Ho Thai H, Choueiri Toni K, Wang Kai, Karam Jose A, Chalmers Zachary, Frampton Garrett, Elvin Julia A, Johnson Adrienne, Liu Xueli, Lin Yulan, Joseph Richard W, Stanton Melissa L, Miller Vincent A, Stephens Philip J, Ross Jeffrey S, Ali Siraj M, Pal Sumanta K
Epigenomics Program, Center for Individualized Medicine, Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA.
Division of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
Eur Urol Focus. 2016 Jun;2(2):204-209. doi: 10.1016/j.euf.2015.11.007. Epub 2015 Dec 9.
Vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR)-directed therapies are the standard of care in metastatic clear cell renal cell carcinoma (mccRCC) but are not used based on molecular subclassifications of ccRCC.
To determine if an association exists between genomic alterations (GAs) detected by comprehensive genomic profiling (CGP) in the course of clinical care and the response to anti-VEGF receptor (VEGFR) and anti-MTOR pathway targeted therapies in a cohort of patients with treated mccRCC.
DESIGN, SETTING, AND PARTICIPANTS: CGP, using a Clinical Laboratory Improvement Amendments-certified platform, was performed on 31 formalin-fixed, paraffin-embedded tissue specimens (84% from cytoreductive nephrectomies) obtained from patients with metastatic renal cell carcinoma who had received VEGFR and/or mTOR inhibitors. Duration of treatment (DOT) and extent and duration of clinical response were obtained from review of medical records.
All classes of GAs-base substitutions, short insertions, deletions, gene fusions, rearrangements, and copy number-were assessed via hybrid capture-based CGP. Descriptive statistics were used to determine the frequency of GAs in groups segregated by the DOT with VEGF-directed agents.
The most common GAs detected in this series were in VHL (70%), PBRM1 (48%), SETD2 (32%), TSC1 (29%), MLL (19%), TERT (16%), ARID1B (16%), and KDM5C (16%). Across 61 administrations of VEGF-directed therapy in 27 patients, exceptional responses (DOT >21 mo) were more frequent among patients with GAs in KDM5C, PBRM1, and VHL. Conversely, these patients also featured a lower frequency of GA associated with response to mTOR-directed therapy, such as TSC1.
Molecular subclassifications may affect response to VEGF-directed therapy. The predictive and prognostic nature of these molecular subclassifications in the metastatic setting should be explored in an extended series.
Comprehensive genomic profiling in the course of clinical care in the community oncology setting can delineate subgroups of patients with advanced kidney cancer who stand to benefit more from specific molecular-targeted agents.
血管内皮生长因子（VEGF）和雷帕霉素哺乳动物靶点（mTOR）导向疗法是转移性透明细胞肾细胞癌（mccRCC）的标准治疗方法，但并非基于ccRCC的分子亚分类来使用。
确定在临床治疗过程中通过综合基因组分析（CGP）检测到的基因组改变（GAs）与一组接受治疗的mccRCC患者对抗VEGF受体（VEGFR）和抗mTOR通路靶向治疗的反应之间是否存在关联。
设计、设置和参与者：使用经临床实验室改进修正案认证的平台，对31份福尔马林固定、石蜡包埋的组织标本（84%来自减瘤性肾切除术）进行CGP，这些标本取自接受VEGFR和/或mTOR抑制剂治疗的转移性肾细胞癌患者。从病历回顾中获取治疗持续时间（DOT）以及临床反应的程度和持续时间。
通过基于杂交捕获的CGP评估所有类型的GAs——碱基替换、短插入、缺失、基因融合、重排和拷贝数。使用描述性统计来确定在接受VEGF导向药物治疗的患者中，按DOT分组的GAs频率。
本系列中检测到的最常见GAs存在于VHL（70%）、PBRM1（48%）、SETD2（32%）、TSC1（29%）、MLL（19%）、TERT（16%）、ARID1B（16%）和KDM5C（16%）中。在27例患者接受的61次VEGF导向治疗中，KDM5C、PBRM1和VHL存在GAs的患者出现异常反应（DOT>21个月）的频率更高。相反，这些患者中与mTOR导向治疗反应相关的GAs频率也较低，如TSC1。
分子亚分类可能影响对VEGF导向治疗的反应。应在更大规模的研究中探索这些分子亚分类在转移情况下的预测和预后性质。
在社区肿瘤学环境的临床治疗过程中进行综合基因组分析，可以区分出哪些晚期肾癌患者可能从特定分子靶向药物中获益更多。
