Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut2Department of Pathology, Yale University School of Medicine, New Haven, Connecticut3Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut.
JAMA Dermatol. 2015 Nov;151(11):1240-3. doi: 10.1001/jamadermatol.2015.1925.
Inhibition of angiogenesis is an effective anticancer strategy because neoplasms require a rich blood supply. Ramucirumab, approved by the US Food and Drug Administration in 2014 to treat gastric adenocarcinomas and non-small cell lung carcinomas, targets vascular endothelial growth factor 2 (VEGFR2). We identified a patient prescribed a regimen of irinotecan hydrochloride, cetuximab, and ramucirumab for metastatic rectal cancer (diagnosed in November 2013 and treated through early January 2015) who developed a new-onset, expanding vascular lesion on his right leg. Via exome sequencing, we found that the lesion contained a single somatic mutation in KDR (encodes VEGFR2), possibly in response to ramucirumab. Vascular tumors are not a known complication of antiangiogenic therapeutics.
Exome sequencing of the well-demarcated, blanching vascular lesion on the lateral right shin revealed a somatic p.T771R mutation in KDR, without evidence of other somatic mutations or loss of heterozygosity. Histological features included lobules of small vessels within the dermis, resembling a tufted angioma.
A potential adverse effect of ramucirumab in combination therapy is the development of sporadic angiomas. The p.T771R mutation was previously implicated in autophosphorylation of VEGFR2 and reported in angiosarcomas alongside other driver mutations. Our observations suggest that this mutation confers a proliferative advantage in the setting of ramucirumab therapy. Patients receiving ramucirumab should be monitored for the development of new vascular lesions.
抑制血管生成是一种有效的抗癌策略，因为肿瘤需要丰富的血液供应。雷莫芦单抗于 2014 年被美国食品和药物管理局批准用于治疗胃腺癌和非小细胞肺癌，其作用靶点是血管内皮生长因子 2（VEGFR2）。我们发现了一名转移性直肠癌患者（2013 年 11 月诊断，2015 年 1 月初治疗），他接受了盐酸伊立替康、西妥昔单抗和雷莫芦单抗的治疗方案，在右腿上出现了一个新出现的、不断扩大的血管病变。通过外显子组测序，我们发现病变部位的 KDR（编码 VEGFR2）中存在一个单一的体细胞突变，可能是对雷莫芦单抗的反应。血管肿瘤不是已知的抗血管生成治疗的并发症。
对右小腿外侧边界清楚、苍白的血管病变进行外显子组测序，发现 KDR 中的体细胞 p.T771R 突变，没有其他体细胞突变或杂合性丢失的证据。组织学特征包括真皮内的小血管小叶，类似于丛状血管瘤。
雷莫芦单抗联合治疗的一个潜在不良反应是散发性血管瘤的发生。p.T771R 突变先前与 VEGFR2 的自动磷酸化有关，并与其他驱动突变一起报告在血管肉瘤中。我们的观察结果表明，这种突变在雷莫芦单抗治疗的情况下赋予了增殖优势。接受雷莫芦单抗治疗的患者应监测新血管病变的发生。
