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PDGFRA in Gastrointestinal Stromal Tumours (GIST): ESMO Biomarker Factsheet

ESMO Factsheets on Biomarkers


The PDGFRA gene encodes the platelet-derived growth factor receptor alpha, a member of the type III tyrosine kinase receptor family, which also includes the stem cell factor receptor, KIT[1]PDGFRA and KIT map to the same genomic loci, 4q12, and their protein structures are highly homologous, composed of several domains that each have a specific role in the process of tyrosine kinase activation [1, 2]. Several platelet-derived growth factor (PDGF) isoforms can bind and activate PDGFRA[2, 3]. Activated PDGFRA initialises similar downstream pathways as activated KIT, including the JAK–STAT3, phosphatidylinositide-3- kinase (PI3K)–AKT–mTOR, and RAS–MAPK pathways, important in regulating critical cellular functions such as proliferation and apoptosis[1, 2].

Gastrointestinal stromal tumours (GISTs) are the most common type of mesenchymal tumours of the digestive tract, the majority of which (82-87%) are characterised by the presence of mutually exclusive gain-of-function mutations in PDGFRA and KIT [1, 4-6]. After KITPDGFRA is the second most commonly mutated oncogene in GISTs[2]. Gain-of-function mutations lead to constitutive, ligand independent activation of PDGFRA and its downstream pathways, ultimately increasing cell proliferation and inhibiting apoptosis[1]. The discovery of activating mutations in the KIT and PDGFRA tyrosine kinase receptors and their role in the pathogenesis of GIST has revolutionised understanding of the biology and therapy of this disease[1].

PDGFRA mutations in GIST

PDGFRA mutation frequency is variable, ranging from <2% to 14% of GISTs, likely reflecting the low representation of PDGFRA-mutated GISTs in clinical trials due to their largely benign clinical behaviour[1, 7-14]PDGFRA-mutated GISTs are mostly of gastric origin and display epithelioid morphology or mixed epithelioid and spindle histology[10, 13-16]. Mutations (deletions, point mutations, duplications, insertions, and complex mutations) are found in exons coding for the functional domains of PDGFRA[17].

Primary PDGFRA mutations are found mainly in exons 12 and 18 and more rarely in exon 14[18]. PDGFRA mutations affecting exon 18 (the second kinase domain, corresponding to exon 17 of KIT) have been identified in approximately 6% of GISTs and are believed to aberrantly stabilise the kinase activation loop[2, 19]. The most frequent mutation results in an exon 18 D842V substitution, detected in up to 75% of all PDGFRA-mutated tumours[1, 7-11, 13-15]. Mutations affecting exon 12 (the juxtamembrane domain) are the second most common form of PDGFRA mutation, identified in approximately 1–2% of GISTs[2, 3, 20]. The PDGFRA juxtamembrane domain, is believed to mediate an autoinhibitory function and mutation in this inhibitory domain induces hyperactivation[2, 19]. Mutations in exon 14 are rare (<0.1% of GISTs), and frequently cluster at codon 659[2, 18, 21]. The function of exon 14 is less well studied but being close to exon 12 it may contribute to the autoinhibitory function of the juxtamembrane domain[2]. Secondary PDGFRA mutations have been identified in exon 18, generally accompanied by a primary mutation in same gene[17].

PDGFRA mutations as a diagnostic biomarker in GIST

KIT (CD117) expression is detected immunohistochemically in >95% of GISTS, making it a key diagnostic marker, together with anoctamin1 (DOG1)[18]. Approximately 5% of patients with GIST do not express KIT but may harbour KIT or PDGFRA mutations[1, 15, 18, 22].  Mutational analysis of GIST-mutated genes such as PDGFRA is paramount for selection of appropriate therapy for GIST (see below) but may also help confirm the diagnosis of suspect GIST that do not exhibit positive immunoreactivity for CD117/DOG1[23].

PDGFRA mutations as a prognostic biomarker in GIST

PDGFRA-mutated GISTs tend to follow a more indolent clinical course and are almost exclusively (90–93%) of prognostically favourable gastric origin[1, 10-12, 16]. A multivariate analysis of the Polish Clinical GIST registry that included 427 tumours found PDGFRA mutations in 12.9% of the cases and that mutations were associated with a 70% lower risk of 5-year relapse (hazard ratio = 0.298, 95% confidence interval 0.147– 0.602; P = 0.001) than patients with KIT deletions involving codons 557/558[10]. In the ConticaGIST study of 1,056 treatment-naïve patients with localised GIST who underwent surgery with curative intention, PDGFRA exon 18 mutation status correlated with a favourable disease outcome (median disease-free survival [DFS] not reached; 5-year DFS, 75%) in comparison with other mutations. There was no significant difference in DFS of PDGFRA D842V versus other exon 18 mutations; however, among gastric PDGFRA mutations, the vast majority that progressed (11 of 14) carried the exon 18 D842V substitution[11]

PDGFRA mutations as a predictive biomarker in GIST

Tyrosine kinase inhibitor therapy has improved survival in patients with GIST, increasing the life expectancy from about 1 year to 5 years in the advanced setting[24] . However, GISTs are composed of many different molecular subtypes, and response to tyrosine kinase therapy correlates with the underlying kinase genotype of the tumour[1, 4]. Routine genotyping has therefore become an integral part of management of GISTs undergoing tyrosine kinase inhibitor therapy[1]

The tyrosine kinase inhibitor, imatinib (Glivec®, Novartis Pharmaceuticals), was licensed >15 years ago for the treatment of adult patients with KIT (CD 117) positive unresectable and/or metastatic malignant GIST, and for the adjuvant treatment of adult patients who are at significant risk of relapse following resection of KIT (CD117)-positive GIST[25-27].  Imatinib has demonstrated pronounced clinical efficacy in GISTs, however, approximately 10–15% of patients show primary resistance with early progression within 3–6 months of initiating therapy and 40-50% of patients with advanced GIST subsequently develop secondary resistance with a mean time to progression of about 24 months[1, 28]. Imatinib can only bind to the inactive conformation of tyrosine kinase receptors and both primary and secondary resistance to imatinib can be partially explained by mutations that cause a conformational shift in the kinase domain that favours the activated state[1, 28, 29]. The most common mutation in PDGFRA, the exon 18 D842V substitution, results in a distortion of the kinase activation loop, thus strongly tilting the protein conformation in favour of the activated structure and is generally believed to lead to primary imatinib resistance[1, 4-6, 9, 14]. Patients with PDGFRA D842V‑mutant GIST have low response rates and short progression-free and overall survival during imatinib treatment[4, 30-33]. In vitro and clinical studies suggest that PDGFRA exon 18 mutations not involving D842 and exon 12 mutations are generally sensitive to imatinib treatment[5, 6, 14, 33]. In patients with the D842V mutation, adjuvant therapy with imatinib is not recommended and mutational testing is highly relevant to avoid overtreatment of GISTs with imatinib in this setting[1]

A second tyrosine kinase inhibitor, sunitinib (Sutent®, Pfizer), is licensed for use in imatinib-resistant GIST[34, 35], however preclinical studies of imatinib-resistant GIST cell lines evaluating sunitinib sensitivity PDGFRA D842V (activation loop) mutants remained resistant[1, 36]. Clinical data are as yet too limited to investigate the effects of PDGFRA mutations on efficacy outcomes following sunitinib treatment[1, 33, 37].

Regorafenib (Stivarga®, Bayer), is indicated as a third-line tyrosine kinase inhibitor for patients with unresectable or metastatic GIST who progressed on or are intolerant to prior treatment with imatinib and sunitinib[38, 39]. While the predictive power of mutational status for this agent is not yet known, it has demonstrated efficacy in one case of GIST with a PDGFRA D842A mutation[40].

An ongoing phase I study (NCT2508532) in advanced GIST is assessing the safety and clinical activity of a novel agent, BLU-285, a potent, highly selective oral inhibitor that targets PDGFRA D842V and KIT exon 17 mutants[41]. Adult patients with unresectable GISTs who had received two or more kinase inhibitors previously were given BLU-285 once daily[2]. The treatment was well tolerated and among 17 patients with tumours harbouring PDGFRA D842V mutations, seven had a PR while ten had stable disease, suggesting that precision-targeted therapy with BLU-285 is associated with significant activity against tumours previously resistant to other GIST therapies[2].

PDGFRA mutation analysis in GIST

Mutation analysis should be performed using an appropriate, validated, technique, and performed by specifically trained personnel and results should always specify the type of analysis performed, the region or mutations evaluated, and the sensitivity of the detection method used[18].  

The most widely used method for detecting PDGFRA mutations is amplification of the exons of interest by polymerase chain reaction (PCR) followed by direct sequencing (Sanger method) of amplification products. Due to limitations in the sensitivity of this technique it is essential that the methodology is appropriately optimised and controlled and performed only on samples containing ≥50% tumour cells[18]. Next-generation sequencing can provide greater sensitivity with several GIST-specific gene panels are now commercially available[18].

Patient selection

Given its diagnostic, prognostic and predictive value, mutational analysis of PDGFRA should be included in the diagnostic work-up of all GISTs as standard practice for optimal management[23].


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Last update: 06 Jul 2018

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