HER2 amplification / overexpression in breast cancer (IHC 3+ OR IHC 2+ with ISH amplified...

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

ID	`RF-BREAST-HER2-AMP-ACTIONABLE`
Type	Red flag
Status	reviewed 2026-04-27 \| pending_clinical_signoff
Diseases	`DIS-BREAST`
Sources	`SRC-DESTINY-BREAST03-CORTES-2022` `SRC-ESMO-BREAST-METASTATIC-2024` `SRC-HER2CLIMB-MURTHY-2019` `SRC-NCCN-BREAST-2025`

Red Flag Origin

Definition	HER2 amplification / overexpression in breast cancer (IHC 3+ OR IHC 2+ with ISH amplified) — ~15-20% of invasive breast. Defines HER2-positive treatment track: trastuzumab + pertuzumab + chemo (CLEOPATRA 1L), T-DXd 2L (DESTINY-Breast03 — mPFS 28.8 vs 6.8 mo vs T-DM1).
Clinical direction	intensify
Category	high-risk-biology
Shifts algorithm	ALGO-BREAST-1L, ALGO-BREAST-HER2-POS-2L

Trigger Logic

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

Notes

Scoring: 2018 ASCO/CAP guideline. IHC 2+ → reflex ISH; HER2/CEP17 ≥2.0 OR average HER2 signals ≥6 = amplified. Brain metastases — tucatinib + trastuzumab + capecitabine (HER2CLIMB) preferred. T-DXd ILD risk ~10-15% — baseline + serial chest CT. Cardiomyopathy on trastuzumab — q3-monthly LVEF (early-stage) or q6-monthly (metastatic on extended therapy).

Used By

Algorithms

ALGO-BREAST-1L - ALGO-BREAST-1L
ALGO-BREAST-HER2-POS-2L - ALGO-BREAST-HER2-POS-2L

Red flag

RF-BREAST-TNBC - Triple-negative breast cancer (TNBC): estrogen receptor (ER) <1% nuclear staining on IHC...