Impact of RAS and BRAFV600E mutations on tumor immune microenvironment and associated genomic alterations in patients with microsatellite instability (MSI) or DNA mismatch repair deficient (dMMR) colorectal cancers

09/09/2024

Impact of RAS and BRAFV600E mutations on tumor immune microenvironment and associated genomic alterations in patients with microsatellite instability (MSI) or DNA mismatch repair deficient (dMMR) colorectal cancers

ESMO 2024

Authors Alberto Puccini, David Foureau, Elizabeth Mauer, Thierry André, Wei Zhang, Sherif M. El-Refai, Thomas J. George, Josep Tabernero, Frank A. Sinicrope, Jeanne Tie, Scott Kopetz, Eric Van Cutsem, Sara Lonardi, Michael J. Overman, Mohamed E. Salem

Background – All international guidelines currently recommend routine testing of all CRC for MSI/dMMR for Lynch Syndrome screening, prognosis information and treatment guidance. In metastatic setting, the analysis for allRAS and BRAF mutational status is recommended to select the most appropriate treatment choice. However, the impact of RAS and BRAF mutations on prognosis and treatment effect in MSI/dMMR patients is not understood in either localized or metastatic setting.

Methods – A retrospective analysis was performed on 463 de-identified records of patients with stage I-IV MSI/dMMR CRC that were profiled by next-generation sequencing (NGS) (Tempus xT DNA-seq of 595-648 genes at 500x coverage and Tempus xR whole-exome capture RNA-seq). MSI status was determined by assessment of 44 or 239 loci by NGS. dMMR was determined by Tempus IHC testing. Tumor mutational burden (TMB), tumor neoantigen burden (TNB), PD-L1 positivity, immune infiltration, and canonical immune pathways (82 gene set signatures) were analyzed.

Results – Among the 463 MSI/dMMR CRCs, 110 tumors harbored a RAS mutation (RASmut) (23.8%) and 123 a BRAF ^V600Emutation (26.6%) Age at diagnosis was significantly lower amongst RASmut patients versus RAS wild-type patients (RASwt) (57 vs. 71 yo, p <.001) and significantly higher amongst BRAF ^V600Emutated patients versus BRAF wild-type (BRAFwt) patients (76 vs. 62 yo, p<.001). RAS^mutpatients exhibited lower TNB (12 vs. 16, p<.001) as well as PD-L1 positivity (15% vs. 31%, p=.058) compared to RASwt patients. Furthermore, the pathway enrichment analyses showed a lower tumor inflammatory profile of tumor immune microenvironment (TIME) amongst RASmut. By contrast, BRAF ^V600Etumors exhibited hyperproliferative characteristics associated with broad metabolic reprogramming, but similarly inflamed TIME compared to the wild type counterpart.

Conclusions – Overall, these data suggest that MSI/dMMR CRC harboring RAS mutations are less immunogenic and appear to contain a lower tumor inflammatory profile of TIME than RASwt or BRAF ^V600Emutated tumors. Further analysis and validation are needed to confirm our data.

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