Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with metastatic colorectal cancer (mCRC) presenting a significant challenge due to its poor prognosis. Despite advancements in treatment, the five-year survival rate for mCRC is only 10–15%. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) like pembrolizumab, has emerged as a promising treatment for certain mCRC patients, specifically those with microsatellite instability (MSI) or high tumor mutational burden (TMB).
TMB, defined as the total number of somatic non-synonymous mutations per coding region of a tumor genome, has been recognized for its potential to predict response to immunotherapy. High TMB is associated with a greater presence of neoantigens, which can elicit an antitumor immune response. However, the prognostic role of TMB in CRC, especially in MSS tumors, has been less clear, with studies showing mixed results.
This study aimed to clarify the prognostic impact of TMB in a well-characterized cohort of MSS metastatic colon cancer patients who received standard treatments. The research involved 102 patients, with a median follow-up of 46 months, and found that high TMB (≥10 mutations/megabase) was associated with significantly improved overall survival (OS). Patients with high TMB had a median OS of 70 months, compared to 45 months for those with low TMB. Multivariate analysis confirmed TMB as an independent prognostic factor, alongside the response to first-line chemotherapy.
The study also explored the relationship between TMB levels and genetic mutations, finding a significant association between BRAF p.V600E mutation status and higher TMB levels. Additionally, an exploratory analysis suggested that high TMB levels might influence the efficacy of first-line anti-VEGF therapy, with patients having low TMB showing a better response.
These findings contribute to the growing body of evidence supporting the role of TMB as a prognostic biomarker in colon cancer, particularly in MSS tumors. The study underscores the importance of further research to understand the complex interplay between TMB, genetic mutations, and treatment responses in mCRC, potentially guiding more personalized and effective treatment strategies.
