Abstract 7363: Clinical, genomic, transcriptomic and immunologic profile of BRAF mutant colorectal tumors

Abstract

Abstract Background: Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. BRAF, a protein kinase of the Mitogen-Activated Protein Kinase (MAPK) pathway, is mutated in 12% of colorectal cancers and is a poor prognostic factor for patients. BRAF mutations at the V600 codon are most studied but non-V600 BRAF mutations also exist and behave differently. BRAF V600 CRC treated with BRAF+MEK inhibitors show 12% response rates while we observe 65% response rates in BRAF V600 Melanoma. Additionally, no approved targeted therapies exist for non-V600 BRAF mutant cancers and retrospective studies show poorer PFS with BRAF+MEK inhibitors vs BRAF V600 cancers. We interrogated publicly available data of BRAF mutant CRC to uncover differences in the tumor microenvironment and signalling pathways of BRAF V600 and non-V600 tumors in hopes of uncovering better treatments. Methods: We analyzed the clinical and genomic profile of BRAF mutant CRC tumors from the GENIE v12 data. Gene Set Enrichment Analysis was performed on RNAseq from the TCGA data (discovery cohort) and the combined data from CPTAC and Sidra-LUMC data (validation cohort). We investigated the composition of tumor infiltrating immune cells using CIBERSORTx (deconvolution algorithm for bulk RNAseq). Results: Non-V600 mutations (n=219/1061) were most represented in patients of Asian or Black race compared to White patients (p<0.0001) and importantly, were found in younger patients (p<0.0001). We identified n=67 and n=74 BRAF mutant RNAseq samples in the discovery and validation cohorts, respectively. In the discovery cohort: BRAF V600 CRC were enriched for Interferon Gamma Signaling, Complement pathway, and IL6 JAK STAT3 Signaling (p<0.05) while the non-V600 BRAF mutant CRC showed an enrichment for Wnt-beta Catenin, Notch, and Hedgehog Signaling pathways (p<0.05). In the validation cohorts these same pathways were enriched in V600 and non-V600 BRAF mutant tumors. Interestingly, enrichment of genes co-mutated (GENIE data) in non-V600 BRAF mutant CRC also revealed the Wnt pathway. Non-V600 CRC tumors have a higher proportion of M0 macrophages (p=0.0035) and CD4 memory resting T cells (p<0.0001) while patients with V600 CRC have higher proportions of CD8 T cells (p=0.006) and activated mast cells (p=0.0341). Conclusion: No optimal therapeutic strategies have been defined for these potentially actionable non-V600 BRAF mutant CRCs. By exploring the multi-omic landscape of these tumors we have identified unique characteristics of non-V600 BRAF mutant CRC that could be therapeutically exploited. Citation Format: Emmanuelle Rousselle, Suzanne Kazandjian, April Rose. Clinical, genomic, transcriptomic and immunologic profile of BRAF mutant colorectal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7363.