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There seem to be strong associations between intrinsic muscle-invasive bladder cancer subtype membership and enrichment with clinically actionable genetic and epigenetic features.
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It seems that the intrinsic subtypes display differences in sensitivity to cisplatin-based combination chemotherapy.
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Because basal tumors are aggressive and chemosensitive, the overall impact of chemotherapy on disease-specific and overall survival should be carefully evaluated in patients with these tumors.
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Epigenetic
Therapeutic Opportunities in the Intrinsic Subtypes of Muscle-Invasive Bladder Cancer
Section snippets
Key points
Intrinsic subtypes of breast cancer
Perou and colleagues13 first observed the intrinsic molecular subtypes of breast cancer in a relatively small cohort of 65 tumors from 42 different patients. They used an in-house cDNA microarray that contained a total of 8102 different probes, filtered out the genes that displayed the greatest variations in expression across the dataset, and then used the filtered genes to perform an unbiased (unsupervised hierarchical clustering) analysis of the relationships among the gene expression
Intrinsic subtypes of bladder cancer
One of the most important objectives in cancer research is to develop molecular classifiers that can inform prognostication and predict therapeutic efficacy. It might seem that the most straightforward way to do this would be to assemble cohorts of tumors from patients who experienced extreme clinical outcomes (ie, very short vs very long disease-specific survival or complete pathologic response vs progression with neoadjuvant or adjuvant chemotherapy), perform deep genomic profiling, and
Biological properties of the intrinsic subtypes
Bioinformatic analyses of the gene expression signatures that characterized the MIBC subtypes revealed roles for transcription factors that had also been implicated in breast cancer.7 The basal epithelial/stem cell transcription factors ΔNp63α and STAT3 were both identified as central regulators of basal MIBC gene expression, and ΔNp63 has also been implicated in basal breast cancers.36, 37, 38 Basal expression of active STAT3 promoted carcinogen-induced tumorigenesis in a mouse model39;
Effects of chemotherapy in the intrinsic subtypes
Approximately 35% of patients receiving neoadjuvant cisplatin-based combination chemotherapy are downstaged to no residual muscle-invasive disease at cystectomy. These patients have excellent long-term survival, indicating that downstaging can serve as an excellent immediate surrogate for disease-specific survival. The same situation exists in breast cancer, which prompted the Food and Drug Administration to grant fast-track approval to agents that produce high pathologic complete response
Biological targets in the intrinsic subtypes: receptor tyrosine kinases
One of the most important products of the recently completed first phase of the TCGA bladder cancer project was the identification of novel activating mutations, translocations, and copy number alterations in signal transduction pathways that can be targeted with clinically available inhibitors. For example, activating mutations in PIK3CA and TSC1, 2 central components of the PI3 kinase-AKT-mTOR pathway,54 were observed in 20% and 8% of tumors, respectively; the pathway was predicted to be
Other candidate biological targets
One of the dominant features of luminal MIBC biology is PPARγ. As discussed earlier, luminal tumors are enriched with PPARγ gene expression signatures7; exposure to PPAR agonists promotes bladder cancer in rodent models.64, 65, 66 In the TCGA cohort, PPARG was amplified in 17% of tumors4; this amplification was enriched in luminal tumors (see Fig. 2). In ongoing studies, the authors are defining its role in tumorigenesis and progression preclinical models. It is possible that PPARγ will emerge
Summary and future directions
There seem to be strong associations between intrinsic MIBC subtype membership and enrichment with clinically actionable genetic and epigenetic features. In addition, it seems that the intrinsic subtypes display differences in sensitivity to cisplatin-based combination chemotherapy. Because basal tumors are aggressive and chemosensitive, the overall impact of chemotherapy on disease-specific and overall survival should be carefully evaluated in patients with these tumors. Epigenetic mechanisms,
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2020, Clinical Genitourinary CancerCitation Excerpt :Clinical response to chemotherapy and the interval between diagnosis and metastatic disease could be prognostic in terms of survival after metastasectomy. With further work being done to identify intrinsic subtypes of UC (ie, luminal and basal) and subsequent response to chemotherapy, such data could be useful to better identify candidates for metastasectomy.31 Data suggest that patients with solitary metastases to the lung and lymph nodes fare better than patients with multiple visceral sites of disease, and better than patients with large lesions (> 3 cm) or multiple lesions within the same organ.
M.D. Anderson has filed for patent protection for the subtype classifier.