The role of genomics in the management of advanced bladder cancer

Advanced bladder cancer (ABC) is an aggressive malignancy with a poor prognosis. For the last 30 years, the standard of care for this disease has consisted of combination chemotherapy with a platinum-containing regimen as first-line therapy. Cisplatin is the most active cytotoxic agent against bladder cancer, but because of competing comorbidities, many patients are ineligible for this agent and instead receive carboplatin. The two-drug regimen of cisplatin and gemcitabine was found to be better tolerated and have comparable efficacy as the four-drug regimen of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) in a randomized study of patients with advanced disease. Therefore, cisplatin (or carboplatin) and gemcitabine is the most commonly used first-line regimen in this setting. No agents have been approved by the Food and Drug Administration (FDA) for second-line therapy in ABC. If patients are eligible for additional systemic treatment at the time of progression, options include single-agent therapy such as a taxane or pemetrexed, though given the lack of standard approaches participation in a clinical trial should be strongly encouraged. Recent molecular characterization of ABC reveals significant genetic heterogeneity and actionable genomic alterations in the majority of tumors. Emerging therapies may effectively target known molecular drivers of ABC, including the FGFR2, EGFR/HER2, VEGF, MET, and PI3/AKT/mTOR pathways. Reports of dramatic and prolonged responses to targeted therapy provide additional support for the use of genome sequencing in the rationale selection of treatment for subsets of patients. The current focus of clinical trial development is to design molecularly driven studies that "match" tumors with driver mutations and appropriate targeted therapies rather than a "one-size-fits-all" approach based on clinical and pathologic parameters of disease. The hope of patients and clinicians alike is that this therapeutic approach combined with novel agents may usher in a new era of effective treatments for patients with ABC.