(P 41) GENOMIC ANALYSIS OF SECONDARY KIT MUTATIONS IN CHINESE PATIENTS WITH IMATINIB-RESISTANT ADVANCED GASTROINTESTINAL STROMAL TUMORS USING NEXT-GENERATION SEQUENCING (NGS)

Objective: Gastrointestinal stromal tumors (GISTs) are primarily driven by the abnormal activation of proto-oncogenes KIT/PDGFRA. Although imatinib significantly improved the prognosis of GIST patients, resistance caused by secondary mutations poses a considerable challenge for the treatment of advanced GIST. Secondary mutations often exhibit various types and numbers, with the types and frequencies of such mutations differing based on the primary mutations. As sunitinib and regorafenib are only effective against certain secondary mutations, ripretinib can broadly inhibit a wide range of primary and secondary KIT mutations. Consequently, identifying the secondary mutations of imatinib-resistant GIST patients is crucial for treatment selection in second- and later-line settings. This study aims to analyze the resistance mutation status of Chinese advanced GIST patients who failed first-line imatinib treatment and to investigate the differences in resistance mechanisms resulting from distinct KIT primary mutations.

Methods: Patients with recurrent or metastatic GIST who were admitted to Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University from July 2019 to January 2023 were included. First-line treatment with imatinib was administered to all participants, and surgical or puncture tissue samples were subsequently collected. NGS was performed on tissue samples with a tumor cell proportion exceeding 20% in the rapidly progressing metastatic lesions. The analysis focused on mutations in nine genes, namely KIT, PDGFRA, KRAS, BRAF, NF1, SDHA, SDHB, SDHC, and SDHD. Additionally, relevant clinicopathological characteristics of the patients were recorded. Approval for this study was granted by the Internal Review Board of Sir Run Run Shaw Hospital.

Results: A total of 69 patients with recurrent or metastatic GIST were administered first-line imatinib treatment. Post-treatment, 65 surgical biopsies and 4 needle biopsies were collected. Among the surgical specimens, 42 (64.6%) were imatinib-resistant while 23(35.4%) were non-resistant. Of the 42 patients exhibiting imatinib resistance, 61.9% were male and 83.3% were aged over 55 years. The primary tumor site was predominantly the small intestine in 66.7% (n=28) and stomach in 7.1% (n=3). Additionally, 52.4% of these patients had a tumor diameter of 5 cm or greater. Primary KIT Exon 9 and KIT Exon 11 mutations were observed in 23.8% (10/42) and 76.2% (32/42), respectively. Among patients with KIT Exon 9 mutations, 20% (2/10) had secondary mutations, all of which were KIT Exon 17 mutations. For patients with KIT Exon 11 mutations, 84.3% (27/32) had secondary mutations, distributed as follows: 33.3% (9/27) in KIT Exon 13, 3.7% (1/27) in Exon 14, 51.9% (14/27) in Exon 17, and 11.1% (3/27) in Exon 18.

Conclusion: The proportion of secondary mutations in KIT Exon 11 primary mutations is significantly higher than that in KIT Exon 9 primary mutations following progression on first-line imatinib treatment. Furthermore, the main resistance mechanism of KIT Exon 11 mutant GISTs continues to rely on complex secondary mutations in KIT signaling. Differences in resistance mechanisms among various primary mutations imply that subsequent treatment should take into account both the patient 's primary and resistance mutations.