The Neoadjuvant Paradigm for Development of Systemic Therapy and Precision Medicine for Bladder Cancer

Cisplatin-based neoadjuvant chemotherapy extends overall survival (OS) in resectable muscle-invasive urothelial carcinoma of the bladder (UCB) [1]. Pathologic response assessed at the time of radical cystectomy (RC) is an excellent indicator of antitumor activity, and both pathologic complete response (pT0) and the presence of non–muscle-invasive disease correlate with OS [2]. Consequently, a rationale exists to use the neoadjuvant chemotherapy paradigm to expedite the development of new regimens and precision medicine. Despite these attractive qualities, the neoadjuvant model has seldom been used to accelerate the development of systemic therapy for this disease. Advanced age, comorbidities, toxicity concerns, and the perception of modest incremental benefit have been suggested as reasons for this poor uptake of neoadjuvant chemotherapy. Fortunately, a recent study of the US National Cancer Data Base identified an increase in use of neoadjuvant chemotherapy from 10.1% in 2006 to 20.8% in 2010 [3]. Nevertheless, some commendable efforts have used the neoadjuvant chemotherapy design to develop systemic therapy and to interrogate tumor tissue. In separate studies of patients receiving cisplatin-based neoadjuvant chemotherapy, alterations of DNA repair genes (ATM, RB1, FANCC), ERBB2 mutations, and ERCC2 mutations were associated with pathologic response [4–6]. The possibility exists that a more comprehensive molecular profile may more accurately predict pathologic response and long-term outcomes than alterations in individual genes. Recently, different groups of investigators have identified distinct luminal and basal molecular subtypes of UCB (and some have additionally described p53-like and claudin-low/ mesenchymal tumors) based on gene expression [7–9]. Naturally, significant interest exists regarding the potential ability of these molecular subtypes to predict responsiveness to systemic chemotherapy as well as emerging biologic agents. In this month’s issue of European Urology, the group from MD Anderson Cancer Center led by McConkey and SiefkerRadtke reported improved outcomes in the basal subtype, whereas the p53-like subtype was associated with dismal outcomes in the context of neoadjuvant cisplatin-based chemotherapy [10]. Specifically, the authors investigated the ability of intrinsic subtypes of UCB to predict outcomes with neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) and bevacizumab. The overall pT0 rate in this cohort of 60 patients was 38%, which is similar to the pT0 rate withMVAC alone. Thosewith basal tumors in the baseline transurethral resection (TUR) samples exhibited improved 5-yr OS compared with luminal and p53-like tumors (91%, 73%, and 36%, respectively). These findings were externally validated in a historic cohort of 49 patients that received perioperative MVAC. The caveat is that the sample size was small and somewhat heterogeneous due to the inclusion of UCB and upper tract urothelial carcinoma, and baseline TUR tumor tissue was available in only 38 patients [10]. A correlation with tumor recurrence was not studied by McConkey and colleagues but may have been a better long-term end point, since many of these generally elderly patients die from comorbidities and not recurrent disease. It is unclear if the EU RO P E AN URO LOGY 6 9 ( 2 0 1 6 ) 8 6 3 – 8 6 5