Immune checkpoint blockade therapy for BRAF mutant metastatic colorectal cancer: the efficacy, new strategies, and potential biomarkers

Abstract

BRAF mutant metastatic colorectal cancer has long been considered a tumor with a poor prognosis and a poor response to chemotherapy. Despite the efficacy of targeted therapy with multi-targeted blockade of the mitogen-activated protein kinase (MAPK) signaling pathway has brought a glimmer of hope to this group of patients, the need to improve treatment efficacy remains unmet, especially for the microsatellite stability/DNA proficient mismatch repair (MSS/pMMR) subtype. BRAF mutant colorectal cancer patients with high microsatellite instability/DNA deficient mismatch repair (MSI-H/dMMR) have high tumor mutation burden and abundant neoantigen, who are deemed as ones that could receive expected efficacy from immunotherapy. Generally, it is believed that MSS/pMMR colorectal cancer is an immunologically “cold” tumor that is insensitive to immunotherapy. However, targeted therapy combined with immune checkpoint blockade therapy seems to bring light to BRAF mutant colorectal cancer patients. In this review, we provide an overview of clinical efficacy and evolving new strategies concerning immune checkpoint blockade therapy for both MSI-H/dMMR and MSS/pMMR BRAF mutant metastatic colorectal cancer and discuss the potential biomarkers in the tumor immune microenvironment for predicting immunotherapeutic response in BRAF mutant colorectal cancer.

Advances in Precision Medicine Approaches for Colorectal Cancer: From Molecular Profiling to Targeted Therapies

“…In addition to RAS mutations, alterations in the BRAF gene, particularly the V600E mutation, are another important genetic event in colorectal cancer. BRAF mutations are observed in approximately 5–10% of colorectal cancer cases and are associated with poor prognosis . The BRAF V600E mutation leads to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, driving uncontrolled cell growth and tumor progression.…”

“…BRAF mutations are observed in approximately 5−10% of colorectal cancer cases and are associated with poor prognosis. 116 The BRAF V600E mutation leads to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, driving uncontrolled cell growth and tumor progression. Patients with BRAF-mutated colorectal cancer often have a more aggressive disease course and a limited response to conventional therapies.…”