Acquired resistance to dabrafenib + trametinib in BRAF-mutant ATC (secondary BRAF / MEK /...

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

ID	`RF-THYROID-ANAPLASTIC-TRANSFORMATION-PROGRESSION`
Type	Red flag
Status	reviewed 2026-04-27 \| pending_clinical_signoff
Diseases	`DIS-THYROID-ANAPLASTIC`
Sources	`SRC-ATA-THYROID-2015` `SRC-NCCN-THYROID-2025`

Red Flag Origin

Definition	Acquired resistance to dabrafenib + trametinib in BRAF-mutant ATC (secondary BRAF / MEK / RAS / MAPK reactivation, NRAS or KRAS mutations, BRAF amplification), rapid local progression on cytotoxic CRT, new distant metastases (lung, bone, brain), or transformation from differentiated thyroid cancer (DTC) into ATC component (dedifferentiation event) — triggers re-staging, re-biopsy, salvage immunotherapy (pembrolizumab or pembrolizumab + lenvatinib) or trial enrollment.
Clinical direction	hold
Category	transformation-progression

Trigger Logic

{
  "any_of": [
    {
      "finding": "braf_mek_resistance_mutation",
      "value": true
    },
    {
      "finding": "rapid_progression_on_crt",
      "value": true
    },
    {
      "finding": "new_metastatic_disease",
      "value": true
    },
    {
      "finding": "dtc_to_atc_dedifferentiation",
      "value": true
    }
  ],
  "type": "composite_clinical"
}

Notes

Most BRAF+ ATC will progress on dabrafenib + trametinib within 6-12 months due to MAPK pathway reactivation (acquired NRAS / KRAS, BRAF amplification, MEK1 mutation). Salvage options: pembrolizumab monotherapy (KEYNOTE-158 ATC cohort ORR ~16%, durable in responders), pembrolizumab + lenvatinib (ATLAS investigational), or salvage cytotoxic (cisplatin-paclitaxel). DTC→ATC dedifferentiation: ~5-15% of long- standing PTC develops anaplastic transformation — re-biopsy any new rapidly enlarging mass in DTC patient. Brain metastases: stereotactic RT + dabrafenib (CNS-penetrant). Priority 30 reflects critical-tier override given disease tempo.

Used By

No reverse references found in the YAML corpus.