Advances in biomarkers, ctDNA analysis, and combination therapies are revolutionizing colorectal cancer detection and personalized treatment.

Anti-EGFR antibody treatment is given to treat patients with metastatic colorectal cancer (CRC). However, due to mutations in the tumor cells, it becomes resistant to the treatment making it less effective (1^✔ ✔Trusted Source
Establishment of liquid biopsy procedure for the analysis of circulating cell free DNA, exosomes, RNA and proteins in colorectal cancer and adenoma patients

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CRC is one of the most common types of cancer worldwide. With the anti-EGFR antibody treatment using drugs like cetuximab and panitumumab, metastatic CRC can be managed effectively in patients with RAS and BRAF wild-type tumors.

Resistance to Anti-EGFR Therapy

Mutations in RAS and EGFR extracellular domain (ECD) can become resistant to the drugs. Amplifications of MET and ERBB2 can create resistance to the treatment. Using the circulating tumor DNA (ctDNA) analysis, mutations in the gene can be identified and monitor resistance to the treatment.

Studies have found that KRAS mutations can be identified within 5–6 months of treatment, indicating their presence in subclones before therapy. However, EGFR ECD variants show de novo mutations.

When the drug is discontinued, the tumor cells lose their resistance restoring sensitivity. The drug can be administered later to manage resistance and improve long-term outcomes. The CRICKET and CHRONOS trials demonstrated that readministering patients with cetuximab or panitumumab could give positive results in selected populations based on ctDNA-guided screening. The CAPRI-GOIM and CAVE trials also highlighted the effectiveness of combining anti-EGFR antibodies with irinotecan or avelumab, achieving improved progression-free survival (PFS) and overall survival (OS).

Biomarkers in Colorectal Cancer (CRC)
Other genetic mutations such as MSI, BRAF, MET, and ERBB2 can play an important role in CRC prognosis and therapy selection:

• Microsatellite Instability (MSI): High MSI (MSI-H) is found in 20% of early-stage CRCs and about 5% of metastatic cases. MSI-H tumors are predictive biomarkers for immunotherapy responses.
• BRAF Mutations: BRAF mutations, particularly V600E found in 10% of mCRC cases, are associated with poor prognosis and resistance to EGFR therapies.
• MET Amplifications: MET amplifications are increasingly recognized as a mechanism of acquired resistance to anti-EGFR treatments. Integrating MET inhibitors into treatment regimens could benefit patients with MET-driven resistance.
• ERBB2 Overexpression: Detected in 3% of mCRC cases, ERBB2 (HER2) amplifications is another biomarker of CRC.

Future Diagnosis and Treatment for CRC

Novel approaches like cfDNA fragmentomics show high potential in early cancer detection. Researchers can differentiate between cancerous and healthy cells by analyzing fragmentation patterns, nucleosome footprints, and end motifs, offering the potential for earlier diagnosis and personalized treatment.

As clinical trials continue to explore ctDNA-guided interventions and combination therapies, the future of CRC treatment appears increasingly precise and individualized. These advancements can help in overcoming CRC resistance and make personalized treatments based on genetic profiles.

1. Establishment of liquid biopsy procedure for the analysis of circulating cell free DNA, exosomes, RNA and proteins in colorectal cancer and adenoma patients – (https://www.nature.com/articles/s41598-024-78497-x)

Source-Medindia