Clinical Impact of Sub-Clonal RAS/BRAF Alterations in Liquid Biopsies From Patients With Advanced or Metastatic CRC

Area of Science:

• Oncology
• Genomics
• Translational Medicine

Background:

• Colorectal cancer (CRC) is a significant global health challenge.
• Anti-epidermal growth factor receptor (anti-EGFR) therapies are standard for RAS wild-type, BRAF V600 mutation-negative metastatic CRC (mCRC).
• Current guidelines do not recommend anti-EGFRs for RAS mutant CRC, despite evidence suggesting potential benefit in cases with sub-clonal mutations.

Purpose of the Study:

• To evaluate the efficacy of anti-EGFR therapy in advanced/metastatic CRC (mCRC) patients with sub-clonal RAS/BRAF mutations.
• To compare treatment outcomes based on the clonality of RAS/BRAF mutations using real-world clinical-genomic data.
• To determine if patients with sub-clonal RAS/BRAF mutations benefit from anti-EGFR therapy similarly to those without these mutations.

Main Methods:

• Analysis of the GuardantINFORM real-world database of US patients with advanced CRC.
• Inclusion criteria: presence of BRAF V600/KRAS/NRAS mutations and initiation of anti-EGFR therapy within 90 days of Guardant360 testing.
• Primary endpoints: time-to-next treatment (TTNT) and overall survival (OS), analyzed using Cox proportional hazards models across varying mutation clonality cut-offs (0.3-0.8).

Main Results:

• 11% of 446 patients initiating anti-EGFR therapy had BRAF V600E, 9% KRAS, and 1% NRAS mutations; median RAS/BRAF clonality was 0.84.
• Patients with sub-clonal RAS/BRAF mutations showed similar TTNT and OS compared to patients without RAS/BRAF mutations, across specified clonality cut-offs.
• Conversely, patients with clonal RAS/BRAF mutations exhibited significantly shorter TTNT and OS.

Conclusions:

• Real-world data suggest that patients with CRC harboring sub-clonal RAS/BRAF mutations, as detected by liquid biopsy, may benefit from anti-EGFR therapy.
• These findings align with previous tumor tissue biopsy data, supporting the potential utility of anti-EGFRs in a broader CRC patient population.
• Further investigation is warranted to confirm these outcomes and refine treatment strategies for CRC patients with sub-clonal mutations.