(P 183) ACTIONABLE GENOMICS IN GASTROINTESTINAL STROMAL TUMORS LACKING KIT OR PDGFRA MUTATIONS.

Objective: KIT or PDGFRA mutations are established drivers of GIST, targeted via tyrosine kinase inhibition. Less is understood of the pathogenesis of KIT/PDGFRA-wild type GIST, for which therapies are limited.

Methods: cBioPortal was queried for GIST without KIT/PDGFRA alteration (WT). Frequency of mutations (mut), copy number alterations including homologous deletions (homdel), and gene structural variants was described. Alterations (alt) were assessed for potential actionability (PA); marked ‘*’, based on at least “compelling biological evidence” of an alteration’s role as a predictive biomarker per OncoKB. Clinicopathologic characteristics were compared between WT and patients with KIT/PDGFRA-mutated (MUT) via chi square and Wilcoxon tests. Overall survival (OS) was compared via Kaplan-Meier.

Results: Of 499 cases, 68 (13.6%) were WT: 36 gastric (59.0%), 23 small bowel (37.7%), 1 colorectal and 1 esophageal (1.6%) . Alt in 97 genes were identified, most commonly NF1 (31%), SDHA (22%), TP53 (10%), TERT (9%) and MAX (7%). PA alt were found in n=7/68 tumors (10.3%), most in primary (n=5/7; 71.4%) vs metastatic tissue (28.6%). Identified RTK/MAPK pathway alt included BRAF (n=2 mut* + 1 structural variant*, 4.4%), EGFR (n=2 mut, 2.9%), ROS1 (n=2 mut, 2.9%), FGFR1 (n=1 mut*, 1.5%), and RET (n=1 homdel, 1.5%). PI3K/AKT/mTOR pathway alt included AKT1 (n=3 homdel, 4.4%), MTOR (n=2 mut*, 2.9%), PIK3CD (n=2 homdel, 2.9%), TSC2 (n=1 homdel* + 1 mut, 2.9%), and TSC1 (n=1 mut, 1.5%). DNA damage repair pathway alt included PALB2 (n=1 mut, 1.5%), RAD51D (n=1 homdel, 1.5%), FANCC (n=1 mut, 1.5%), ATM (n=1 mut*, 1.5%), and CHEK2 (n=1 homdel, 1.5%). Patients with WT were younger (median age 48 vs 63; p< 0.001) and more often female (64.7% vs 44.1%, p< 0.001). OS between cohorts did not differ after controlling for stage (IV) and primary site (gastric), likely due to limited sample (log-rank p=0.323). However, median OS was 52.5 months in MUT and not reached in WT gastric, stage IV GIST.

Conclusion: Actionable somatic alterations may occur in ~10% of KIT/PDGFRA-WT GIST. RTK/MAPK pathway and less commonly the PI3K/AKT/MTOR and homologous recombination repair pathways are affected.