Bladder cancer pharmacogenomics: recent insights and future perspectives.

Urothelial cancer of the bladder and upper urinary tract is currently the fifth most common cancer and the sixth leading cause of cancer death in the USA [1]. Despite its prevalence and significant mortality, almost no novel therapies have been produced in the past 20 years for this disease, and only marginal improvements in survival have occurred, likely owing to improved knowledge about existing therapies and better supportive care. Cisplatin-based chemotherapy represents the only available standard for locally advanced and metastatic urothelial cancer. While cisplatin-based therapy improves survival in these settings, only approximately one-third of patients achieve a complete pathologic response to cisplatin in the neoadjuvant setting [2], and only 50% respond in the metastatic setting [3]. Prediction of which individuals will benefit is currently not possible. Cisplatin-based therapy is not without significant toxicity and can even be associated with treatment-related death in up to 3% of patients [3]. This begs a logical question: is there a biomarker or biomarkers that can help identify the patients most likely to benefit from cisplatinbased chemotherapy, while allowing others who will not benefit be spared chemotherapy-related toxicity and instead considered for novel agents? Pharmacogenomic investigations may be useful in answering this question. If responders and nonresponders could be preidentified, it seems rational that not only could the existing standard treatment be more appropriately applied, but it might even accelerate the development of new agents (which are desperately needed) for this difficult disease. p53 as a first pharmacogenomic test case in bladder cancer The concept of applying pharmacogenomic biomarkers to the treatment of urothelial cancer, like other cancers, is not new, and indeed prospective testing of at least one prominent example has already been conducted – albeit with highly disappointing results. Tumor p53 dysregulation was, based on retrospective data, believed to be associated with both a worse prognosis for patients with urothelial cancer and simultaneously with increased likelihood of responding to DNA-damaging chemotherapy [4]. This was the basis for a Phase III study in which approximately 500 patients with pT1/pT2 N0 disease at cystectomy were screened for the presence of tumor p53 (≥10% nuclear immunoreactivity by immunohistochemistry [IHC] was considered indicative of p53 dysregulation), and patients with p53 reactivity (‘p53 altered’) were randomized to either adjuvant therapy with methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) or observation [4]. Unfortunately, the study was halted after interim data and safety monitoring board review found that the trial met criteria for futility. Importantly, only approximately 40% of patients with dysregulated p53 agreed to randomization, and only two-thirds of the patients randomized to MVAC received the planned three cycles. There was no difference in disease recurrence among the randomized, p53-dysregulated patients who were given adjuvant therapy versus those that were observed. While p53 was unable to be confirmed as a biomarker for adjuvant chemotherapy use in urothelial cancer, the execution and observed limitations of the trial are likely to inform future