KIT and PDGFRA Mutation Profiling in Resected Specimens and Plasma Samples from Patients with Gastrointestinal Stromal Tumours: A Review

Abstract

Gastrointestinal stromal tumour was the first solid tumour in which genotype dictated the choice and dose of drug, and it remains one of the few where the mutation determines almost everything. The unresolved question is whether plasma can substitute for tissue, and here the answer is less encouraging than in most other tumours. Objectives: To review the published evidence on KIT and PDGFRA mutation profiling in gastrointestinal stromal tumours: the distribution of primary mutations, what genotype predicts for each licensed agent, how secondary resistance mutations arise, and how far circulating tumour DNA can replace tissue for either purpose.
Material and Methods: Narrative review of mutation profiling series, prospective trials with prespecified genotype analyses, resistance studies and circulating tumour DNA cohorts indexed in PubMed and the major oncology and pathology journals. Studies were eligible if they reported mutation frequency in a defined population, outcomes stratified by genotype, mechanisms of acquired resistance, or the performance of plasma testing against tissue. No new patient data were generated; every frequency and effect estimate quoted is one published by the original investigators. Results: Among 127 patients with metastatic disease, activating KIT mutations were present in 88.2 per cent and PDGFRA mutations in 4.7 per cent. Genotype predicted imatinib benefit sharply: partial response was achieved by 83.5 per cent of patients with KIT exon 11 mutations, 47.8 per cent of those with exon 9 mutations and none of those without a detectable kinase mutation. The ordering reverses on sunitinib, where exon 9 disease showed higher response and longer median progression-free survival, 19.4 against 5.1 months, and longer overall survival, 26.9 against 12.3 months. PDGFRA D842V,
the single commonest PDGFRA variant, is resistant to imatinib but produced an 88 per cent overall response rate with avapritinib. In plasma, sequencing detected cell-free DNA mutations in only five of 18 patients, an overall sensitivity of 28.6 per cent, and only in advanced disease after imatinib failure. Conclusion: Tissue genotyping is not optional in this disease; it sets the drug and the dose from the outset. Plasma cannot replace it at diagnosis, because these tumours shed little circulating DNA and localised disease yields essentially none. Where plasma earns its place is after progression, when it detects the polyclonal secondary mutations that no single rebiopsy can capture. Abbreviations: GIST – Gastrointestinal Stromal Tumour, KIT – KIT Proto-Oncogene Receptor Tyrosine Kinase, PDGFRA – Platelet-Derived Growth Factor Receptor Alpha, TKI – Tyrosine Kinase Inhibitor, ctDNA – Circulating Tumour DNA, cfDNA – Cell-Free DNA, NGS – Next-Generation Sequencing, ddPCR – Droplet Digital Polymerase Chain Reaction, ORR – Overall Response Rate, PR – Partial Response, CR – Complete Response, PFS – Progression-Free Survival, OS – Overall Survival, AF – Allele Frequency.