Chedgy Edmund C P, Douglas James, Wright Jonathan L, Seiler Roland, van Rhijn Bas W G, Boormans Joost, Todenhöfer Tilman, Dinney Colin P, Collins Colin C, Van der Heijden Michiel S, Black Peter C
Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada; Department of Urology, University Hospital Southampton, UK.
Urol Oncol. 2016 Oct;34(10):469-76. doi: 10.1016/j.urolonc.2016.05.012. Epub 2016 Jun 15.
Bladder cancer is a leading cause of morbidity and mortality. Despite recent advances in understanding its molecular biology, the 5-year survival for muscle-invasive disease (muscle-invasive bladder cancer [MIBC]) remains approximately 50%. Although neoadjuvant chemotherapy (NAC) offers an established 5% absolute survival benefit at 5 years, only the 40% of patients with a major tumor response appear to benefit. There remains, therefore, a critical unmet need for predictive markers to determine which patients are best managed with NAC, as well as for novel targeted therapies to overcome resistance to NAC.
The NAC paradigm offers the optimal clinical context for developing precision therapy for MIBC. Abundant tissue is available for analysis before NAC in all patients and after NAC in patients with residual MIBC. Technologic advances have enabled next-generation sequencing and gene expression microarray analysis of routinely collected and even archived tissue specimens. These technologies provide a foundation for the identification of markers of chemoresistance and for the development of rational cotargeting strategies.
Modern computational methods allow for some measure of target validation, which can be enhanced by the use of patient-derived primary xenografts (PDX). These PDX can be established at the time of radical cystectomy after NAC if there is residual MIBC. By the time a patient recurs clinically, candidate drugs targeting specific molecular changes in the patient tumor and corresponding PDX would have been tested in the PDX model, and only the most efficacious drug(s) would be administered to the patient. Liquid biopsies in the form of circulating tumor DNA and circulating tumor cells allow noninvasive longitudinal monitoring of the molecular landscape of an advanced tumor as it is being treated with successive courses of systemic therapy.
These tools combined form the foundation of an evidence-based precision oncology strategy for MIBC.
膀胱癌是发病和死亡的主要原因。尽管在了解其分子生物学方面取得了最新进展，但肌肉浸润性疾病（肌肉浸润性膀胱癌[MIBC]）的5年生存率仍约为50%。尽管新辅助化疗（NAC）在5年时可带来5%的绝对生存获益，但似乎只有40%出现主要肿瘤反应的患者从中受益。因此，对于确定哪些患者最适合接受NAC治疗的预测标志物以及克服对NAC耐药的新型靶向治疗，仍存在关键的未满足需求。
NAC模式为开发MIBC的精准治疗提供了最佳临床背景。所有患者在接受NAC之前以及残留MIBC患者在接受NAC之后都有大量组织可用于分析。技术进步使得对常规收集甚至存档的组织标本进行下一代测序和基因表达微阵列分析成为可能。这些技术为识别化疗耐药标志物和制定合理的联合靶向策略奠定了基础。
现代计算方法可对靶点进行一定程度的验证，使用患者来源的原发性异种移植（PDX）可增强验证效果。如果存在残留MIBC，可在NAC后的根治性膀胱切除术时建立这些PDX。当患者临床复发时，针对患者肿瘤和相应PDX中特定分子变化的候选药物已在PDX模型中进行了测试，只有最有效的药物才会给予患者。以循环肿瘤DNA和循环肿瘤细胞形式进行的液体活检可在晚期肿瘤接受连续全身治疗过程中对其分子格局进行无创纵向监测。
这些工具结合起来构成了MIBC循证精准肿瘤学策略的基础。
