Dr Kelly on the Treatment and Heterogeneity of GIST

Ciara Kelly, MBBCh, BAO, interim clinical director, Sarcoma Oncology Service, Memorial Sloan Kettering Cancer Center (MSKCC), discusses how the heterogeneity of gastrointestinal stromal tumors (GIST) affects treatment decisions and highlights the importance of testing for genetic abnormalities in this patient population.

GIST is defined at the molecular level, with individual subtypes identified based on primary oncogenic alterations in each patient, Kelly begins. Most patients exhibit KIT alterations, which generally respond well to imatinib (Gleevec), she explains. Other patients have PDGFRA alterations, and rarer subtypes of GIST include SDH-deficient GIST, BRAF-mutant GIST, NF1-associated GIST, and fusion-driven GIST, Kelly notes.

The primary oncogenic alteration in a patient’s tumor can predict the potential effectiveness of treatments such as imatinib, she continues. Patients with KIT-mutated metastatic GIST often develop secondary resistance alterations after exposure to TKIs, Kelly states. Research indicates that there is heterogeneity both between different metastatic sites and within a single metastatic site of GIST, she elucidates.

Regarding patients with GIST harboring genetic abnormalities, Kelly says that ideally, tumors would be sequenced at baseline, upon recurrence, and serially during the progression of metastatic disease treated with TKIs. She goes on to add that in her own practice, she sequences GIST tumors at baseline to determine their molecular subtypes, then again at recurrence. At selected points, Kelly notes that she considers sequencing if its results may influence treatment decisions.

The standard method for molecularly characterizing GIST is tumor tissue sequencing, which has advanced significantly over the years, Kelly reports. At MSKCC, she says that treatment providers use a next-generation sequencing platform, Kelly explains. Circulating tumor DNA (ctDNA) is also becoming popular for identifying gene mutations by analyzing extracellular DNA from tumor cells, which reveals specific mutations, she says. ctDNA sequencing technology is FDA-approved as a companion diagnostic in other cancers and is increasingly used in GIST, according to Kelly. Many GIST trials now incorporate ctDNA technology, providing valuable insights into its utility in this disease, Kelly concludes.