Germline BRCA1 or BRCA2 pathogenic variant in HER2-negative breast cancer (HR+ or TNBC)....

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

ID	`RF-BREAST-BRCA-GERMLINE-ACTIONABLE`
Type	Red flag
Status	reviewed 2026-04-27 \| pending_clinical_signoff
Diseases	`DIS-BREAST`
Sources	`SRC-EMBRACA-LITTON-2018` `SRC-ESMO-BREAST-METASTATIC-2024` `SRC-NCCN-BREAST-2025` `SRC-OLYMPIAD-ROBSON-2017`

Red Flag Origin

Definition	Germline BRCA1 or BRCA2 pathogenic variant in HER2-negative breast cancer (HR+ or TNBC). Olaparib (OlympiAD — mPFS 7.0 vs 4.2 mo vs chemo) and talazoparib (EMBRACA — mPFS 8.6 vs 5.6 mo) are FDA-approved for metastatic gBRCA HER2-negative breast. Adjuvant olaparib (OlympiA) for high-risk HER2-negative gBRCA early breast.
Clinical direction	intensify
Category	high-risk-biology
Shifts algorithm	ALGO-BREAST-HR-POS-2L, ALGO-BREAST-TNBC-2L

Trigger Logic

{
  "any_of": [
    {
      "finding": "brca1_germline",
      "value": "pathogenic"
    },
    {
      "finding": "brca2_germline",
      "value": "pathogenic"
    },
    {
      "finding": "brca1_brca2_germline",
      "value": "positive"
    },
    {
      "finding": "brca1_brca2_pathogenic",
      "value": true
    },
    {
      "finding": "germline_brca_status",
      "value": "pathogenic"
    }
  ],
  "type": "biomarker"
}

Notes

Germline-only — somatic BRCA1/2 in breast lacks the same prospective RCT evidence (use HRD assay where pathway-altered status sought). Genetic counseling mandatory (cascade testing of first-degree relatives; risk-reducing salpingo-oophorectomy). PALB2 has analogous HRR-deficient biology — emerging data support PARPi but off-label. Toxicity: cytopenias (~grade 3 anemia 16-25%), MDS / AML <1.5% long-term. Test before starting any PARPi candidate (chemotherapy de-escalation argument: avoid platinum-based sensitizing regimens if PARPi readily available).

Used By

Algorithms

ALGO-BREAST-HR-POS-2L - ALGO-BREAST-HR-POS-2L
ALGO-BREAST-TNBC-2L - ALGO-BREAST-TNBC-2L

Red flag

RF-PAN-PALB2-PARPI-CANDIDATE - Germline PALB2 pathogenic variant — BRCA2's recruitment partner; biallelic LOF produces a...