disease (p < 0.001; Wilcoxon rank sum test). Applying subgroup analysis we found a significantly higher FN1 mRNA expression between organ-confined and advanced disease in the papillary and not in the clear cell RCC group (p = 0.02 vs. p = 0.2; Wilcoxon rank sum test). There was an increased expression in RCC compared to oncocytoma (p = 0.016; ANOVA).ConclusionsTo our knowledge, this is the first study to show that FN1 mRNA expression is higher in RCC compared to normal renal tissue. FN1 mRNA expression might serve as a marker for RCC aggressiveness, indicating early systemic progression particularly for patients with papillary RCC.

Morbidity and Quality of Life in Bladder Cancer Patients following Cystectomy and Urinary Diversion: A Single-Institution Comparison of Ileal Conduit versus Orthotopic Neobladder

Objective. To evaluate and compare noncontinent and continent urinary diversion after radical cystectomy in patients with bladder cancer. Methods. A total of 301 patients submitted to radical cystectomy at the Charité-University Hospital Berlin from 1993 to 2007 including 146 with an ileal conduit and 115 with an ileal neobladder. Clinical and pathological data as well as oncological outcome were retrospectively analyzed and compared. Quality of life was analyzed using the EORTC QLQ-C30 and BLM30 questionnaires. Results. 69.1% and 69.6% of all patients who received an ileal conduit and ileal neobladder, respectively, developed early complications. The two groups differed significantly concerning the occurrence of postoperative ileus (P = 0.02) favoring patients who received an ileal conduit but not with regard to any other early-onset complication evaluated. Patients with ileal neobladder had a significantly better global health status and quality of life (P = 0.02), better physical functioning (P = 0.02), but also a higher rate of diarrhoea (P = 0.004). Conclusion. Cystectomy with any type of diversion remains a complication-prone surgery. Even if the patient groups are not homogeneous in all respects, there are many arguments in favor of the ileal neobladder as the urinary diversion of choice.

Correlation of Intraprostatic Tumor Extent with 68Ga-PSMA Distribution in Patients with Prostate Cancer

We evaluated the diagnostic value and accuracy of prostate-specific membrane antigen (PSMA) PET for the intraprostatic delineation of prostate cancer before prostatectomy. Methods: We identified 6 patients with biopsy-proven high-risk prostate cancer who were referred for 68Ga-PSMA PET/CT before radical prostatectomy to rule out metastasis. After prostatectomy, a histologic map of the prostate was reconstructed. The histologic extent and Gleason score of each segment of the prostate were compared with 68Ga-PSMA PET images resliced to the histologic axis. Sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratios were calculated. The SUV of each segment was measured, and median values were compared. Results: Of the 132 segments, 112 were eligible for analysis. The correlation of histologic results with 68Ga-PSMA PET images showed a specificity and sensitivity of 92%. The positive and negative likelihood ratio and the positive and negative predictive value for detection of prostate cancer on 68Ga-PSMA PET were 11.5, 0.09, 96%, and 85%, respectively. The median SUVmax of true-positive prostate segments was significantly higher than that of true-negative segments (11.0 ± 7.8 vs. 2.7 ± 0.9, P < 0.001), and a cutoff of 4 revealed a sensitivity and specificity of 86.5% and an accuracy of 87.5%. Conclusion: These preliminary results show that the intraprostatic localization and extent of prostate cancer may be estimated by 68Ga-PSMA PET. This imaging method may be helpful for identifying target lesions before prostate biopsy and may support decision making before focal or radical therapy.

Does Obesity Influence the Prognosis of Metastatic Renal Cell Carcinoma in Patients Treated with Vascular Endothelial Growth Factor–Targeted Therapy?

BACKGROUND Obesity increases the risk for renal cell carcinoma (RCC). However, it has only recently been identified as an independent positive prognostic factor for localized RCC. OBJECTIVE To determine whether obesity influences long-term prognosis in metastatic RCC patients receiving vascular endothelial growth factor-targeted therapy. DESIGN, SETTING, AND PARTICIPANTS In 116 patients with metastatic RCC who received antiangiogenic agents (sunitinib, sorafenib, axitinib, bevacizumab) in 2005-2010, we evaluated whether body mass index (BMI), a body surface area (BSA) above the European average, the visceral fat area (VFA), or s.c. fat area (SFA) were of predictive relevance. MEASUREMENTS BMI was categorized based on current World Health Organization definitions. BSA was stratified according to the European average for men (1.98 m(2)) and women (1.74 m(2)). VFA and SFA were dichotomized using the median of the observed distribution as the cutoff. The primary endpoints of this study were time to progression and overall survival time. RESULTS AND LIMITATIONS The whole population had median progression-free and overall survival times of 8.3 months and 20.5 months, respectively. In contrast to BMI and BSA, higher than average VFA and SFA levels were significant predictors of longer progression-free and overall survival times. The major limitations of this study are its retrospective design and its heterogeneous patient population. CONCLUSION This is the first study to identify high VFA and SFA levels as positive predictive biomarkers for patients who receive first-line antiangiogenic agents for metastatic RCC.

JS-K, a glutathione/glutathione S-transferase-activated nitric oxide releasing prodrug inhibits androgen receptor and WNT-signaling in prostate cancer cells

BackgroundNitric oxide (NO) and its oxidative reaction products have been repeatedly shown to block steroid receptor function via nitrosation of zinc finger structures in the DNA-binding domain (DBD). In consequence NO-donors could be of special interest for the treatment of deregulated androgen receptor(AR)-signaling in castration resistant prostate cancer (CRPC).MethodsProstate cancer (PCa) cells were treated with JS-K, a diazeniumdiolate derivate capable of generating large amounts of intracellular NO following activation by glutathione S-transferase. Generation of NO was determined indirectly by the detection of nitrate in tissue culture medium or by immunodetection of nitrotyrosine in the cytoplasm. Effects of JS-K on intracellular AR-levels were determined by western blotting. AR-dimerization was analyzed by mammalian two hybrid assay, nuclear translocation of the AR was visualized in PCa cells transfected with a green fluorescent AR-Eos fusion protein using fluorescence microscopy. Modulation of AR- and WNT-signalling by JS-K was investigated using reporter gene assays. Tumor cell proliferation following JS-K treatment was measured by MTT-Assay.ResultsThe NO-releasing compound JS-K was shown to inhibit AR-mediated reporter gene activity in 22Rv1 CRPC cells. Inhibition of AR signaling was neither due to an inhibition of nuclear import nor to a reduction in AR-dimerization. In contrast to previously tested NO-donors, JS-K was able to reduce the intracellular concentration of functional AR. This could be attributed to the generation of extremely high intracellular levels of the free radical NO as demonstrated indirectly by high levels of nitrotyrosine in JS-K treated cells. Moreover, JS-K diminished WNT-signaling in AR-positive 22Rv1 cells. In line with these observations, castration resistant 22Rv1 cells were found to be more susceptible to the growth inhibitory effects of JS-K than the androgen dependent LNCaP which do not exhibit an active WNT-signaling pathway.ConclusionsOur results suggest that small molecules able to inhibit WNT- and AR-signaling via NO-release represent a promising platform for the development of new compounds for the treatment of CRPC.

Overexpression of p16INK4a in Urothelial Carcinoma In Situ Is a Marker for MAPK-Mediated Epithelial-Mesenchymal Transition but Is Not Related to Human Papillomavirus Infection

Background The role of human papillomavirus (HPV) in bladder carcinogenesis remains controversial. Overexpression of p16INK4a, a surrogate marker for infection with oncogenic HPV in other tumours, has been described for urothelial carcinoma in situ (UCIS). Our goal was therefore to evaluate whether overexpression of p16INK4a is associated with HPV infection and to identify mechanisms of p16INK4a upregulation in UCIS. Materials and Methods In 60 tissue specimens from a total of 45 patients (UCIS and controls), we performed p16INK4a immunohistochemistry followed by detection and subclassification of HPV DNA. In a subset of samples, we tested for gene amplification of p16INK4a applying fluorescence in situ hybridization (FISH). RAS/MAPK signalling and epithelial-mesenchymal transition (EMT) was assessed using immunohistochemistry. Finally, we transfected urothelial carcinoma cells with KRAS and examined the expression of p16INK4a as well as markers of EMT. Results We found overexpression of p16INK4a in 92.6% of UCIS and in all cervical intraepithelial neoplasia (CIN) controls. In contrast, we detected high-risk HPV DNA in 80% of CIN, but none in UCIS. There was no gene amplification of p16INK4a. High levels of phosphorylated kinases and urokinase plasminogen activator (uPA) and loss of membraneous E-cadherin were detected in UCIS. KRAS transfection of urothelial carcinoma cells led to upregulation of p16INK4a and uPA accompanied by loss of E-cadherin that could be inhibited by application of the kinase-inhibitor Sorafenib. Conclusions Our results show that overexpression of p16INK4a in UCIS is neither associated with HPV infection nor p16INK4a gene amplification but is a consequence of enhanced RAS/MAPK signalling that promotes EMT, possibly due to Sorafenib-sensitive paracrine secretion of the EMT activator uPA. These findings might open a novel therapeutic option for localized but aggressive urothelial cancer.