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

Introduction: Colorectal cancer (CRC), a global health concern, requires effective treatments. Anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies are used for RAS wild-type and BRAF^V600 mutation-negative metastatic CRC (mCRC) but are not indicated for RAS mutant CRC. Evidence suggests CRC patients with sub-clonal RAS/BRAF mutations in tumor tissue may benefit from anti-EGFRs. We assessed the outcomes of patients with sub-clonal RAS/BRAF mutated advanced/mCRC receiving anti-EGFRs using liquid-based GuardantINFORM real-world clinical-genomic analysis.

Patients and methods: GuardantINFORM analyzed US patients with advanced CRC with BRAF^V600/KRAS/NRAS mutations who received anti-EGFR therapies within 90 days after a Guardant360 test. Primary endpoints were time-to-next treatment (TTNT) and overall survival (OS) (compared across RAS/BRAF mutation clonality cut-offs of 0.3-0.8 using the Cox proportional hazards model).

Results: In GuardantINFORM, 446 patients initiated anti-EGFR therapy within 90 days after the Guardant360 test, and 11%, 9%, and 1% had BRAF^V600E, KRAS, or NRAS mutations, respectively; median distribution of RAS/BRAF clonality was 0.84 (IQR, 0.57-1.00). The data show that patients harboring sub-clonal RAS/BRAF mutations benefited from anti-EGFR therapy to a degree similar to patients without RAS/BRAF mutations. For cut-offs of 0.3 to 0.8, sub-clonal RAS/BRAF had similar TTNT to patients without RAS/BRAF mutations, while clonal RAS/BRAF had a significantly shorter TTNT. For cut-offs of 0.3 to 0.7, sub-clonal RAS/BRAF had similar OS to RAS/BRAF mutations not detected, while clonal RAS/BRAF had a significantly shorter OS.

Conclusion: Consistent with tumor tissue biopsy data, patients with CRC harboring sub-clonal RAS/BRAF mutations as assessed by liquid biopsy may derive benefit from anti-EGFR therapy, warranting further investigation.