What is the role of the PDGFRA (Platelet-Derived Growth Factor Receptor Alpha) gene in disease and its treatment?

Role of PDGFRA Gene in Disease and Treatment

The PDGFRA (Platelet-Derived Growth Factor Receptor Alpha) gene plays a critical role in gastrointestinal stromal tumors (GISTs) and other neoplastic disorders, with mutations in this gene significantly impacting treatment response and patient survival.

PDGFRA in Gastrointestinal Stromal Tumors (GISTs)

Molecular Characteristics

• PDGFRA mutations occur in approximately 5-10% of GISTs 1
• Most GISTs (80%) have KIT mutations, while 10-15% have no detectable KIT or PDGFRA mutations (wild-type GISTs) 1
• PDGFRA mutations result in constitutive tyrosine kinase activity, similar to KIT mutations 1
• PDGFRA-mutant GISTs typically have:
  • Gastric location (predominantly) 1
  • Epithelioid morphology 1
  • More indolent clinical behavior compared to KIT-mutated GISTs 1

Diagnostic Approach

• Immunohistochemistry shows that PDGFRA-mutant GISTs are often positive for:
  • PDGFRA (94.4% sensitivity, 81.0% specificity) 2
  • CD117/KIT (95% of all GISTs) 1
  • DOG1 (80% of all GISTs) 1
• Molecular genetic testing is essential for confirming PDGFRA mutations 1
• PDGFRA immunohistochemistry can be used to triage epithelioid GISTs for PDGFRA sequencing 2

Clinical Significance of PDGFRA Mutations

Treatment Response

• Most PDGFRA mutations are associated with response to imatinib, with the notable exception of D842V mutation which confers resistance to imatinib, sunitinib, and regorafenib 1
• Patients with D842V mutation show:
  • No response in 100% of cases in clinical studies
  • Disease progression in 68% of cases
  • Median progression-free survival of only 2.8 months (vs. 28.5 months for other PDGFRA mutations)
  • Median overall survival of 14.7 months (vs. not reached for other PDGFRA mutations) 1

Treatment Options Based on Mutation Status

1. For most PDGFRA mutations (except D842V):

   • Imatinib is first-line therapy 1, 3
   • Sunitinib for imatinib-resistant tumors 1
   • Regorafenib for progression after imatinib and sunitinib 1

2. For PDGFRA D842V mutation:

   • Dasatinib has shown activity 1
   • Avapritinib is FDA-approved specifically for D842V-mutant GISTs 4
   • Ripretinib and crenolanib have also shown efficacy 4

PDGFRA in Other Diseases

PDGFRA mutations/alterations are implicated in several other conditions:

• Inflammatory fibroid polyps (55-70% have PDGFRA mutations) 2
• Myeloid neoplasms with hypereosinophilia 3, 5
• Gliomas 5, 6
• Some cases of acute myeloid leukemia 6

Clinical Management Algorithm

1. Diagnosis:

   • Perform immunohistochemistry for CD117, DOG1, and PDGFRA
   • Conduct molecular genetic testing for KIT and PDGFRA mutations
   • If both are negative, consider additional testing for SDH deficiency, BRAF, and other mutations 1

2. Risk Stratification:

   • Assess tumor size, mitotic rate, and anatomic location 1
   • Consider PDGFRA mutation type (D842V vs. others) 1

3. Treatment Selection:

   • For resectable disease: Complete surgical resection
   • For unresectable/metastatic disease with PDGFRA mutations:
     • Non-D842V mutations: Imatinib 400mg daily 1, 3
     • D842V mutation: Avapritinib or clinical trial with newer agents 4
   • For disease progression: Switch to sunitinib, then regorafenib 1

Important Clinical Considerations

• Pitfall to avoid: Treating all GIST patients with imatinib without genetic testing. The D842V mutation in PDGFRA is inherently resistant to imatinib and requires alternative therapy 1
• Critical caveat: Some PDGFRA mutations in other cancers may be passenger mutations without functional significance 6
• Emerging concept: PDGFRA immunohistochemistry can help identify potential PDGFRA-mutant GISTs, but molecular confirmation is essential for treatment decisions 2

Genetic testing for PDGFRA mutations should be standard practice in all GISTs (except perhaps <2cm non-rectal GISTs) to guide appropriate therapy selection and predict treatment response 1.