HER2 amplification in metastatic colorectal cancer — IHC 3+ OR (IHC 2+ AND ISH amplified,...

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

ID	`RF-CRC-HER2-AMP-ACTIONABLE`
Type	Red flag
Status	reviewed 2026-04-30 \| pending_clinical_signoff
Diseases	`DIS-CRC`
Sources	`SRC-ESMO-COLON-2024` `SRC-MOUNTAINEER-STRICKLER-2022` `SRC-NCCN-COLON-2025`

Red Flag Origin

Definition	HER2 amplification in metastatic colorectal cancer — IHC 3+ OR (IHC 2+ AND ISH amplified, HER2/CEP17 ≥2.0). Present in ~3% of mCRC, enriched in left-sided RAS-WT tumors. Treatment-defining for RAS-WT subset: tucatinib + trastuzumab (MOUNTAINEER ORR 38%, mPFS 8.2 mo, mOS 24.1 mo; FDA Jan 2023) as 2L+/3L+ standard; T-DXd (DESTINY-CRC01) as alternative for IHC 3+ heavily pretreated. Excludes RAS-mutant (MOUNTAINEER eligibility) and MSI-H (pembrolizumab supersedes). Distinct from BIO-HER2-SOLID composite IHC marker: this red-flag is the actionability gate that fires for the CRC HER2-amp + RAS-WT subset specifically.
Clinical direction	intensify
Category	high-risk-biology
Shifts algorithm	ALGO-CRC-METASTATIC-2L

Trigger Logic

{
  "all_of": [
    {
      "any_of": [
        {
          "finding": "her2_status",
          "value": "amplified"
        },
        {
          "finding": "her2_status",
          "value": "positive"
        },
        {
          "finding": "her2_ihc",
          "value": "3+"
        },
        {
          "finding": "her2_ish",
          "value": "amplified"
        }
      ]
    },
    {
      "finding": "ras_status",
      "value": "wild_type"
    }
  ],
  "type": "biomarker"
}

Notes

Hierarchy in 2L mCRC: MSI-H (KEYNOTE-164) > BRAF V600E (BEACON) > KRAS G12C (CodeBreaK 300) > HER2-amp + RAS-WT (MOUNTAINEER / DESTINY-CRC01) > EGFRi rechallenge > FOLFIRI + bev. Captured in ALGO-CRC-METASTATIC-2L decision tree. UA access barrier: tucatinib not registered (named-patient pathway only); trastuzumab biosimilar available but NSZU does not fund CRC HER2-amp indication. T-DXd registered for breast / not CRC. RF informational; engine step 4 is free-text condition (not modified by this chunk).

Used By

Algorithms

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