Abstract 89P
Background
GIST is the most common mesenchymal tumor of the gastrointestinal tract. Clinical trials or targeted therapies are recommended for c-kit and PDGFRA wild-type GIST patients who are unable to obtain multi-target protein tyrosine kinase inhibitors therapy. Thus, the identification of targetable mutations will gain new insights into the etiology of c-kit and PDGFRA wild-type GIST.
Methods
We screened 295 Chinese GIST patients and identified 23 patients without c-kit and PDGFRA mutations as wild-type GIST. To characterize therapeutic targets in these 23 wild-type GIST patients, a 831-gene next-generation sequencing panel (Onco PanScan™, Genetron Health) was applied to assess somatic mutations and germline variants.
Results
The most frequently mutated genes in this wild-type GIST cohort were TP53 (17%), NTRK1 (13%), TET2 (13%), APC (9%), CTNNB1 (9%), ERBB2 (9%), MED12 (9%), and SPEN (9%). Potentially targetable alterations include ERBB2 (9%), BRAF (4%), NRAS (4%), PIK3CA (4%), and EGFR (4%). We found BRAF V600E and NRAS Q61K which can be targeted by BRAF and/or MEK inhibitors. ERBB2 driver mutations were seen in 2 (9%) patients including V842I and R190W. These two patients were good candidates for HER2-targeted therapy clinical trials. We also observed one activating PIK3CA mutations (D549N) which may be sensitive to mTOR inhibitors and one targetable gene mutation of EGFR T790M which can be targeted by the third-generation EGFR-TKI osimertinib. One patient carried an activating ZFYVE26-ALK fusion gene. Of note, this is the first report of ALK fusion event detected in the GIST patients. Among six patients with available MSI status, none of them showed microsatellite instability. The median TMB of eight patients was 3.3 mutations/Mb. Lastly, we observed four deleterious germline mutations, two for PTCH2, one each for SDHA and SDHB. Overall, at least 18 (78%) patients harbored actionable genetic mutations.
Conclusions
The mutational landscape of our wild-type GIST cohort provided evidence that many driver mutations in these pathways are targetable. Our findings indicated that wild-type GIST patients should be tested for alternative driver mutations and receive the corresponding targeted therapies.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.