Bladder Ca subtypes ID’d, may yield personalized therapies

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Following a comprehensive molecular characterization of 412 muscle-invasive bladder cancers, researchers in The Cancer Genome Atlas (TCGA) Research Network have outlined five distinct expression subtypes, each of which may be targetable by different treatments.

One of the five subtypes might be particularly responsive to FGFR3 inhibitors, for example, while two other subtypes may be amenable to treatment with checkpoint inhibitors, TCGA investigators hypothesized on the basis of the analysis, which was recently published in Cell (2017; 171:540-56.e25).

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“First and foremost, (the analysis) really elucidates a lot of biology about the heterogeneity of muscle-invasive bladder cancer, and then it suggests that these different subtypes may facilitate a more personalized medicine approach to treating patients with muscle-invasive disease,” said researcher Seth P. Lerner, MD, of Baylor College of Medicine, Houston.

The framework as published in Cell represents a refinement of the original report from TCGA investigators published in 2014 in Nature (2014; 507:315-22) that was based on analysis of just 131 bladder cancers.

One of the most significant updates is the identification of a mutation signature associated with favorable prognosis. In particular, an APOBEC-related mutational signature corresponded to a 75% 5-year survival, according to investigators.

“APOBEC-signature mutagenesis is associated with both a high mutation rate and improved clinical outcome, an expression subtype that we term ‘neuronal,’ ” the authors wrote in the more recent report.

Next: The five subtypes

Now, with additional tumor samples and genomic data, the TCGA investigators were able to take the well-known luminal and basal subtypes of bladder cancer and further stratify them into five distinct subtypes: luminal, luminal-papillary, luminal-infiltrated, basal/squamous, and the new “neuronal” category, which was identified in 5% of samples and is characterized by “expression of both neuroendocrine and neuronal genes, as well as a high cell-cycle signature reflective of a proliferative state,” according to the investigators.

Why the neuronal subtype with its higher mutational rate would be associated with a favorable prognosis needs to be researched further, Dr. Lerner said in an interview with Urology Times.

“It may just be that there's better recognition by the immune system, but there could be other factors at work,” said Dr. Lerner, senior author of the report in Cell.

Also see: Better models needed for predicting bladder Ca recurrence

The TCGA investigators have encouraged others to take their data and use it to develop prospective clinical trials to see if targeting the subtypes does indeed result in improved clinical outcomes.

Some compelling results have already emerged based on the previously published TCGA classification. One notable example is a phase II study reported in The Lancet (2016; 387; 1909-20) showing that patients with metastatic or unresectable bladder cancers of the luminal-infiltrated subtype tend to respond well to treatment with the immuno-oncologic agent atezolizumab (Tecentriq), a PD-L1 inhibitor.

“We certainly think that it's incumbent upon pharma to really look at these types of predictive biomarkers in their clinical trials,” Dr. Lerner told Urology Times. “It makes a lot of sense for immuno-oncology agents, but it also makes sense for targeted therapies, because there are specific pathways of targets that are activated in these different subtypes.”

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