Subbiah Vivek, Meric-Bernstam Funda, Mills Gordon B, Shaw Kenna R Mills, Bailey Ann Marie, Rao Priya, Ward John F, Pagliaro Lance C
Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 455, Houston 77030, Texas, USA.
J Hematol Oncol. 2014 Aug 1;7:52. doi: 10.1186/s13045-014-0052-x.
Germ cell tumors (GCT) are the most common solid tumors in adolescent and young adult males (age 15 and 35 years) and remain one of the most curable of all solid malignancies. However a subset of patients will have tumors that are refractory to standard chemotherapy agents. The management of this refractory population remains challenging and approximately 400 patients continue to die every year of this refractory disease in the United States.
Given the preclinical evidence implicating vascular endothelial growth factor (VEGF) signaling in the biology of germ cell tumors, we hypothesized that the vascular endothelial growth factor receptor (VEGFR) inhibitor sunitinib (Sutent) may possess important clinical activity in the treatment of this refractory disease. We proposed a Phase II efficacy study of sunitinib in seminomatous and non-seminomatous metastatic GCT's refractory to first line chemotherapy treatment (ClinicalTrials.gov Identifier: NCT00912912). Next generation targeted exome sequencing using HiSeq 2000 (Illumina Inc., San Diego, CA, USA) was performed on the tumor sample of the unusual responder.
Five patients are enrolled into this Phase II study. Among them we report here the clinical course of a patient (Patient # 5) who had an exceptional response to sunitinib. Next generation sequencing to understand this patient's response to sunitinib revealed RET amplification, EGFR and KRAS amplification as relevant aberrations. Oncoscan MIP array were employed to validate the copy number analysis that confirmed RET gene amplification.
Sunitinib conferred clinical benefit to this heavily pre-treated patient. Next generation sequencing of this 'exceptional responder' identified the first reported case of a RET amplification as a potential basis of sensitivity to sunitinib (VEGFR2/PDGFRβ/c-kit/ FLT3/RET/CSF1R inhibitor) in a patient with refractory germ cell tumor. Further characterization of GCT patients using biomarkers for clinical response and patient selection is warranted.
ClinicalTrials.gov Identifier: NCT00912912.
生殖细胞肿瘤（GCT）是青少年和年轻成年男性（15至35岁）中最常见的实体瘤，并且仍然是所有实体恶性肿瘤中最可治愈的肿瘤之一。然而，一部分患者的肿瘤对标准化疗药物难治。对这一难治人群的管理仍然具有挑战性，在美国，每年约有400名患者死于这种难治性疾病。
鉴于临床前证据表明血管内皮生长因子（VEGF）信号传导与生殖细胞肿瘤生物学相关，我们假设血管内皮生长因子受体（VEGFR）抑制剂舒尼替尼（索坦）在治疗这种难治性疾病中可能具有重要的临床活性。我们提出了一项舒尼替尼治疗一线化疗难治的精原细胞瘤和非精原细胞瘤转移性GCT的II期疗效研究（ClinicalTrials.gov标识符：NCT00912912）。对异常反应者的肿瘤样本进行了使用HiSeq 2000（美国加利福尼亚州圣地亚哥的Illumina公司）的新一代靶向外显子测序。
五名患者入组了这项II期研究。在此，我们报告其中一名患者（患者5）对舒尼替尼有异常反应的临床过程。为了解该患者对舒尼替尼的反应而进行的新一代测序揭示了RET扩增、EGFR和KRAS扩增为相关异常。使用Oncoscan MIP阵列来验证确认RET基因扩增的拷贝数分析。
舒尼替尼给这名经过大量前期治疗的患者带来了临床益处。对这名“异常反应者”的新一代测序确定了首例报告的RET扩增病例，这可能是一名难治性生殖细胞肿瘤患者对舒尼替尼（VEGFR2/PDGFRβ/c-kit/FLT3/RET/CSF1R抑制剂）敏感的潜在基础。有必要使用生物标志物对GCT患者进行进一步的特征分析，以指导临床反应和患者选择。
ClinicalTrials.gov标识符：NCT00912912。
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