Solid tumor patients with G12V and G13D KRAS aberrations have poor survival following ICI treatment.

Abstract

e14567 Background: KRAS gene has been well known as a dominant oncogene which activates downstream signaling for tumor growth. The new therapeutic drug targeting specific KRAS mutation (G12C) has been developed and several clinical trials are testing KRAS inhibitors in solid tumor patients. In line with this, we have surveyed the prevalence and clinical features of solid tumor patients with KRAS aberration in 1,744 oncology patients who received next generation sequencing (NGS) in a clinical practice. Methods: Between 2019 amd 2021, 1,744 oncology patients have received NGS (TruSight Oncology 500 panel; 523 genes) at Samsung Medical Center. . Matched clinical and histology outcomes including programmed cell death-ligand 1 (PD-L1) 22C3 expression (n = 798) and immunotherapy treatment outcomes (n = 409) were analyzed based on genomic alteration. Results: Among the thirty-three different cancer types, the most common cancer types were colorectal cancer (CRC) (N = 547, 31.4%), followed by gastric cancer (GC) (N = 381, 21.8%), and sarcoma (N = 155, 8.9%). Of 1,744 patients, any KRAS aberrations (CNVs, SNVs) were detected in 487 (27.9%) patients (CNV: Copy Number Variation, SNV: Small Nucleotide Variation). Of the 51 (2.9%) patients with KRAS amplification, 18 (35.3%) patients were CRC followed by GC (N = 9, 17.6%). Each 4 cases were found in Cholangiocarcinoma (CCC), sarcoma, melanoma and pancreatic cancer (8%, respectively). Copy number of KRAS were distributed from 4 to over 50, while bladder cancer had the highest median value of copy number(median: 148), followed by CCC(median: 16.2). Of 454 SNV cases, the most frequent cancer type was CRC (N = 259, 57.0%) and pancreatic cancer (N = 89, 19.6%). Except 4 cases, all SNV mutation type was missense mutation. G12D amino acid change was the most frequent(N = 182), followed by G12V(N = 100), G13D(N = 48), and G12C(N = 20). However, only the patients with G12V and G13D mutation had significantly shorter OS and PFS in ICI treatment. Conclusions: Based on our comprehensive survey of next generation sequencing focused on KRAS aberration, we identified approximately 2.9% KRAS amplification and 26.0% KRAS SNV in patients with metastatic solid tumors. It was demonstrated that G12V, G13D were important mutations which were related to the response to ICI treatment in real-world data.[Table: see text]