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
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39 combinations

MSI-H + BRAF WT Prognosis intermediate Targeted treatment 5% of cases MSI-HBRAF Wild-type

Excellent prognosis with immunotherapy. BRAF wild-type MSI-H has best outcomes.

Recommended treatments

Pembrolizumab first-lineNivolumab + Ipilimumab
General · Evidence: grade A See full page
KRAS G12C Prognosis intermediate Targeted treatment 3,5% of cases KRAS First targetable KRAS! Sotorasib/adagrasib + anti-EGFR show ~30% ORR.

First targetable KRAS! Sotorasib/adagrasib + anti-EGFR show ~30% ORR.

Combinations extend benefit vs monotherapy.

Recommended treatments

Sotorasib + PanitumumabAdagrasib + CetuximabSotorasibAdagrasib

Treatments to avoid

Anti-EGFR monotherapy
RAS pathway · Evidence: level 1 CodeBreaK 100/101KRYSTAL-1 See full page
HER2 Amplified (RAS WT) Prognosis intermediate Targeted treatment 3% of cases HER2ERBB2 FDA APPROVED: Tucatinib + Trastuzumab (MOUNTAINEER, ORR 38%, OS 24.1mo, approved Jan 2023). Also: T-DXd 5.4mg/kg (DESTINY-CRC02), Trastuzumab + Pertuzumab (MyPathway). First-line:…

FDA APPROVED: Tucatinib + Trastuzumab (MOUNTAINEER, ORR 38%, OS 24.1mo, approved Jan 2023). Also: T-DXd 5.4mg/kg (DESTINY-CRC02), Trastuzumab + Pertuzumab (MyPathway). First-line: Zanidatamab + chemo showing 91% ORR in early data.

HER2+ RAS WT has multiple FDA-approved options. MOUNTAINEER: Tucatinib + Trastuzumab approved Jan 2023. Test all mCRC for HER2 (IHC, FISH if 2+). Best outcomes in IHC 3+. MOUNTAINEER-03 testing first-line combination.

Recommended treatments

Tucatinib + TrastuzumabTrastuzumab Deruxtecan 5.4 mg/kgTrastuzumab + PertuzumabZanidatamab + chemotherapy

Treatments to avoid

Anti-EGFR monotherapy
HER2 pathway · Evidence: level 1 MOUNTAINEERDESTINY-CRC02 See full page
Lynch Syndrome Prognosis favourable Targeted treatment 3% of cases MLH1MSH2MSH6PMS2EPCAM Hereditary. MSI-H tumors respond to immunotherapy. Family screening essential.

Hereditary. MSI-H tumors respond to immunotherapy. Family screening essential.

Screen all CRC <50 and all MSI-H.

Recommended treatments

ImmunotherapySurveillanceFamily counseling
Special situations · Evidence: level 1 NCCN Genetic See full page
HER2+ + RAS WT Prognosis intermediate Targeted treatment 3% of cases HER2RAS Wild-type Tucatinib + Trastuzumab (MOUNTAINEER, ORR 38%, OS 24.1mo, FDA approved Jan 2023). Trastuzumab Deruxtecan 5.4mg/kg (DESTINY-CRC02). Trastuzumab + Pertuzumab. Consider Zanidatamab c…

Tucatinib + Trastuzumab (MOUNTAINEER, ORR 38%, OS 24.1mo, FDA approved Jan 2023). Trastuzumab Deruxtecan 5.4mg/kg (DESTINY-CRC02). Trastuzumab + Pertuzumab. Consider Zanidatamab combinations in trials.

Updated 2024: Multiple anti-HER2 options now available. Consider chemotherapy first-line, then anti-HER2 at progression. MOUNTAINEER-03 may change to first-line anti-HER2. CNS metastases: tucatinib has brain penetration.

Recommended treatments

Tucatinib + TrastuzumabTrastuzumab Deruxtecan 5.4 mg/kgTrastuzumab + Pertuzumab
General · Evidence: grade B MOUNTAINEERDESTINY-CRC02 See full page
TMB-High + MSS Prognosis intermediate Targeted treatment 3% of cases TMB-HighMSS

TMB-H tumors may respond to immunotherapy even if MSS. Pembrolizumab has tumor-agnostic approval.

Recommended treatments

Pembrolizumab (FDA approved for TMB-H)Consider combination immunotherapy
General · Evidence: grade B See full page
MSI-H + BRAF V600E (Sporadic) Prognosis intermediate Targeted treatment 2,5% of cases BRAFMLH1 Better than BRAF V600E/MSS. Usually sporadic with MLH1 methylation.

Better than BRAF V600E/MSS. Usually sporadic with MLH1 methylation.

BRAF V600E + MLH1 methylation virtually excludes Lynch.

Recommended treatments

PembrolizumabNivolumab + IpilimumabEncorafenib + Cetuximab

Treatments to avoid

Anti-EGFR monotherapy
Immunotherapy biomarkers · Evidence: level 1 BEACON CRCCheckMate 142 See full page
EGFR S492R Prognosis intermediate Targeted treatment 2% of cases EGFR Blocks cetuximab but panitumumab still binds.

Blocks cetuximab but panitumumab still binds.

S492R = cetuximab-specific resistance.

Recommended treatments

Switch to Panitumumab

Treatments to avoid

Continue Cetuximab
Resistance mechanisms · Evidence: level 2B Montagut et al See full page
BRAF V600E + MSI-H Prognosis intermediate Targeted treatment 2% of cases BRAF V600EMSI-H

MSI-H status confers better prognosis even with BRAF mutation. Immunotherapy highly effective.

Recommended treatments

PembrolizumabNivolumab + Ipilimumab
General · Evidence: grade A See full page
MET Amplification + RAS WT Prognosis intermediate Targeted treatment 2% of cases MET AmplificationRAS Wild-type

May emerge as resistance mechanism to anti-EGFR therapy. MET inhibitors in development.

Recommended treatments

MET inhibitors (clinical trials)CapmatinibTepotinib
General · Evidence: grade C See full page
HER2+ IHC 3+ Prognosis intermediate Targeted treatment 2% of cases HER2 Best outcomes with anti-HER2 therapy. Options: Tucatinib + Trastuzumab (if RAS WT), Trastuzumab Deruxtecan (regardless of RAS), Trastuzumab + Pertuzumab, Zanidatamab combinations.…

Best outcomes with anti-HER2 therapy. Options: Tucatinib + Trastuzumab (if RAS WT), Trastuzumab Deruxtecan (regardless of RAS), Trastuzumab + Pertuzumab, Zanidatamab combinations. IHC 3+ patients have higher response rates across all anti-HER2 studies.

IHC 3+ represents ~2% of mCRC but has best responses to anti-HER2. DESTINY-CRC02 showed superior outcomes in IHC 3+ vs IHC 2+/FISH+. Test with validated HER2 IHC assay. Consider central confirmation for borderline cases. First-line data emerging (Zanidatamab 91% ORR).

Recommended treatments

Tucatinib + Trastuzumab (if RAS WT)Trastuzumab Deruxtecan 5.4 mg/kgTrastuzumab + PertuzumabZanidatamab + chemotherapy
HER2 pathway · Evidence: level 2 MOUNTAINEERDESTINY-CRC02MyPathway See full page
POLE/POLD1 Ultramutated Prognosis favourable Targeted treatment 1% of cases POLEPOLD1 Ultramutated (>100 mut/Mb). Exceptional immunotherapy responders.

Ultramutated (>100 mut/Mb). Exceptional immunotherapy responders.

Screen for germline POLE/POLD1 (PPAP syndrome).

Recommended treatments

PembrolizumabNivolumab
Immunotherapy biomarkers · Evidence: level 2B TCGACase series See full page
HER2 + KRAS Co-Mutation Prognosis intermediate Targeted treatment 0,5% of cases HER2KRAS UPDATED 2024: Trastuzumab Deruxtecan (T-DXd) 5.4 mg/kg - DESTINY-CRC02 showed efficacy regardless of RAS status. ORR 37.8% in RAS mutant patients. NOTE: Tucatinib + Trastuzumab (M…

UPDATED 2024: Trastuzumab Deruxtecan (T-DXd) 5.4 mg/kg - DESTINY-CRC02 showed efficacy regardless of RAS status. ORR 37.8% in RAS mutant patients. NOTE: Tucatinib + Trastuzumab (MOUNTAINEER) requires RAS wild-type and is NOT appropriate for this combination.

CRITICAL UPDATE 2024: DESTINY-CRC02 demonstrated T-DXd activity in HER2+ CRC regardless of RAS mutation status. This changes the treatment paradigm. Best results in IHC 3+ patients. Monitor for ILD (~10%).

Recommended treatments

Trastuzumab Deruxtecan (T-DXd) 5.4 mg/kgStandard chemotherapy + BevacizumabClinical trials
HER2 pathway · Evidence: level 2 DESTINY-CRC02 See full page
NTRK Fusion Prognosis favourable Targeted treatment 0,5% of cases NTRK1NTRK2NTRK3 Rare but dramatic responses >75% ORR. Tumor-agnostic approval.

Rare but dramatic responses >75% ORR. Tumor-agnostic approval.

More common in MSI-H tumors.

Recommended treatments

LarotrectinibEntrectinibRepotrectinib
Rare fusions · Evidence: level 1 NAVIGATESTARTRK-2 See full page
FAP/AFAP Prognosis intermediate Targeted treatment 0,5% of cases APC Hereditary polyposis. May need colectomy.

Hereditary polyposis. May need colectomy.

Extracolonic manifestations (desmoids, thyroid).

Recommended treatments

SurgeryCelecoxibFamily screening
Special situations · Evidence: level 1 NCCN Genetic 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.