University of Colorado researchers found that arise from stem cells of muscle invasion and another muscle-invasive bladder cancer

Published today in the journal stem cells University of Colorado Cancer Center Research create a dangerous, invasive bladder cancer precursor cells shows that muscle with non-invasive bladder cancer to create progenitor cells.

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Multicenter study underscores need for uniform approach to bladder cancer

Nov. 15, 2013 — New study, involving eight Italian research centres, concluded that an aligned approach to the treatment of advanced bladder cancer is much needed, while confirming previously published results on survival estimates of associated salvage therapies.

According to the lead author, Dr. Francesco Atzori, progress in developing new effective drugs in bladder cancer has been stagnant in the last decades.

"In patients who recur or who are refractory to first-line therapy, response rates and outcomes are grim, and to date, no second-line therapy has been clearly established," he explained.

The authors state that while upfront chemotherapy (CT) confers over 50% response rate, progression free survival and overall survival rates are still dismal. While vinflunine is approved by the EMA for progressive bladder cancer after platinum-based therapy, the US FDA has no approved agents.

In the course of the study, the researchers retrospectively queried all patients receiving 2nd and 3rd line regimens in Italy in the period between 2001 and 2013. The inclusion criteria included failure of one or two prior CT regimens for metastatic disease and no exclusion of specific salvage regiments, including targeted agents. Distribution of treatments and outcome parameters were the primary endpoints.

The authors identified a total of 160 eligible pts across 8 centers nationwide. Median age was 67 years (IQR 39-82), most frequent sites of disease at relapse were: nodes 71% (nodes only 43, 26.9%); lung 30%, bone 26% and liver 20%. Bellmunt Score available in 147 out of 160 patients was 0, 1, 2 and 3 in 63 (43%), 59 (40%), 20 (14%) and 5 (3%) patients respectively.

Regiments used as upfront CT were cisplatin-gemcitabine in 65 patients (41%), carboplatin-G in 50 patients (31%), MVAC in 25 patients (16%), other combination CT in 5 patients (3%) and single-agent CT in 15 patients (9%).

In 2nd line 42 patients (26%) received paclitaxel, 40 (25%) vinflunine, 21 (13%) pazopanib, 10 (6%) MVAC, 47 (29%) other drugs alone or combined.

75 out of 160 patients (47%) received a 3rd line regimen: 19 (25%) paclitaxel, 15 (20%) pazopanib, 11 (15%) MVAC, 30 patients (40%) miscellaneous. Median time-to-relapse to 1st line was 2 months. Overall response rate in 2nd line was 21% (32 out of 160 patients) and 21% in 3rd line (16 out of 75 patients); median progression-free survival was 2,8 and 2 months in 2nd and 3rd line respectively, median overall survival was 16 months and 20 months, in 2nd and 3rd lines respectively. Patients treated with paclitaxel and vinflunine in 2nd line showed a median progression free survival of 2.7 and 3.3 months while overall survival was 13.5 and 13.4 months respectively.

The results of this study will be presented at the European Multidisciplinary Meeting on Urological Cancers, in Marceille, France, on 15-17 November 2013.

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Three of four cases of bladder cancer display mutations in the same gene

Sep. 10, 2013 — Researchers from the Spanish National Cancer Research Centre (CNIO) have discovered that more than 70% of bladder tumours display somatic mutations in the TERT gene (telomerase reverse transcriptase). The TERT gene is involved in the protection of DNA and in cellular ageing processes and cancer. These results make this gene the most mutated in these tumours, which represent a serious public health problem in Spain, where the highest rates in the world are registered with 11,200 new cases each year.

The study was led by Francisco X. Real, head of the Epithelial Carcinogenesis Group at CNIO, together with Nuria Malats, the head of the Genetic & Molecular Epidemiology Group at CNIO, as well as other European groups, especially Yves Allory, a pathologist at the Mondor Hospital (Creteil, Paris, France), who is on a sabbatical year with Real and Malats's groups at CNIO, and Ellen Zwarthoff's group at the Erasmus Medical Centre in Rotterdam. The results are published in the online version of the journal European Urology.

The conclusions come from an exhaustive genetic and molecular study of more than 450 patients diagnosed with bladder cancer. Among the cases explored are both indolent tumours and more aggressive tumours and, therefore, those most likely to develop localised or spreading metastasis in the organism.

"When we analysed the frequency of TERT mutations in this group of patients, we observed that there was no correlation between the presence of mutations and the aggressiveness of the tumour or the survival or the patients," says Real. The authors' description in the article explains that: "The fact that these mutations are present in any phase of the urothelial tumoural process suggests that they occur in an early phase during carcinogenesis."

The product of the TERT gene is a protein, the reverse transcriptase of the telomerase complex, which increases the length of telomeres, protective structures for genetic material located at the ends of chromosomes and associated with cellular aging. "How TERT mutations affect the length of the telomeres and encourage carcinogenesis still needs to be discovered," says Real, adding that: "We believe that they could increase the gene expression, but additional studies are necessary."

The authors think that the clinical implications of their study could be of great relevance, both from a diagnostic point of view and in the follow up treatment of these patients.

A NEW BIOMARKER

From the diagnostic and treatment of patients points of view, the authors propose TERT as a new biomarker for bladder cancer: "We are able to detect gene mutations in urine samples from patients, in such a way that the analysis of these mutations, combined with other markers, could be promising for the detection of the illness."

But the consequences could go even further, due fundamentally to the fact that medicines capable of slowing down TERT activity already exist. In this case, and if future trials confirm the possibility, "we could think about the use of these inhibitors to slow down the growth of bladder cancers with these characteristics," says Real.

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