Tag: Urothelial Cancer (Bladder-Ureters-Renal-Pelvis)

SUMMARY: The American Cancer Society estimates that in the United States for 2015, about 74,000 new cases of bladder cancer will be diagnosed and approximately 16,000 patients will die of the disease. A third of the patients initially present with locally invasive or metastatic disease. Even though radical cystectomy was considered the standard of care for patients with localized Muscle Invasive Bladder Cancer (MIBC), two large randomized trials and two meta-analysis have shown greater survival benefit with neoadjuvant Cisplatin-based chemotherapy combinations for patients with MIBC, compared to surgery alone. However, not all patients with MIBC benefit from neoadjuvant Cisplatin based therapy, with only 25-50% attaining a pathologic response. The authors in this publication evaluated the role of genetic testing and genetic biomarkers prior to chemotherapy, in order to select the appropriate group of patients who would benefit from neoadjuvant Cisplatin based chemotherapy and thereby exclude those who are unlikely to benefit from chemotherapy.

Muscle Invasive Bladder Cancer (MIBC) patients from two prospective multicenter clinical trials of Cisplatin-based neoadjuvant chemotherapy were included and pretreatment MIBC samples were prospectively collected and this provided the discovery and validation sets. DNA from pre-treatment tumor tissue was sequenced for all coding exons of 287 cancer related genes and was analyzed for presence of base substitutions, indels, copy number alterations and selected rearrangements. The discovery set allowed for improved prognostic strength, by combining existing known high risk genetic markers with other novel risk markers. The validation set validated these markers. This study included data from 34 patients in the discovery cohort and 24 patients in the validation cohort.

It was noted that patients with a pathologic Complete Response had more alterations in the genes compared to those with residual tumor, both in the discovery (P= 0.024) and validation (P=0.018) sets. Further, in the discovery set, alteration in one or more of the three DNA repair genes ATM, RB1, and FANCC predicted pathologic Complete Response (P<0.001; 87% sensitivity, 100% specificity) as well as improved Overall Survival (P=0.007). DNA repair is one of the mechanisms postulated to contribute to Cisplatin chemo-resistance. This test remained predictive for pathologic Complete Response in the validation set (P=0.033), with a trend towards improved Overall Survival (P=0.055).

The authors concluded that defective DNA repair renders tumors sensitive to Cisplatin and genomic alterations in the DNA repair-associated genes ATM, RB1, and FANCC predict response and clinical benefit for MIBC, treated with Cisplatin-based chemotherapy. Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer. Plimacka ER, Dunbracka RL, Brennan TA, et al. European Urology 2015;68:959-967

The active metabolite of Vitamin D is Vitamin D3. In a recent study published in the JNCI, September 2012 issue, the authors noted a statistically significant increase in the risk of Bladder Cancer in individuals with low plasma concentrations of Vitamin D3. It is felt that Vitamin D3 favorably upregulates Fibroblast Growth Factor Receptor 3 (FGFR3). Mutations in FGFR3 are known to be associated with urothelial carcinoma. Urine samples evaluating for FGFR3 mutations, to diagnose urothelial carcinoma, has a positive predictive value of 95% when detected in patients with no history of Bladder Cancer. It appears that patients with aggressive bladder cancer have low expression of wild- type FGFR3 in association with low plasma concentrations of Vitamin D3. Therefore, it is possible that low plasma concentrations of Vitamin D3 may predict increased risk for bladder cancer, with more aggressive types of bladder cancer manifesting in those with significantly low Vitamin D3 levels.

SUMMARY: In this phase III trial, 360 patients with muscle-invasive bladder cancer were randomized to receive radiation therapy with or without concurrent chemotherapy. The chemotherapy regimen consisted of 5-fluorouracil given on days 1-5 and days16-20 of radiotherapy and mitomycin C given on day 1. The primary end point of this study was locoregional disease free survival. Secondary end points included overall survival and toxicities. The locoregional disease–free survival at two years was 67% in the chemoradiation group and 54% in the radiation therapy only group. With a median follow-up of 69.9 months, the hazard ratio in the chemoradiation group was 0.68 (P=0.03). The overall survival at five years was 48% in the chemoradiation group and 35% in the radiation therapy only group with a hazard ratio of 0.82 (P=0.16). The authors concluded that for patients with muscle invasive bladder cancer, concurrent chemoradiation significantly improved locoregional disease free survival compared to radiation therapy only. James ND, Hussain SA, Hall E, et al. N Engl J Med 2012; 366:1477-1488