Kwiatkowski David J, Choueiri Toni K, Fay André P, Rini Brian I, Thorner Aaron R, de Velasco Guillermo, Tyburczy Magdalena E, Hamieh Lana, Albiges Laurence, Agarwal Neeraj, Ho Thai H, Song Jiaxi, Pignon Jean-Christophe, Barrios Pablo M, Michaelson M Dror, Van Allen Eliezer, Krajewski Katherine M, Porta Camillo, Pal Sumanta, Bellmunt Joaquim, McDermott David F, Heng Daniel Y C, Gray Kathryn P, Signoretti Sabina
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, US.
Department of Medicine, Brigham and Women's Hospital, Boston, MA, US.
Clin Cancer Res. 2016 May 15;22(10):2445-2452. doi: 10.1158/1078-0432.CCR-15-2631. Epub 2016 Feb 1.
We examined the hypothesis that mutations in mTOR pathway genes are associated with response to rapalogs in metastatic renal cell carcinoma (mRCC).
We studied a cohort of mRCC patients who were treated with mTOR inhibitors with distinct clinical outcomes. Tumor DNA from 79 subjects was successfully analyzed for mutations using targeted next-generation sequencing of 560 cancer genes. Responders were defined as those with partial response (PR) by RECIST v1.0 or stable disease with any tumor shrinkage for 6 months or longer. Nonresponders were defined as those with disease progression during the first 3 months of therapy. Fisher exact test assessed the association between mutation status in mTOR pathway genes and treatment response.
Mutations in MTOR, TSC1, or TSC2 were more common in responders, 12 (28%) of 43, than nonresponders, 4 (11%) of 36 (P = 0.06). Mutations in TSC1 or TSC2 alone were also more common in responders, 9 (21%), than nonresponders, 2(6%), (P = 0.05). Furthermore, 5 (42%) of 12 subjects with PR had mutations in MTOR, TSC1, or TSC2 compared with 4 (11%) of 36 nonresponders (P = 0.03). Eight additional non-mTOR pathway genes were found to be mutated in at least 4 of 79 tumors (5%); none were associated positively with response.
In this cohort of mRCC patients, mutations in MTOR, TSC1, or TSC2 were more common in patients who experienced clinical benefit from rapalogs than in those who progressed. However, a substantial fraction of responders (24 of 43, 56%) had no mTOR pathway mutation identified. Clin Cancer Res; 22(10); 2445-52. ©2016 AACRSee related commentary by Voss and Hsieh, p. 2320.
我们检验了如下假设，即mTOR信号通路基因的突变与转移性肾细胞癌（mRCC）患者对雷帕霉素类似物的反应相关。
我们研究了一组接受mTOR抑制剂治疗且具有不同临床结局的mRCC患者。使用560个癌症基因的靶向二代测序技术成功分析了79名受试者的肿瘤DNA中的突变情况。根据实体瘤疗效评价标准（RECIST）v1.0，将部分缓解（PR）或疾病稳定且肿瘤缩小持续6个月或更长时间的患者定义为反应者。将治疗前3个月内疾病进展的患者定义为无反应者。采用Fisher精确检验评估mTOR信号通路基因突变状态与治疗反应之间的关联。
与无反应者相比，反应者中MTOR、TSC1或TSC2的突变更为常见，43名反应者中有12名（28%）发生突变，而36名无反应者中有4名（11%）发生突变（P = 0.06）。单独TSC1或TSC2的突变在反应者中也更为常见，9名（21%）反应者发生突变，而2名（6%）无反应者发生突变（P = 0.05）。此外，12名PR患者中有5名（42%）MTOR、TSC1或TSC2发生突变，而36名无反应者中有4名（11%）发生突变（P = 0.03）。还发现另外8个非mTOR信号通路基因在79个肿瘤中至少有4个（5%）发生突变；均与反应无正相关。
在这组mRCC患者中，与疾病进展的患者相比，从雷帕霉素类似物治疗中获得临床益处的患者中MTOR、TSC1或TSC2的突变更为常见。然而，相当一部分反应者（43名中的24名，56%）未检测到mTOR信号通路突变。《临床癌症研究》；22(10)；2445 - 52。©2016美国癌症研究协会。见Voss和Hsieh的相关评论，第2320页。
