Genomic landscape of lymphatic malformations: a case series and response to the PI3Kα inhibitor alpelisib in an N-of-1 clinical trial

Elife. 2022 Jul 5:11:e74510. doi: 10.7554/eLife.74510.

Abstract

Background: Lymphatic 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.

Methods: We examined the genomic landscape of a patient cohort of LMs (n = 30 cases) that underwent comprehensive genomic profiling using a large-panel next-generation sequencing assay. Immunohistochemical analyses were completed in parallel.

Results: These LMs had low mutational burden with hotspot PIK3CA mutations (n = 20) and NRAS (n = 5) 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 LM harboring a somatic PIK3CA gain-of-function mutation (H1047R). The patient achieved a rapid and durable radiologic complete response, as defined in RECIST1.1, 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 to alpelisib treatment in vitro, which was demonstrated by a concentration-dependent drop in measurable impedance, an assessment of cell status.

Conclusions: Our findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations.

Funding: R.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 number: NCT03941782.

Keywords: NGS; PI3Kα; genomics; human; lymphatic malformations; medicine.

Publication types

  • Clinical Trial
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Class I Phosphatidylinositol 3-Kinases* / antagonists & inhibitors
  • Class I Phosphatidylinositol 3-Kinases* / genetics
  • Class I Phosphatidylinositol 3-Kinases* / metabolism
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • GTP Phosphohydrolases* / genetics
  • Genomics
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunohistochemistry
  • Lymphangioma* / drug therapy
  • Lymphangioma* / genetics
  • Lymphatic Abnormalities* / drug therapy
  • Lymphatic Abnormalities* / genetics
  • Membrane Proteins* / genetics
  • Mutation
  • Sequence Analysis, DNA
  • Thiazoles* / pharmacology
  • Thiazoles* / therapeutic use

Substances

  • Antineoplastic Agents
  • Membrane Proteins
  • Thiazoles
  • Alpelisib
  • Class I Phosphatidylinositol 3-Kinases
  • Class Ia Phosphatidylinositol 3-Kinase
  • PIK3CA protein, human
  • GTP Phosphohydrolases
  • NRAS protein, human

Associated data

  • ClinicalTrials.gov/NCT03941782

Grants and funding

The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication.