Genomic Landscape of Lymphatic Malformations: A Case Series and Response to the PI3Kα Inhibitor Alpelisib in an N-of-One Clinical Trial

BackgroundLymphatic malformations (LMs) often pose treatment challenges due to a large size or a critical location that could lead to disfigurement, and there are no standardized treatment approaches for either refractory or unresectable cases.MethodsWe examined the genomic landscape of a patient cohort of LMs (n=30 cases) that underwent comprehensive genomic profiling (CGP) using a large-panel next generation sequencing (NGS) assay. Immunohistochemical analyses were completed in parallel.ResultsThese LMs had low mutational burden with hotspot PIK3CA mutations and NRAS mutations being most frequent, and mutually exclusive. All LM cases with Kaposi sarcoma-like (kaposiform) histology had NRAS mutations. One index patient presented with subacute abdominal pain and was diagnosed with a large retroperitoneal lymphatic malformation harboring a somatic PIK3CA gain-of-function mutation (H1047R). The patient achieved a rapid and durable complete response to the PI3Kα inhibitor alpelisib within the context of a personalized N-of-1 clinical trial (NCT03941782). In translational correlative studies, canonical PI3Kα pathway activation was confirmed by immunohistochemistry and human LM-derived lymphatic endothelial cells carrying an allele with an activating mutation at the same locus were sensitive in vitro to alpelisib in a concentration-dependent manner.ConclusionsOur findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations.FundingR.P. and W.A. are supported by awards from the Levy-Longenbaugh Fund. S.G. is supported by awards from the Hugs for Brady Foundation. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of Arizona Cancer Center (CA023074), the University of New Mexico Comprehensive Cancer Center (CA118100), and the Rutgers Cancer Institute of New Jersey (CA072720). B.K.M. was supported by National Science Foundation via Graduate Research Fellowship DGE-1143953.Clinical trial numberNCT03941782