Clinical Impact of Sub-Clonal RAS/BRAF Alterations in Liquid Biopsies From Patients With Advanced or Metastatic CRC
Peter Gibbs1, Khalid Abubaker2, Danyi Wang3
1Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
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 BRAFV600 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 BRAFV600/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 BRAFV600E, 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.
Insights
Patients with advanced colorectal cancer (CRC) and sub-clonal RAS/BRAF mutations may benefit from anti-epidermal growth factor receptor (anti-EGFR) therapies, similar to those without these mutations. This finding suggests a potential for broader anti-EGFR use in CRC treatment.
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.
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