Genomic landscape of lymphatic malformations: a case series and response to the PI3K[alpha] inhibitor alpelisib in an N-of-1 clinical trial

• Published in: eLife 2022-07, Vol.11
• Main Authors: Shaheen, Montaser F, Tse, Julie Y, Sokol, Ethan S, Masterson, Margaret, Bansal, Pranshu, Rabinowitz, Ian, Tarleton, Christy A, Dobroff, Andrey S, Smith, Tracey L, Bocklage, Thèrése J, Mannakee, Brian K, Gutenkunst, Ryan N, Bischoff, Joyce, Ness, Scott A, Riedlinger, Gregory M, Groisberg, Roman, Pasqualini, Renata, Ganesan, Shridar, Arap, Wadih
• Format: Article
• Language: English
• Subjects: Cellular proteins; Clinical trials; Immunohistochemistry; Medical research; Medicine, Experimental; Sarcoma
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.74510

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. 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. 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 PI3K[alpha] inhibitor alpelisib within the context of a personalized N-of-1 clinical trial (NCT03941782). In translational correlative studies, canonical PI3K[alpha] 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. Our findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations.