Mutation Combinations Database
Comprehensive guide to genetic mutation combinations in colorectal cancer, their clinical implications, and treatment recommendations.
Clinical Implications
STANDARD (SUNLIGHT): TAS-102 + Bevacizumab (OS 10.8mo vs 7.5mo, new standard 2023). ALTERNATIVE: Fruquintinib (FRESCO-2, OS 7.4mo). Regorafenib (CORRECT, OS 6.4mo). Consider clinical trials. Re-test for actionable mutations.
Updated 2023: SUNLIGHT trial established TAS-102 + Bevacizumab as preferred third-line option. Superior to TAS-102 monotherapy (HR 0.61). Fruquintinib approved as additional option (FRESCO-2). Always check for targetable alterations before palliative therapy.
Recommended
Clinical Implications
EMERGING: Botensilimab + Balstilimab showing breakthrough activity (ORR 24%, DCR 73% in refractory MSS mCRC). FDA breakthrough therapy designation. Phase 3 trials ongoing. Standard options: Chemotherapy, TAS-102 + Bevacizumab (SUNLIGHT), Fruquintinib (FRESCO-2).
MSS/pMMR tumors are traditionally resistant to checkpoint inhibitors. Botensilimab is Fc-enhanced anti-CTLA-4 with improved T-reg depletion. First IO showing meaningful activity in MSS CRC. SUNLIGHT established TAS-102 + Bevacizumab as third-line standard (OS 10.8mo).
Recommended
Clinical Implications
Better prognosis. If RAS WT, strongly prefer anti-EGFR.
Sidedness is independent prognostic factor.
Recommended
Clinical Implications
Higher BRAF, MSI-H. Worse prognosis. Check MSI always.
Different biology regardless of RAS status.
Recommended
Clinical Implications
RAS clones may decline after withdrawal. Rechallenge possible.
Clonal evolution is reversible.
Recommended
Avoid
Clinical Implications
Best anti-EGFR candidates. PARADIGM showed superiority vs bevacizumab.
Left-sided + RAS WT = anti-EGFR preferred.
Recommended
Clinical Implications
Best candidates for anti-EGFR therapy. Left-sided tumors have superior outcomes with anti-EGFR.
Recommended
Clinical Implications
ctDNA MRD identifies high recurrence risk. DYNAMIC trial validated.
Transforming adjuvant decisions.
Recommended
Clinical Implications
FIRST-LINE: Nivolumab + Ipilimumab (CheckMate-8HW, ORR 71%, 24mo PFS 72%) OR Pembrolizumab (KEYNOTE-177). CheckMate-8HW showed superiority over chemotherapy. Later lines: Nivolumab, Pembrolizumab, Dostarlimab.
Updated 2024: CheckMate-8HW established Nivo+Ipi as preferred first-line for MSI-H mCRC. ORR 71% vs 14% chemo, 24mo PFS 72% vs 14%. Prevalence: ~15% all stages, ~4-5% metastatic. Test all mCRC at diagnosis.
Recommended
Avoid
Clinical Implications
Higher hereditary rate. Screen all for Lynch.
All <50 should have genetic evaluation.
Recommended
Clinical Implications
Despite RAS WT, right-sided benefit less from anti-EGFR.
Bevacizumab may be preferred first-line.
Recommended
Clinical Implications
FIRST-LINE (NEW 2025): Encorafenib + Cetuximab + mFOLFOX6 (BREAKWATER, OS 30.3 mo vs 15.1 mo - DOUBLES SURVIVAL). SECOND-LINE+: Encorafenib + Cetuximab doublet (BEACON, OS 9.3 mo).
BREAKWATER 2025: Practice-changing for first-line BRAF V600E mCRC. PFS 12.8 vs 7.1 mo, OS 30.3 vs 15.1 mo. FDA accelerated approval. Always test for MSI-H as BRAF V600E + MSI-H has better prognosis.
Recommended
Avoid
Clinical Implications
FIRST-LINE: Encorafenib + Cetuximab + mFOLFOX6 (BREAKWATER, OS 30.3mo). SECOND-LINE+: Encorafenib + Cetuximab (BEACON). Note: MSS BRAF V600E has very poor prognosis without targeted therapy.
BRAF V600E + MSS is one of the worst prognostic groups in mCRC. BREAKWATER data now offers hope with targeted first-line therapy. Median OS improved from 15 to 30 months. Test all mCRC for BRAF at diagnosis.
Recommended
Avoid
Clinical Implications
Strong aspirin benefit data. Regular aspirin improves survival.
Discuss aspirin with patient if no contraindications.
Recommended
Clinical Implications
FDA-approved tumor-agnostic biomarker for pembrolizumab.
Can occur in MSS tumors. Check NGS for TMB score.
Recommended
About This Database
This database contains clinically relevant mutation combinations in colorectal cancer. Each combination includes:
- Genes involved - The genetic alterations present
- Prognosis - Expected outcome classification
- Prevalence - How common in CRC patients
- Recommended treatments - Evidence-based options
- Treatments to avoid - Known ineffective therapies
- Evidence level - Strength of supporting data
Actionable combinations have FDA-approved targeted therapies or strong clinical trial evidence. Always consult with your oncologist for personalized treatment decisions.