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Impact Of BRAF V600E, RAS Mutations On Immune Microenvironment Of MSI-H/dMMR CRC Mapped

Research sheds light on the immunogenicity of microsatellite instability-high or mismatch repair-deficient colorectal cancer with concomitant BRAF V600E or RAS mutations
02 Jul 2022
Targeted Therapy
Colon and Rectal Cancer

Author: By Shreeya Nanda, Senior medwireNews Reporter


medwireNews: Researchers have characterised the immunological features of the tumour microenvironment in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) colorectal cancer (CRC) and co-existing BRAF V600E or RAS mutations.

There was no significant difference between the BRAF V600E and wild-type subgroups with regard to neoantigen tumour burden (NTB) and T-cell infiltration, reported Mohamed Salem, from Levine Cancer Institute in Charlotte, North Carolina, USA, at the ESMO World Congress on Gastrointestinal Cancer 2022, held in Barcelona, Spain.

This suggests that both subsets are “equally likely to benefit from immune checkpoint inhibitors”, which aligns with the subgroup analysis of the KEYNOTE-177 trial of pembrolizumab versus mFOLFOX6 in MSI-H CRC showing the PD-1 inhibitor was favoured in both the BRAF-mutated and wild-type subgroups, he commented.

However, the current study found that RAS-mutated tumours were less immunogenic than those wild-type for the gene, and have a tumour microenvironment “that may be less sensitive to immune checkpoint blockade”, added Mohamed Salem.

The investigators applied next-generation sequencing (including whole-transcriptome RNA sequencing) to tumour samples from 459 patients with MSI-H/dMMR disease, of whom 27% carried BRAF V600E mutations, while the remaining 73% were BRAF wild-type.

The analyses showed that patients with BRAF-mutated tumours had a similar NTB to those who were wild-type, at an identical median of 15 mutations/Mb, and the levels of CD4+ and CD8+ infiltrating T cells were also comparable between the groups.

The groups did differ, however, with respect to the proportion of infiltrating natural killer (NK) cells, which was significantly higher in the patients with BRAF-mutated than wild-type tumours, and the TH1 immune pathway was also significantly upregulated in BRAF-mutated tumours.

Mohamed Salem and colleagues also found that cancer stem cell pathways, including the Notch and WNT/Catenin signalling pathways, were significantly downregulated in BRAF-mutated tumours. By contrast, cyclin-dependent cell signalling as well as glycerophospholipid, galactose and nucleotide metabolism were significantly upregulated, pointing to “accelerated growth and metabolic reprograming”, noted the presenter.

Turning to the RAS part of the study, he reported that analysis of samples from 463 patients with MSI-H/dMMR CRC showed that the NTB was significantly lower among the 24% harbouring RAS mutations than the 76% who were wild-type, at a median of 12 versus 16 mutations/Mb

RAS-mutated tumours also had lower inflammation relative to wild-type tumours, as indicated by the significant downregulation of cytokine signalling pathways such as JAK-STAT and TH1, as well as significantly lower enrichment of CD8+ and regulatory T cells.

In a comment to medwireNews, Mohamed Salem said that “immunotherapy represents a good therapeutic strategy for BRAF V600E-mutated tumors.”

He added that “single-agent immunotherapy has demonstrated benefits in RAS-mutated MSI-H/dMMR CRC tumors”, but “further studies are needed to determine the optimal strategy” for these patients.

“I personally believe that ‘CRC’ is no longer an accurate name for this disease but it is rather the ‘family name’ and we must start calling these tumors by their first name, eg, MSI-H/dMMR BRAF V600E right-sided colon cancer”, said Mohamed Salem.

And he concluded: “The burgeoning fields of precision medicine and immunotherapy are in the vanguard and hold great promise in the treatment of CRC, but we must strive to choose the right patients with the right target for the right treatment.”


medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group

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