Prospective randomized double-blind multicentre phase II study comparing gemcitabine and cisplatin plus sorafenib chemotherapy with gemcitabine and cisplatin plus placebo in locally advanced and/or metastasized urothelial cancer: SUSE (AUO-AB 31/05).

OBJECTIVE: To evaluate the efficacy and safety of gemcitabine and cisplatin in combination with sorafenib, a tyrosine-kinase inhibitor, compared with chemotherapy alone as first-line treatment in advanced urothelial cancer. PATIENTS AND METHODS: The study was a randomized phase II trial. Its primary aim was to show an improvement in progression-free survival (PFS) of 4.5 months by adding sorafenib to conventional chemotherapy. Secondary objectives were objective response rate (ORR), overall survival (OS) and toxicity. The patients included in the trial had histologically confirmed locally advanced and/or metastatic urothelial cancer of the bladder or upper urinary tract. Chemotherapy with gemcitabine (1250 mg/qm on days 1 and 8) and cisplatin (70 mg/qm on day 1) repeated every 21 days, was administered to all patients in a double-blind randomization of additional sorafenib (400 mg twice daily) vs placebo (two tablets twice daily) on days 3-21. Treatment continued until progression or unacceptable toxicity, the maximum number of cycles was limited to eight. The response assessment was repeated after every two cycles. RESULTS: Between October 2006 and October 2010, 98 of 132 planned patients were recruited. Nine patients were ineligible. The final analysis included 40 patients in the sorafenib and 49 patients in the placebo arm. There were no significant differences between the two arms concerning ORR (sorafenib: complete response [CR] 12.5%, partial response [PR] 40%; placebo: CR 12%, PR 35%), median PFS (sorafenib: 6.3 months, placebo: 6.1 months) or OS (sorafenib: 11.3 months, placebo: 10.6 months). Toxicity was moderately higher in the sorafenib arm. Diarrrhoea occurred significantly more often in the sorafenib arm and hand-foot syndrome occurred only in the sorafenib arm. The study was closed prematurely because of slow recruitment. CONCLUSION: Although the addition of sorafenib to standard chemotherapy showed acceptable toxicity, the trial failed to show a 4.5 months improvement in PFS.

Evidence for gains at 15q and 20q in brain metastases of prostate cancer.

Many detailed genetic studies have been reported on prostate carcinogenesis. A major shortcoming of these studies, however, is the fact that most data have been gained from investigations that were performed at a single point of time during tumor development. Only little is known on the dynamic process of genetic changes during the course of the disease. We performed comparative genomic hybridization in two cases of prostate cancer brain metastases. Tissue samples from the primary tumors, the locally recurrent tumor in one case, and the brain metastases from both cases were available for analysis. The number of chromosome abnormalities was found to be increased in the metastases. This contrasts to a remarkably stable chromosome composition of the primary tumor over several years, even in an androgen-depleted environment. When focusing on these changes, which either emerged as new common aberrations in both brain metastases, or which were commonly present in the primary and metastatic tumors, we were able to delineate five chromosomal sites that are assumed to be related to prostate cancer metastasis: 8q21 approximately q22, 8q24, 15q24 approximately q26, 20q12 approximately q13.1, and Xq12 approximately q21. These findings provide new evidence for a putative role of genes at 15q and 20q in the metastatic process of prostate cancer.

Outcome of prostate cancer patients with initial PSA> or =20 ng/ml undergoing radical prostatectomy.

OBJECTIVES: To retrospectively assess the outcome of patients with initial PSA of 20 ng/ml or higher undergoing radical prostatectomy (RP) for prostate cancer (pCA). METHODS: Between January 1986 and June 2005, 275 patients with preoperative PSA> or =20 ng/ml underwent RP for pCA at our institution. Overall, disease-specific and biochemical progression-free survival rates for the entire cohort and for particular subgroups were determined. RESULTS: Median patient age at time of surgery was 64 yr (range: 44-75). Fifty-seven patients (20.7%) had pT2 stage, 206 (74.9%) pT3, and 10 (3.7%) pT4; 78 (28.4%) presented with local nodal metastases (pN+). To date, 40 patients have died (14.5%), 22 of pCA and 18 of other causes. Biochemical progression occurred in 92 patients (33.5%). Overall (and disease-specific) survivals at 5, 10, and 15 yr were 87% (93%), 70% (83%), and 58% (71%), respectively. These survival rates did not significantly differ between patients receiving immediate versus deferred hormonal therapy (in case of progression). Five-year PSA progression-free survival in patients on surveillance (receiving deferred hormonal treatment at the onset of rising PSA values) was 53%. For patients on immediate hormonal treatment following RP, the 5-yr hormone-refractory PSA progression rate was 76%. CONCLUSIONS: According to long-term follow-up results in this high-risk cohort of patients with preoperative PSA> or =20 ng/ml, RP can be considered a viable therapeutic option. With regard to combining immediate hormonal therapy with surgery, the optimal treatment following RP remains to be defined.

Detection of novel amplicons in prostate cancer by comprehensive genomic profiling of prostate cancer cell lines using oligonucleotide-based arrayCGH.

BACKGROUND: The purpose of this study was to prove the feasibility of a longmer oligonucleotide microarray platform to profile gene copy number alterations in prostate cancer cell lines and to quickly indicate novel candidate genes, which may play a role in carcinogenesis. METHODS/RESULTS AND FINDINGS: Genome-wide screening for regions of genetic gains and losses on nine prostate cancer cell lines (PC3, DU145, LNCaP, CWR22, and derived sublines) was carried out using comparative genomic hybridization on a 35,000 feature oligonucleotide microarray (arrayCGH). Compared to conventional chromosomal CGH, more deletions and small regions of gains, particularly in pericentromeric regions and regions next to the telomeres, were detected. As validation of the high-resolution of arrayCGH we further analyzed a small amplicon of 1.7 MB at 9p13.3, which was found in CWR22 and CWR22-Rv1. Increased copy number was confirmed by fluorescence in situ hybridization using the BAC clone RP11-165H19 from the amplified region comprising the two genes interleukin 11 receptor alpha (IL11-RA) and dynactin 3 (DCTN3). Using quantitative real time PCR (qPCR) we could demonstrate that IL11-RA is the gene with the highest copy number gain in the cell lines compared to DCTN3 suggesting IL11-RA to be the amplification target. Screening of 20 primary prostate carcinomas by qPCR revealed an IL11-RA copy number gain in 75% of the tumors analyzed. Gain of DCTN3 was only found in two cases together with a gain of IL11-RA. CONCLUSIONS/SIGNIFICANCE: ArrayCGH using longmer oligonucleotide microarrays is feasible for high-resolution analysis of chomosomal imbalances. Characterization of a small gained region at 9p13.3 in prostate cancer cell lines and primary prostate cancer samples by fluorescence in situ hybridization and quantitative PCR has revealed interleukin 11 receptor alpha gene as a candidate target of amplification with an amplification frequency of 75% in prostate carcinomas. Frequent amplification of IL11-RA in prostate cancer is a potential mechanism of IL11-RA overexpression in this tumor type.

Telomerase activity and telomerase subunit gene expression levels are not related in prostate cancer: a real-time quantification and in situ hybridization study.

Because the mechanisms of telomerase activation in prostate cancer are mainly unknown, we investigated the relationships between telomerase activity and expression levels of human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) mRNA in benign and malignant alterations of the human prostate gland. Using the LightCycler technology, hTERT mRNA expression was quantified in 46 radical prostatectomy and 10 benign prostatic hyperplasia (BPH) cases; hTR expression was quantified in a subset of these tissue samples. Telomerase activity was measured using a quantitative telomeric repeat amplification protocol ELISA assay. Similar to hTR, which was expressed in all tissue samples tested, hTERT mRNA was detected in 98% of the prostate cancer samples and in 30% of the BPH samples. Regarding clinicopathologic variables, telomerase activity was significantly correlated with Gleason score (<7 vs > or =7, p = 0.02). No relationships emerged between normalized hTR or hTERT expression levels and tumor stage, Gleason score, lymph node status, or preoperative serum prostate-specific antigen. Remarkably, one third of all cancer and BPH tissue samples with hTR and hTERT expression lack telomerase activity. Quantitative analyses contradict the assumption that a certain threshold level of hTR or hTERT mRNA is required for telomerase activation, thus indicating that telomerase regulation in prostate cancer occurs more likely on a posttranscriptional level. Nevertheless, the observation that hTR and hTERT mRNA levels are significantly (p < 0.002) correlated suggests some common mechanisms in the up-regulation of hTR and hTERT expression. Because in situ hybridization revealed strong hTERT expression in all cells of the tumor glands but also in high-grade prostatic intraepithelial neoplasia foci, this up-regulation seems to occur early in prostate carcinogenesis.