High-grade bladder Ca: New data improve risk stratification

At the Society of Urologic Oncology annual meeting in San Antonio, Joaquim Bellmunt, MD, PhD, highlighted potential means to improve risk stratification in patients with high-grade T1 bladder cancer, a population with highly variable prognosis and poorly understood risk factors.

“We need to identify those patients with high-grade T1 bladder cancer that are likely to recur or progress… and find additional options to prevent recurrence and progression in these patients.” Dr. Bellmunt pointed out during his presentation on targeted approaches for T1 bladder cancer.

In a recent meta-analysis of over 15,000 patients conducted at the Dana-Farber Cancer Institute, Boston, where Dr. Bellmunt is director of the Bladder Cancer Center, investigators identified clinico-pathologic factors associated with poor outcomes (J Clin Oncol 2015; 33:643-50). The authors found that lamina propria invasion into or beyond the muscularis mucosa or vascular plexus (subclassifications T1b/c) had the largest negative impact on the risks of progression and cancer-specific death. Additionally, lymphovascular invasion, associated carcinoma in situ, nonuse of bacillus Calmette–Guérin (BCG), tumor size >3 cm, and older age were also associated with worse outcomes.

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The importance of T1 subclassification in predicting disease progression was then prospectively validated in a cohort of 200 patients with high-grade T1 disease (Br J Cancer 2015; 112:468-74).

Next: Dr. Bellmunt's group seeking to identify genetic factors underlying aggressive tumors

To further improve risk-stratification in these high-risk patients, Dr. Bellmunt’s group, using DNA and RNA next-generation sequencing, is currently seeking to identify genetic factors underlying aggressive tumors. Furthermore, they are examining the impact of epigenetic alterations by annotating genome-wide histone methylation in human bladder tissue (ChiP-sequencing) and correlating the impact of chromatin-modifying gene mutations, and their interactions with the whole genome, with patient outcomes.

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Dr. Bellmunt demonstrated that mutation frequencies in their cohort of high-grade T1 bladder tumors, specifically with respect to TP53 and KMT2D mutations, are very similar to those described in The Cancer Genome Atlas analysis of muscle-invasive tumors. In their cohort, genomic alterations in the cell cycle pathway (p53, Rb1, E2F3, and MYBL2) were the main drivers of disease progression. Interestingly, those patients who recurred had very few mutations, which might imply other events such as gene fusion, translocation, or copy number events. Pointing to ongoing work in their epigenetic analysis, he demonstrated that histone mark H3K4m2 may be used to identify patients at the highest risk for progression.

Turning to therapeutics, Dr. Bellmunt stated, “We need to explore potential targets for patients with high-grade nonmuscle-invasive bladder cancer.” While there are ongoing trials, some of which include the targeting of FGFR3, he hypothesized that additional therapeutic approaches might include CDK4/CD6K inhibitors, use of epigenetic modifiers to prevent recurrence, or identification of specific mutational signatures (ie, ERCC2) that may predict response to immunotherapy.

Dr. Bellmunt is a consultant for Sanofi, Merck, and Pfizer, and has received honoraria from Genentech and Novartis.

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