(P 35) GENOMIC ALTERATIONS IN ADVANCED GASTROINTESTINAL STROMAL TUMORS AS REVEALED BY COMPREHENSIVE GENOMIC PROFILING TESTS

Objective: Gastrointestinal stromal tumors (GISTs) are a rare and aggressive type of mesenchymal tumor that develops in the gastrointestinal tract with heterogeneous molecular features. According to the mutation status of KIT and/or PDGFRA, GISTs are classified into KIT/PDGFRA-mutated GISTs and wild-type GISTs. Few studies have focused on genomic alterations (GAs) and their applicability for molecular-targeting agents based on comprehensive genomic profiling (CGP) tests for advanced GISTs in clinical practice. We investigated actionable GAs and targetable GAs in advanced GISTs.

Methods: We retrospectively reviewed data on patients with advanced GISTs who underwent CGP tests and were registered with the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan. The data cutoff was April 2023 using the C-CAT database's latest version 6.0.0. CGP tests were conducted by NCC Oncopanel System (NOP) or FoundationOne CDx (F1). We examined somatic GAs, microsatellite status, and tumor mutation burden (TMB) of KIT/PDGFRA-mutated GISTs (the KIT/PDGFRA group) and wild-type GISTs (the wild-type group). Actionable GAs were counted if they were classified as “pathogenic/oncogenic” or “likely pathogenic/likely oncogenic variants”. Targetable GAs are actionable GAs, excluding KIT and PDGFRA, which can be treated with drugs approved for GIST or other types of cancer or have shown efficacy in clinical trials for either GIST or different types of cancer.

Results: Up to April 2023,144 patients with advanced GIST were enrolled into the C-CAT database. As platforms for the CGP tests, NOP was performed in eight (6%), F1 in 136 (94%). Fifty-four patients (38%) underwent CGP tests using specimens obtained before initiating treatment with imatinib and 90 (63%) using specimens obtained after imatinib. A total of 119 patients (83%) were in the KIT/PDGFRA group, while 25 patients (17%) were in the wild-type group. Actionable GAs were detected in 95 patients (80%) in the KIT/PDGFRA group and 22 patients (88%) in the wild-type group. In the KIT/PDGFRA group, common actionable GAs were CDKN2A (45%), CDKN2B (34%), RB1 (13%), STK11 (10%), TP53 (7%), with PDGFRA D842V mutation being found in four patients (3%). In the wild-type group, SDHB (36%), TP53 (20%), NF1 (12%), STK11 (12%), SDHA (8%) were common actionable GAs with ETV6-NTRK3 fusion being detected in one patient (2%). Neither group had patients with the BRAF V600E mutated or MSI-high tumors. TMB-high (> 10 Muts/Mb) were observed in one patient (1%) in the KIT/PDGFRA group and in two patients (8%) in the wild-type group. In the KIT/PDGFRA group, 29 patients (24%) had targetable GAs such as small-scale variants in BRCA2, TSC1, KRAS, PALB2 and ERBB2 amplification. In the wild-type group, 12 patients (48%) had targetable GAs, including small-scale variants in NRAS, PIK3CA, PTEN and NF1. Four patients were proposed for treatment with approved drugs: three patients with TMB-high status for pembrolizumab and one patient with ETV6-NTRK3 fusion for entrectinib or larotrectinib.

Conclusion: The present study highlights that approximately 25% and 50% of patients in each KIT/PDGFRA and wild-type group exhibit targetable GAs, thereby illustrating the clinical utility of CGP tests in identifying therapeutic targets in advanced GISTs.