Abstract P136: Response to alpelisib in an adolescent with PIK3CA-mutated metastatic gastrointestinal stromal tumour
Authors: Cohen-Gogo Sarah , Kanwar Nisha , Shaikh Furqan , Baertschiger Reto M. , Shlien Adam , Malkin David , Putra Juan , Coblentz Ailish , Villani Anita , Gupta Abha A. , Morgenstern Daniel A. 
Published: December 2021

Abstract
Introduction Gastrointestinal stromal tumours (GISTs) are mesenchymal neoplasms that arise in the gastrointestinal tract. While most GISTs are driven by mutations in cKIT or PDGFR, approximately 10% lack these variants and are referred to as ‘wild-type’. Wild-type GISTs are commonly succinate dehydrogenase (SDH)-deficient and are characterized by indolent, multi-focal disease at presentation. On occasion, patients experience symptomatic disease progression warranting treatment ; imatinib or sunitinib offer minimal benefit. PIK3CA mutations have recently been described in a small proportion of GIST. Case report A previously healthy 16-year-old female presented with a five-month history of vomiting and weight loss, compatible with gastric outlet obstruction. Computerized tomography demonstrated a large gastric mass, and multiple liver and peritoneal metastases. Biopsy showed nests of epithelioid cells with round nuclei, vesicular chromatin, and eosinophilic cytoplasm. The lesional cells were immunoreactive for CD117, DOG1, CD34, and smooth muscle actin, while negative for SDH-B immunohistochemistry, in keeping with SDH-deficient GIST. Germline and somatic panel sequencing were performed through the SickKids Cancer Sequencing Program along with RNA sequencing by Illumina TruSight RNA Pan-Cancer NGS analysis. Somatic analysis revealed a PIK3CA p.Glu545Lys (E545K) mutation at 0.12 variant allele fraction (VAF). The patient was also found to have germline heterozygous pathogenic splice variant in the SDHB gene c.75+1 G&gt;T (p?). In the light of the molecular findings and no alternative curative options, compassionate access to alpelisib was sought. The patient started drug at the recommended adult dose of 300 mg by mouth daily, and after completing two 28-day cycles, showed marked improvement in her abdominal distension and discomfort. Her appetite improved with documented nutritional weight gain. Reimaging at this time showed a 20% reduction in the sum of maximum dimensions of target lesions (per RECIST 1.1). Repeat imaging after five months on treatment confirmed continued improvement with 25% reduction compared to baseline.The patient did not experience hypersensitivity, severe cutaneous adverse reactions, hyperglycemia or pneumonitis. She currently continues on alpelisib monotherapy. Conclusion We describe the first report of a clinically meaningful response to a PIK3CA inhibitor in an adolescent patient with advanced metastatic SDH-deficient GIST harbouring a somatic activating PIK3CA hotspot mutation. There is still much to be learned about the biology of pediatric/wild-type GIST. In these rare cases, we recommend referral to specialized centers and incorporation of comprehensive next generation sequencing into care. Sequencing should be performed both on germline and somatic DNA to evaluate for a cancer predisposition syndrome, along with possible druggable targets in PIK3CA, cKIT or PDGFRA. We believe that the lack of routine comprehensive genomic analysis may underestimate the frequency of such rare variants.
Citation Format: Sarah Cohen-Gogo, Nisha Kanwar, Furqan Shaikh, Reto M. Baertschiger, Adam Shlien, David Malkin, Juan Putra, Ailish Coblentz, Anita Villani, Abha A. Gupta, Daniel A. Morgenstern. Response to alpelisib in an adolescent with PIK3CA-mutated metastatic gastrointestinal stromal tumour [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P136.