Association of candidate alterations with primary resistance to KRAS G12D targeting in colorectal cancer.

• DOI: 10.1200/jco.2024.42.3_suppl.170
• Publication Date: 2024-01-22T21:12:58Z
• Authors: Khalid Jazieh; Jill Tsai; Mojun Zhu; Hao Xie
• Keywords: 03 medical and health sciences; 0302 clinical medicine

170 Background: KRAS-mutant colorectal cancer (CRC) has a worse prognosis and greater resistance to therapy, attracting tremendous efforts develop both allele-specific pan-KRAS targeting agents including KRAS G12C G12D inhibitors. CRC demonstrated primary acquired inhibitors, which can be better evaluated by circulating tumor DNA (ctDNA)-based next generation sequencing (NGS) methods without tissue sampling bias. Here, we utilized clinical ctDNA data delineate the landscape of candidate alterations associated with in CRC. Methods: Samples from advanced patients Guardant360 2021 were categorized into group comparator groups not detected (ND) according mutation status. Demographics, MSI-H status, blood mutational burden (bTMB) summarized compared between using t-test for continuous variables Fisher’s exact test categorical variables. Co-occurrence patterns other genes assessed. Primary mutations inferred findings inhibitors reported Awad et al. N Engl J Med. Tanaka Cancer Discov. 2021. Results: Among approximately 2500 samples, 16.8% had G12D, most common The mean allele frequency (11.4%) is comparable that (10.9%). Mean age (61.6 years), (3.8%), bTMB (14.2 Mut/Mb) those ND group. This contrasts significantly lower (60.2 years, p=0.01), (0.56%, p=0.03), higher (16.3 Mut/Mb, p=0.02) ND. Both co-occur APC, PIK3CA, SMAD4 alterations. FBXW7, AR, KEAP1 unique co-occurrences while KIT was G12C. Candidate included simultaneously present Q61H (14.1%), G12V (6.4%), (5.9%), G13D (3.6%), BRAF V600E (2.7%) others, amplification MET (2%), MYC (1.6%), (1.4%), FGFR3-TACC3 translocation (Table). Conclusions: co-occurring molecular ctDNA-based NGS platforms survey Further validation preclinical models needed. [Table: see text]