Metastatic colorectal cancer with KRAS or NRAS hotspot mutation (KRAS exon 2 codons 12/13...

Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.

ID	`RF-CRC-RAS-MUTANT`
Type	Red flag
Status	reviewed 2026-04-27 \| pending_clinical_signoff
Diseases	`DIS-CRC`
Sources	`SRC-ESMO-COLON-2024` `SRC-NCCN-COLON-2025`

Red Flag Origin

Definition	Metastatic colorectal cancer with KRAS or NRAS hotspot mutation (KRAS exon 2 codons 12/13 — most common ~40% of mCRC, exon 3 codons 59/61, exon 4 codons 117/146; NRAS exon 2/3/4 ~5%). RAS-mutant mCRC is REFRACTORY to anti-EGFR monoclonal antibodies (cetuximab, panitumumab) — PRIME post-hoc analysis (Douillard JCO 2013) showed OS detriment with panitumumab + FOLFOX in RAS-mutant patients (mOS 15.5 vs 19.3 mo). Routes 1L mCRC to bevacizumab + FOLFOX/FOLFIRI/FOLFOXIRI; KRAS-G12C subset (~3% of mCRC) eligible for sotorasib + panitumumab 2L+ (CodeBreaK-300, Fakih NEJM 2023). MSI-H or BRAF-V600E status takes priority over RAS for routing.
Clinical direction	de-escalate
Category	high-risk-biology

Trigger Logic

{
  "any_of": [
    {
      "finding": "kras_mutation",
      "value": true
    },
    {
      "finding": "kras_status",
      "value": "mutated"
    },
    {
      "finding": "nras_mutation",
      "value": true
    },
    {
      "finding": "nras_status",
      "value": "mutated"
    },
    {
      "finding": "ras_status",
      "value": "mutated"
    },
    {
      "finding": "extended_ras_status",
      "value": "mutated"
    },
    {
      "finding": "BIO-RAS-MUTATION",
      "value": "positive"
    }
  ],
  "type": "biomarker"
}

Notes

De-escalate direction reflects "anti-EGFR is REMOVED from the option set" — chemo backbone (FOLFOX/FOLFIRI/FOLFOXIRI) + bevacizumab is the routing target. MSI-H + RAS-mut combination (~3% of mCRC) — pembrolizumab still preferred 1L (RF-CRC-MSI-H-ACTIONABILITY priority 50). BRAF V600E + RAS-mut is essentially exclusive (mutual exclusivity ~99%) but if both present, BRAF routing (encorafenib + cetuximab BEACON) takes precedence. KRAS-G12C subset: sotorasib + panitumumab (CodeBreaK-300) 2L mPFS 5.6 vs 2.0 mo, FDA-approved 2024 — counterintuitive that panitumumab adds benefit despite KRAS-mut, mechanism is suppression of adaptive EGFR feedback when KRAS is locked by sotorasib. Adagrasib + cetuximab (KRYSTAL-1, Yaeger NEJM 2023) — similar rationale, FDA- approved 2L+. KRAS-G12D and KRAS-G12V subsets: investigational (MRTX1133, RMC-9805). Detection: NGS panel covers extended-RAS in one test; reflex testing at diagnosis of mCRC mandatory before any anti-EGFR consideration. Liquid-biopsy at progression for clonal evolution if anti-EGFR rechallenge considered (CHRONOS pathway).

Used By

Algorithms

ALGO-CRC-METASTATIC-1L - ALGO-CRC-METASTATIC-1L