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Case Report/Case Series |

Somatic p.T771R KDR (VEGFR2) Mutation Arising in a Sporadic Angioma During Ramucirumab Therapy

Young H. Lim, BS1,2,3; Ian D. Odell, MD, PhD1; Christine J. Ko, MD1,2; Keith A. Choate, MD, PhD1,2,3
[+] Author Affiliations
1Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut
2Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
3Department of Genetics, Yale University School of Medicine, New Haven, Connecticut
JAMA Dermatol. 2015;151(11):1240-1243. doi:10.1001/jamadermatol.2015.1925.
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ABSTRACT

Importance  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.

Observations  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.

Conclusions and Relevance  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.

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Figure 1.
Clinical and Histological Features of a Vascular Lesion Arising in the Setting of Ramucirumab Therapy

A, A single, well-demarcated, blanchable red plaque, measuring 4 cm in diameter. The plaque breaks up into smaller punctate macules at the periphery. B and C, Superficial, small lobules of small-caliber vessels are noted on histology, and the findings are reminiscent of a tufted angioma. The epidermis is normal (hematoxylin-eosin, original magnification ×4 [B] and ×20 [C]).

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Figure 2.
Whole-Exome Sequencing and Sanger Sequencing Identification of a Somatic p.T771R Mutation in the Vascular Lesion Endothelial Cells

A, Following alignment of exome data and filtration against control data sets, nonsynonymous somatic variants with at least 6 nonreference reads (Non Ref.) in tissue and fewer than 2 Non Ref. reads in blood were isolated. The resulting variants were visualized using the Integrated Genomics Viewer (https://www.broadinstitute.org/igv/) to exclude mismapping, identifying a heterozygous KDR c.C2312G, p.T771R mutation as the only somatic variant. B, The mutation was verified via targeted Sanger sequencing of DNA isolated from laser-microdissected vessels. The mutation was absent in blood and laser-microdissected epidermis, implicating the mutation as tumor endothelium specific. Ref indicates reference allele.

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