Mutation-driven treatment pathways in GIST.
| Gene/Mutation | Frequency | Site/Histology | Sensitivity to TKIs | Recommended Therapy | Resistance mechanism/testing workflow |
|---|---|---|---|---|---|
| KIT exon 11 | ~60–70% | Stomach; spindle cell | Sensitive to imatinib 400 mg | Imatinib 400 mg daily | N/A |
| KIT exon 9 | ~10–20% | Small intestine; aggressive | Partially resistant to imatinib 400 mg; better with 800 mg | Imatinib 800 mg daily | Duplication at codons 502–503 |
| KIT secondary mutations (exon 13, 14, 17, 18) | Acquired | Various (post-imatinib) | Resistant to imatinib/sunitinib; variable by exon | Sunitinib → regorafenib → ripretinib | Secondary resistance via ATP-binding/activation loop |
| PDGFRA exon 18 (D842V) | ~5–8% | Gastric; epithelioid | Resistant to imatinib/sunitinib; sensitive to avapritinib | Avapritinib | D842V-specific resistance; test by NGS or PCR |
| PDGFRA non-D842V | < 2% | Gastric; variable | Sensitive to imatinib | Imatinib 400 mg | Includes exon 12/14; test by sequencing |
| SDH-deficient (SDHx mutation or methylation) | ~5–7% | Gastric; multifocal; pediatric | Limited benefit from Imatinib; evidence evolving | Clinical trial; regorafenib in selected cases | SDHB IHC loss → methylation analysis |
| NF1-associated | Rare | Duodenum; small bowel | Limited benefit from Imatinib | Clinical trial; individualized management | NF1 testing; usually lacks KIT/PDGFRA mutation |
| BRAF V600E | Very rare | Variable | Imatinib-resistant | BRAF/MEK inhibitors (off-label) | Test BRAF V600E via NGS |
| NTRK fusion | Very rare | Pediatric/SDH-wild-type | Sensitive to TRK inhibitors | Larotrectinib/Entrectinib | Test via IHC screening; confirm by fusion assay/NGS |
| FGFR fusion | Very rare | Variable | Potential target; evidence evolving | Clinical trial; FGFR inhibitor in selected cases | RNA fusion confirmation; broad NGS panel |
| Triple-negative/Wild-type | Rare | Variable; requires full profiling | Heterogeneous; profile-driven | Comprehensive profiling; clinical trial | Full NGS with CNV, fusion, and methylation panels |
ATP: adenosine triphosphate; BRAF: B-Raf proto-oncogene; CNV: copy number variation; FGFR: fibroblast growth factor receptor; GIST: gastrointestinal stromal tumour; IHC: immunohistochemistry; KIT: KIT proto-oncogene receptor tyrosine kinase; MEK: mitogen-activated protein kinase kinase; N/A: not applicable; NF1: neurofibromin 1; NGS: next-generation sequencing; NTRK: neurotrophic tyrosine receptor kinase; PCR: polymerase chain reaction; PDGFRA: platelet-derived growth factor receptor alpha; SDH: succinate dehydrogenase; SDHB: succinate dehydrogenase subunit B; SDHx: succinate dehydrogenase complex subunit genes; TKI: tyrosine kinase inhibitor; TRK: tropomyosin receptor kinase.