Metastatic colorectal cancer with RAS wild-type status: KRAS exon 2 (codons 12, 13), exon...

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

ID	`RF-CRC-RAS-WT`
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 RAS wild-type status: KRAS exon 2 (codons 12, 13), exon 3 (codons 59, 61), exon 4 (codons 117, 146) AND NRAS exon 2/3/4 ALL wild-type by NGS or extended-RAS PCR. Defines the ~50% of mCRC eligible for anti-EGFR monoclonal antibody therapy (cetuximab, panitumumab) when combined with chemotherapy backbone. Left-sided RAS-WT mCRC particularly benefits from 1L anti-EGFR + FOLFOX/ FOLFIRI (CALGB/SWOG-80405, FIRE-3, PRIME, CRYSTAL — survival benefit driven by left-sided primaries; right-sided RAS-WT does NOT benefit and routes to bevacizumab + chemo).
Clinical direction	intensify
Category	high-risk-biology

Trigger Logic

{
  "all_of": [
    {
      "any_of": [
        {
          "finding": "kras_status",
          "value": "wild_type"
        },
        {
          "finding": "kras_mutation",
          "value": false
        },
        {
          "finding": "kras_extended_status",
          "value": "wild_type"
        }
      ]
    },
    {
      "any_of": [
        {
          "finding": "nras_status",
          "value": "wild_type"
        },
        {
          "finding": "nras_mutation",
          "value": false
        }
      ]
    },
    {
      "any_of": [
        {
          "finding": "ras_status",
          "value": "wild_type"
        },
        {
          "finding": "extended_ras_status",
          "value": "wild_type"
        }
      ]
    }
  ],
  "type": "biomarker"
}

Notes

Sidedness modifier: left-sided primary (splenic flexure to rectum) + RAS-WT — anti-EGFR + chemo strongly preferred (mOS ~38 mo with cetux+ FOLFOX vs ~33 mo with bev+FOLFOX, FIRE-3 left-sided). Right-sided primary (cecum to transverse) + RAS-WT — bev + chemo preferred (anti- EGFR no benefit or harm in right-sided despite RAS-WT). MSI-H still takes priority (RF-CRC-MSI-H-ACTIONABILITY) — pembrolizumab 1L regardless of RAS status. BRAF V600E mutation (RF-CRC-BRAF-V600E) is a DIFFERENT axis — even RAS-WT BRAF-V600E does NOT respond to anti-EGFR alone; routes to encorafenib + cetuximab (BEACON-CRC). HER2 amplification (~3% RAS-WT) — trastuzumab + tucatinib or T-DXd second-line option (MOUNTAINEER, DESTINY-CRC01). Left-sided + RAS-WT + BRAF-WT + HER2-WT + MSS = canonical anti-EGFR target population (~30% of mCRC). Resistance evolution: ctDNA monitoring at progression for emerging RAS or EGFR-ECD (S492R) mutations — anti-EGFR rechallenge after a TKI-free interval (CHRONOS, Sartore-Bianchi 2022) is feasible if ctDNA shows RAS-WT clonal reset.

Used By

Algorithms

ALGO-CRC-METASTATIC-1L - ALGO-CRC-METASTATIC-1L
ALGO-CRC-METASTATIC-2L - ALGO-CRC-METASTATIC-2L