Abstract 2120: Exploring the genomic landscape of colorectal cancer for enabling clinical genomics informed and real-world data based clinical development

Abstract

Abstract Background: Activation of the MAPK-signaling by RAS- (KRAS or NRAS) alterations is an important driver event in colorectal cancer (CRC) tumorigenesis that determines treatment selection (1).Real-world data (RWD) mining is an important tool to inform patient selection and stratification (2,3). Here, RWD genomics data mining was conducted using the Foundation Medicine database to explore RAS and BRAF-alterations in CRC patients and to investigate the general alterations’ landscape - including rare alterations. The prevalence of microsatellite instability (MSI) and tumor mutational burden (TMB) were also explored. Methods: The prevalence of gene alterations and their co-occurrence with RAS/BRAF-alterations in tumor tissue of CRC patients (N=42800) were investigated using the FoundationInsightsTM web platform, which includes harmonized results from the FoundationOneCDx, FoundationOneHeme, and PD-L1 assays from 2012 to March 2022. Data was collected from FMI solid and heme tests from 2012 to March 2022. Alterations that render a particular gene ‘altered’ included single nucleotide variants (SNVs) or insertion-deletion mutations (Indels), collectively referred to as short variants (SVs), rearrangements (RE) and copy number events (CN). TMB (cut-off 10 mut/MB) and MSI status were also characterized. Results: Altogether, 36.9% of CRC samples were RAS/BRAF-WT and 63.1% had a known or likely functional RAS/BRAF-alteration, respectively. Of all KRAS and NRAS alterations (SV, CN and RE regardless of annotation as functional or presence in a hotspot), SVs in exons 2, 3 and 4 constituted 96.1% and 94.2% of all alterations, respectively. Relative to all samples the potentially targetable KRAS p.G12C, p.G12D and p.G12V mutations were present in 3.6%, 15.1% and 10.2% of samples, respectively. The p.G12E variant was present in less than ten samples. The five most frequently altered potentially targetable genes were PIK3CA (19.6%), PTEN (8.7%), ERBB2 (4.7%), EGFR (2.5%) and FGFR1 (2.0%). NTRK-alterations (NTRK1/2/3) were present in 0.9%, ROS1-alterations in 0.4%, RET-alterations in 0.6% and ALK-alterations in 0.5% of samples, respectively. The prevalence of immuno-oncology biomarkers was also explored; overall, 9.6% of samples were TMB-high, 6.1% MSI-high and 0.6% POLE-altered. MSI-high or TMB-high samples were significantly more abundant in the RAS/BRAF-altered subset. In the RAS/BRAF-WT subset 4.6% were MSI-high and 7.9% TMB-high, whereas in the RAS/BRAF-altered subset 7.1% were MSI-high and 10.6% TMB-high. Conclusion: RWD based clinical genomic profiling confirms that the vast majority of RAS-alterations in CRC are SVs in exons 2, 3 and 4. Both TMB-high and MSI-high samples are significantly more abundant in the RAS/BRAF-altered cohort. RWD confirms that PI3K-, ERBB- and FGFR-signaling pathways are frequently altered in CRC. RWD based clinical genomic profiling has the potential to support comprehensive clinical study design as well as patient selection/stratification. Citation Format: Markus Schulze, XiaoZhe (Janet) Wang, Jawad Hamad, Julia F. Hopkins, Julia F. Hopkins, Jürgen Scheuenpflug, Zheng Feng. Exploring the genomic landscape of colorectal cancer for enabling clinical genomics informed and real-world data based clinical development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2120.