Mutation combinations

What your mutation combination means

Tumour alterations rarely come alone. Here you can see how prognosis and treatment change depending on how they combine.

64 combinations 39 with targeted treatment 14 categories
All Prognosis favourable Prognosis intermediate Prognosis unfavourable With targeted treatment

64 combinations

Third-Line Refractory Prognosis unfavourable Targeted treatment 100% of cases Any 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 clini…

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 treatments

TAS-102 + BevacizumabFruquintinibRegorafenibClinical trials
Treatment line · Evidence: level 1 SUNLIGHTFRESCO-2CORRECT See full page
MSS (Immunotherapy Emerging) Prognosis intermediate Targeted treatment 85% of cases MMR proficient EMERGING: Botensilimab + Balstilimab showing breakthrough activity (ORR 24%, DCR 73% in refractory MSS mCRC). FDA breakthrough therapy designation. Phase 3 trials ongoing. Standar…

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 treatments

Botensilimab + Balstilimab (clinical trials)TAS-102 + BevacizumabFruquintinibRegorafenibStandard chemotherapy
Immunotherapy · Evidence: level 3 Botensilimab Phase 1/2SUNLIGHTFRESCO-2 See full page
Left-Sided Primary Prognosis favourable Targeted treatment 60% of cases Location Better prognosis. If RAS WT, strongly prefer anti-EGFR.

Better prognosis. If RAS WT, strongly prefer anti-EGFR.

Sidedness is independent prognostic factor.

Recommended treatments

If RAS WT: Anti-EGFRIf RAS MT: Bevacizumab
Tumour location · Evidence: level 1 CALGB 80405PARADIGM See full page
Right-Sided Primary Prognosis unfavourable Targeted treatment 40% of cases Location Higher BRAF, MSI-H. Worse prognosis. Check MSI always.

Higher BRAF, MSI-H. Worse prognosis. Check MSI always.

Different biology regardless of RAS status.

Recommended treatments

Intensive chemotherapyBevacizumab-based
Tumour location · Evidence: level 1 CALGB 80405 See full page
Acquired RAS (Post-Anti-EGFR) Prognosis intermediate Targeted treatment 30% of cases KRASNRAS RAS clones may decline after withdrawal. Rechallenge possible.

RAS clones may decline after withdrawal. Rechallenge possible.

Clonal evolution is reversible.

Recommended treatments

Chemo holiday from anti-EGFRLiquid biopsy monitoringAnti-EGFR rechallenge

Treatments to avoid

Continuing anti-EGFR
Resistance mechanisms · Evidence: level 2A CHRONOS trial See full page
RAS/BRAF Wild-Type (Left) Prognosis favourable Targeted treatment 25% of cases KRASNRASBRAF Best anti-EGFR candidates. PARADIGM showed superiority vs bevacizumab.

Best anti-EGFR candidates. PARADIGM showed superiority vs bevacizumab.

Left-sided + RAS WT = anti-EGFR preferred.

Recommended treatments

FOLFOX + PanitumumabFOLFIRI + Cetuximab
RAS pathway · Evidence: level 1 PARADIGMFIRE-3 See full page
RAS WT + BRAF WT + Left-sided Prognosis intermediate Targeted treatment 25% of cases RAS Wild-typeBRAF Wild-typeLeft-sided

Best candidates for anti-EGFR therapy. Left-sided tumors have superior outcomes with anti-EGFR.

Recommended treatments

FOLFOX/FOLFIRI + CetuximabFOLFOX/FOLFIRI + Panitumumab
General · Evidence: grade A See full page
ctDNA MRD Positive Prognosis unfavourable Targeted treatment 20% of cases ctDNA ctDNA MRD identifies high recurrence risk. DYNAMIC trial validated.

ctDNA MRD identifies high recurrence risk. DYNAMIC trial validated.

Transforming adjuvant decisions.

Recommended treatments

Adjuvant chemotherapyIntensive surveillance
Emerging targets · Evidence: level 2A DYNAMIC trial See full page
MSI-H / dMMR Prognosis favourable Targeted treatment 15% of cases MLH1MSH2MSH6PMS2 FIRST-LINE: Nivolumab + Ipilimumab (CheckMate-8HW, ORR 71%, 24mo PFS 72%) OR Pembrolizumab (KEYNOTE-177). CheckMate-8HW showed superiority over chemotherapy. Later lines: Nivoluma…

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 treatments

Nivolumab + Ipilimumab (first-line)Pembrolizumab (first-line)Dostarlimab

Treatments to avoid

5-FU monotherapy
Immunotherapy biomarkers · Evidence: level 1 CheckMate-8HWKEYNOTE-177 See full page
Young-Onset CRC (<50) Prognosis intermediate Targeted treatment 15% of cases Multiple Higher hereditary rate. Screen all for Lynch.

Higher hereditary rate. Screen all for Lynch.

All <50 should have genetic evaluation.

Recommended treatments

MSI/MMR testingGermline testingStandard treatment
Special situations · Evidence: level 2A Early-onset CRC literature See full page
RAS/BRAF Wild-Type (Right) Prognosis intermediate Targeted treatment 10% of cases KRASNRASBRAF Despite RAS WT, right-sided benefit less from anti-EGFR.

Despite RAS WT, right-sided benefit less from anti-EGFR.

Bevacizumab may be preferred first-line.

Recommended treatments

FOLFOX + BevacizumabFOLFOXIRI + Bevacizumab
RAS pathway · Evidence: level 2A CALGB 80405 See full page
BRAF V600E (MSS) Prognosis unfavourable Targeted treatment 8% of cases BRAF 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).

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 treatments

Encorafenib + Cetuximab + mFOLFOX6 (first-line)Encorafenib + Cetuximab (second-line)FOLFOXIRI + Bevacizumab

Treatments to avoid

Anti-EGFR monotherapy
BRAF pathway · Evidence: level 1 BREAKWATER (NEJM 2025)BEACON See full page
BRAF V600E + MSS Prognosis intermediate Targeted treatment 8% of cases BRAF V600EMSS FIRST-LINE: Encorafenib + Cetuximab + mFOLFOX6 (BREAKWATER, OS 30.3mo). SECOND-LINE+: Encorafenib + Cetuximab (BEACON). Note: MSS BRAF V600E has very poor prognosis without target…

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 treatments

Encorafenib + Cetuximab + mFOLFOX6 (first-line)Encorafenib + Cetuximab (second-line)

Treatments to avoid

Standard doublet chemotherapy aloneAnti-EGFR monotherapy
General · Evidence: grade A BREAKWATER (NEJM 2025)BEACON See full page
PIK3CA Exon 20 Prognosis intermediate Targeted treatment 7% of cases PIK3CA Strong aspirin benefit data. Regular aspirin improves survival.

Strong aspirin benefit data. Regular aspirin improves survival.

Discuss aspirin with patient if no contraindications.

Recommended treatments

Standard chemotherapyAspirinPI3K inhibitor trials
PIK3CA pathway · Evidence: level 2A Liao et al NEJM 2012 See full page
TMB-High (≥10 mut/Mb) Prognosis intermediate Targeted treatment 5% of cases Multiple FDA-approved tumor-agnostic biomarker for pembrolizumab.

FDA-approved tumor-agnostic biomarker for pembrolizumab.

Can occur in MSS tumors. Check NGS for TMB score.

Recommended treatments

Pembrolizumab
Immunotherapy biomarkers · Evidence: level 2A KEYNOTE-158 See full page

How to read this page

Prognosis
How the disease usually progresses with that combination compared with the average. It is a group trend, not a prediction for you.
With targeted treatment
There are approved or trial drugs that attack that specific alteration.
Share of cases
Roughly how many patients with metastatic colorectal cancer have that combination.
Evidence
How solid the data are: level 1 or grade A come from large trials; higher levels come from small or preliminary studies.

Educational information based on published studies. Your treatment is decided by your care team with all your data.