Heterogeneous response and progression patterns reveal phenotypic heterogeneity of tyrosine kinase inhibitor response in metastatic renal cell carcinoma.
Heterogeneous response and progression patterns reveal phenotypic heterogeneity of tyrosine kinase inhibitor response in metastatic renal cell carcinoma.
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异质反应和进展模式揭示了转移性肾细胞癌中酪氨酸激酶抑制剂反应的表型异质性。
DOI：
10.1186/s12916-016-0729-9
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发表时间：
2016-11-14
期刊：
影响因子：
9.3
通讯作者：
Gerlinger M
中科院分区：
文献类型：
--
作者：
Crusz SM;Tang YZ;Sarker SJ;Prevoo W;Kiyani I;Beltran L;Peters J;Sahdev A;Bex A;Powles T;Gerlinger M
分子肿瘤内异质性（ITH）在透明细胞肾癌（ccRCCs）中很常见。然而，尚不清楚这是否反映在同一患者转移灶之间药物反应的异质性上。我们在三个类似的II期试验中对treatment-naïve转移性ccRCC患者接受抗血管生成酪氨酸激酶抑制剂（TKIs）（舒尼替尼或帕唑帕尼）进行了回顾性中心放射学分析。治疗因细胞减少性肾切除术而短暂中断。所有患者都有多发性转移，从基线到实体肿瘤反应评估标准（RECIST）定义的进展，通过常规计算机断层扫描测量。每个转移被分为反应性、稳定性和进展性。如果所有病变都属于同一反应类别，则将患者归类为均质反应，如果病变不同，则将患者归类为异质性反应。对27例患者的115例转移进行了纵向评估。在这些患者中，56%有异质反应。67%的患者因出现新的转移而进展，11%的患者因现有病变进展而进展，22%的患者因两者进展而进展。尽管有recist定义的进展，57%的现有转移仍然得到控制。在47%仅伴有可测量的新病变的患者中，控制病变的总和大于未控制病变的总和。我们确定了频繁的ITH抗血管生成TKI反应，转移亚群在个体患者中有反应和进展。这反映了分子ITH，可能表明抗血管生成耐药性局限于亚克隆，而不是编码在肿瘤系统发育树的主干上。这在临床上很重要，因为小体积进展的患者可能会从药物继续治疗中获益。新转移的主要进展而不是现有的转移支持通过抗血管生成改变疾病生物学。结果强调了RECIST在异质性癌症中的局限性，这可能会影响临床试验数据的有效性。这种分析需要前瞻性的确认。欧洲临床试验数据库（edract）： 2009-016675-29, 2010年3月17日注册；稿号：2006-004511-21,2007年3月9日注册；稿号：2006-006491-38,2006年12月22日注册。本文的在线版本（doi:10.1186/s12916-016-0729-9）包含补充材料，可供授权用户使用。
Molecular intratumour heterogeneity (ITH) is common in clear cell renal carcinomas (ccRCCs). However, it remains unknown whether this is mirrored by heterogeneity of drug responses between metastases in the same patient. We performed a retrospective central radiological analysis of patients with treatment-naïve metastatic ccRCC receiving anti-angiogenic tyrosine kinase inhibitors (TKIs) (sunitinib or pazopanib) within three similar phase II trials. Treatment was briefly interrupted for cytoreductive nephrectomy. All patients had multiple metastases that were measured by regular computed tomography scans from baseline until Response Evaluation Criteria In Solid Tumours (RECIST)-defined progression. Each metastasis was categorised as responding, stable or progressing. Patients were classed as having a homogeneous response if all lesions were of the same response category and a heterogeneous response if they differed. A total of 115 metastases were assessed longitudinally in 27 patients. Of these patients, 56% had a heterogeneous response. Progression occurred through the appearance of new metastases in 67%, through progression of existing lesions in 11% and by both in 22% of patients. Despite RECIST-defined progression, 57% of existing metastases remained controlled. The sum of controlled lesions was greater than that of uncontrolled lesions in 47% of patients who progressed only with measurable new lesions. We identified frequent ITH of anti-angiogenic TKI responses, with subsets of metastases responding and progressing within individual patients. This mirrors molecular ITH and may indicate that anti-angiogenic drug resistance is confined to subclones and not encoded on the trunk of the tumours’ phylogenetic trees. This is clinically important, as patients with small-volume progression may benefit from drug continuation. Predominant progression with new rather than in existing metastases supports a change in disease biology through anti-angiogenics. The results highlight limitations of RECIST in heterogeneous cancers, which may influence clinical trial data validity. This analysis requires prospective confirmation. European Clinical Trials Database(EudraCT): 2009-016675-29, registered 17 March 2010; EudraCT: 2006-004511-21, registered 09 March 2007; EudraCT: 2006-006491-38, registered 22 December 2006. The online version of this article (doi:10.1186/s12916-016-0729-9) contains supplementary material, which is available to authorized users.
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影响因子：
23.4
作者：
Powles, Thomas;Blank, Christian;Bex, Axel
通讯作者：
Bex, Axel
影响因子：
23.4
作者：
Gulati S;Martinez P;Joshi T;Birkbak NJ;Santos CR;Rowan AJ;Pickering L;Gore M;Larkin J;Szallasi Z;Bates PA;Swanton C;Gerlinger M
通讯作者：
Gerlinger M
影响因子：
158.5
作者：
Motzer, Robert J.;Hutson, Thomas E.;Choueiri, Toni K.
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Choueiri, Toni K.
影响因子：
45.3
作者：
Sternberg, Cora N.;Davis, Ian D.;Hawkins, Robert E.
通讯作者：
Hawkins, Robert E.
影响因子：
2.1
作者：
Kroon, Bin K.;de Bruijn, Roderick;Bex, Axel
通讯作者：
Bex, Axel