Precision and Predictive Medicine in Urothelial Cancer: Are We Making Progress?

This Platinum Opinion article summarizes the bladderKeynote LecturepresentedduringASCO-GU2015inOrlando.Systemic therapy for advanced urothelial carcinoma(UC) has been based on cisplatin-based first-line combina-tion chemotherapy and palliative second-line vinflunine,taxanes, pemetrexed, and other agents administered topatients in an unselected way. However, lessons learnedfrom extreme responses seen with chemotherapy andselected targeted therapies, coupled with the knowledgegenerated by The Cancer Genome Atlas (TCGA) project,now appeartointroduceparadigmshiftsinthetreatmentofUC. An overview of recent advances was presented as thebladder keynote lecture at the Genitourinary CancerSymposium in Orlando, Florida, in February 2015 [1] andis summarized here.1. Cancer genomics in 2015Cancers emerge from genomic errors. Sequencing technol-ogy and computational biology are now at the bedside tohelp analyze and interpret genomic data. From TCGA wehave learned that bladder cancer is a molecularly hetero-geneous disease with a multitude of genomic changesaffecting many signaling pathways [2]. Complexity aside,this information can ultimately guide clinical care and newapproaches to clinical trial design. This will be achieved intwo ways: phenotype to genotype (P2G), involving analysisof exceptional responses to therapies; and genotype tophenotype (G2P), with matching of specific genomicalterations to targeted drugs. An example was the in vitroinvestigation that revealed that TSC1 alterations sensitizeUC cells to mTOR inhibition, which formed the basis for theevaluation of everolimus—with limited results overall—andthe subsequent identification of activating TSC1/mTORmutations in two extreme responders to everolimus andpazopanib/everolimus trials [3,4].2. Precision medicine and oncologyThe next question is how the use of omics technology willfurther our understanding of the mechanisms of disease,guide patient care, and ultimately impact outcomes. Today,precision medicine is based on this new taxonomy thatallows for more accurate diagnosis and therefore targetedtreatment aimed at improving outcomes. Observationalstudies together with biomedical research will close theloop of validation and expansion of information. Anexample is the progression profile of high-risk T1 non–muscle-invasive (NMI) bladder cancer (NMIBC), which wenow know occurs in 21% of cases [5]. A meta-analysis hasdemonstrated that selected clinicopathologic factors playa major role in driving progression. However, we lackvalidated biomarkers to accurately predict progression,even though comparison of mutation frequencies in NMIand muscle-invasive (MI) subsets reveals correspondencewith histology, with clear distinctions at a molecular level.Interestingly,clinicaldata indicate therelative resistanceofa micropapillary variant of NMIBC to bacillus Calmette-Gue´rin. In fact, the micropapillary variant of NMIBCmolecularly resembles MI disease, with aneuploidy andP53 mutations, while retaining FGFR3 mutations but withCDKN2A deletions in some cases. Along the same line, ithas been shown that methylation and other epigeneticregulators are putative drivers of tumorigenesis in some