1. DiGiulio, Sarah

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The gene expression profiles of advanced bladder cancer fall into three molecular categories that closely resemble three of the four major subtypes of breast cancer, according to research in Cancer Cell (2014;25:152-165).

Figure. Bladder Canc... - Click to enlarge in new windowFigure. Bladder Cancer.

"One of the subtypes corresponds to basal breast cancer, and the other two to luminal breast cancers," the study's senior author, David J. McConkey, PhD, Professor of Urology at MD Anderson Cancer Center, explained in an email. "The 'p53-like' subtype shares important similarities with luminal A breast cancers, and the 'luminal' subtype looks more to us like luminal B breast cancers."


For the study, the researchers (first author was Woonyoung Choi, PhD) profiled whole genome mRNA expression and unsupervised hierarchical cluster analyses on a cohort of 73 primary fresh-frozen muscle-invasive bladder cancers.


The three distinct molecular subtypes identified with signature biomarkers similar to those for breast cancers were: (1) basal tumors, which contain the biomarkers CD44, KRT5, KRT6, KRT14, and CDH3; (2) luminal tumors, which contain the biomarkers CD24, FOXA1, GATA3, ERBB2, ERBB3, XBP1, and KRT20); and (3) p53-like tumors, which have gene-expression patterns similar to those stimulated by p53 (but, the study notes, it does not appear that p53 is responsible for those gene-expression patterns).


Key observations about these subtypes of bladder cancer were:


* Basal tumors were enriched with sarcomatoid and squamous features, as well as metastatic disease at presentation. The tumors were associated with shorter overall survival (than the other subtypes) (14.9 months), as well as shorter disease-specific survival (14.9 months). Although the biomarkers indicate the presence of bladder cancer stem cells and other treatment-resistant features, the subtype is sensitive to chemotherapy (so patients with this subtype should be treated aggressively with frontline cisplatin-based regimens).


* Luminal tumors were enriched with epithelial biomarkers (E-cadherin/CDH1 and members of the miR-200 family), high levels of fibroblast growth factor receptor-3, and activating FGFR3 mutations. Many luminal tumors did respond to neoadjuvant chemotherapy, which suggests that targeted therapies should be combined with conventional chemotherapy for maximum efficacy, the study notes.


* P53-like tumors were found to be resistant to neoadjuvant cisplatin-based chemotherapy; and were found to closely resembles luminal A breast cancers, which are estrogen-receptor positive, but proliferate more slowly than luminal B breast cancer. Also "p53-ness," as measured by mRNA expression, would be a more accurate predictor of chemoresistance than would analyses of TP53 mutational status, the study notes.



Another key observation was chemotherapy-induced quiescence in all tumor subtypes as measured by the cystectomies, McConkey added. Gene expression was compared in matched tumors before and after chemotherapy, and p53 activation was found to be the top pathway activated after therapy. "This induced resistance is likely to make the tumors refractory to second-line therapies."


He noted that previous studies in bladder cancer had identified signatures associated with stage, outcomes, and progression, but the biological and clinical significance of those signatures had been unclear.


"Evidence is now emerging from ongoing research that these similarities will help us leverage the relatively vast amount of information from breast cancer research to hasten progress in bladder cancer," McConkey said. "Predicting chemosensitivity in basal tumors and chemoresistance in some luminal tumors is just the first example."