Urologic Medical Oncology, UAB Comprehensive Cancer Center, Birmingham, AL.
Kidney Cancer Center, Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, Brigham and Women's Hospital Harvard Medical School, Boston, MA.
Urol Oncol. 2014 Jan;32(1):5-15. doi: 10.1016/j.urolonc.2013.07.010. Epub 2013 Nov 13.
This review provides a broad overview of emerging data that provide hope that rational precision medicine for metastatic renal cell carcinoma (RCC) may be possible.
PubMed and major conferences were searched for studies reporting potential predictive biomarkers for the therapy of metastatic RCC.
The availability of multiple new agents for the therapy of advanced RCC poses new challenges in terms of optimal selection of patients for the appropriate drug. Prognostic stratification based on routine histopathologic, clinical and laboratory factors have been utilized to broadly select individuals based, i.e. high-dose interleukin (IL)-2 or vascular endothelial growth factor (VEGF) inhibitors for good and intermediate risk patients and temsirolimus for poor risk patients. While multiple candidate predictive molecular biomarkers suggest that rational selection of patients for high-dose interleukin (IL)-2, and VEGF and mammalian target of rapamycin (mTOR) inhibitors may be possible, none have been validated for use in the clinic. Tumor heterogeneity and standardization of tissue collection and analysis are massive challenges that need to be addressed. Predictive molecules derived from tumor tissue, plasma and host tissue may all be predictive for therapeutic benefit. Moreover, gene expression may be modulated by multiple factors including epigenetics, transcription factors and post-transcriptional and post-translational modifications. Indeed, study of the interaction of molecular factors from all of these sources with environmental and clinical factors may be necessary to develop a unified profile composed of a panel of factors predictive of benefit from specific agents (i.e. sustained response, limited toxicity and overall a positive benefit/risk ratio).
Conducting clinical trials with 1) prospective incorporation of promising candidate predictive molecular biomarkers, 2) novel biomarkers endpoints, and 3) mandatory biopsies of metastatic sites at different time points on therapy, are potential important steps in developing the concept of "the right medication for the right patient".
本综述提供了一个广泛的概述，即新兴数据为转移性肾细胞癌（RCC）的合理精准医学带来了希望。
在 PubMed 和主要会议上搜索了报道转移性 RCC 治疗中潜在预测性生物标志物的研究。
多种新药物可用于治疗晚期 RCC，这在为合适的药物选择最合适的患者方面提出了新的挑战。基于常规组织病理学、临床和实验室因素的预后分层已被广泛用于根据高剂量白细胞介素（IL）-2 或血管内皮生长因子（VEGF）抑制剂的选择，根据风险高低选择合适的药物，高剂量 IL-2、VEGF 和哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂适用于低风险患者，替西罗莫司适用于高风险患者。虽然有许多候选预测性分子生物标志物表明，对于高剂量白细胞介素（IL）-2 和 VEGF 和哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂的患者选择可能更合理，但目前尚无任何一种标志物在临床上得到验证。肿瘤异质性和组织收集与分析的标准化是需要解决的巨大挑战。肿瘤组织、血浆和宿主组织中的预测性分子都可能对治疗获益具有预测性。此外，基因表达可能受到多种因素的影响，包括表观遗传学、转录因子以及转录后和翻译后修饰。事实上，研究所有这些来源的分子因素与环境和临床因素的相互作用，可能对于开发由一组预测特定药物获益的因素（即持续反应、有限毒性和总体正获益/风险比）的统一特征是必要的。
进行临床试验时，应 1）前瞻性地纳入有前途的候选预测性分子生物标志物，2）采用新的生物标志物终点，以及 3）在治疗的不同时间点强制性地对转移灶进行活检，这些是开发“正确的药物用于正确的患者”概念的潜在重要步骤。
