Researchers identified new targetable driver mutations in gastrointestinal stromal tumor (GIST) patients without KIT and PDGFRA mutations.
Zhang et al explained, “Clinical trials or targeted therapies are recommended for c-kit [KIT] and PDGFRA wild-type GIST patients who are unable to obtain multitarget protein tyrosine kinase inhibitors therapy.”
According to the study results presented at the European Society for Medical Oncology (ESMO) Congress 2021, the potentially targetable genes in wild-type patients were ERBB2 (9%), BRAF (4%), NRAS (4%), PIK3CA (4%), and EGFR (4%).
ERBB2 mutations included V842I and R190W. The 2 patients with ERBB2 mutations would benefit from enrollment in human epidermal growth factor receptor 2 (HER2)-targeted therapy clinical trials. BRAF and NRAS mutations included V600E and Q61K, respectively. These alterations can be targeted by v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and/or mitogen-activated protein kinase kinase (MEK) inhibitors.
Read more about GIST etiology
One patient had the activating PIK3CA mutation D549N. This alteration may be sensitive to the mechanistic target of rapamycin kinase (mTOR) inhibitors. Moreover, osimertinib (Tagrisso®), a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, could be used to target the EGFR T790M mutation.
The genes most frequently mutated in wild-type patients were TP53 (17%), NTRK1 (13%), TET2 (13%), APC (9%), CTNNB1 (9%), ERBB2 (9%), MED12 (9%), and SPEN (9%). In addition, Zhang et al identified 1 patient carrying an activating ZFYVE26-ALK fusion gene.
The calculated median tumor mutational burden (TMB) for 8 patients was 3.3 mutations per megabase. Of the 6 patients with data available, none presented with microsatellite instability (MSI).
The mutational screening (831-gene next-generation sequencing panel, Onco PanScan™, Genetron Health) was performed in a Chinese cohort of wild-type GIST patients (n=23). This approach allowed the researchers to evaluate somatic mutations and germline variants.
Zhang Y, Zhang X, Niu Y, Ma T. Genomic profiling of wild-type gastrointestinal stromal tumor (GIST) reveals targetable mutations in multiple signaling pathways. Poster presented at: European Society for Medical Oncology (ESMO) Congress 2021; September 16-21, 2021; Virtual.