Researchers sought to identify targetable mutations for c-KIT and PDGFRA wild-type mutations in patients with gastrointestinal stromal tumors (GIST) to gain an improved understanding of the etiology of these driver mutations and shared their findings at the virtual 2021 ESMO Congress.

“Typically, 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,” explained Yanqiao Zhang, MD, Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, China, and co-investigators.

295 patients with GIST were screened to observe that 23 did not have c-KIT nor PDGFRA wild-type mutations. Further investigation was required to characterize therapeutic targets via a 831-gene next-generation sequencing panel (Onco PanScan™) to assess somatic mutations and germline variants.

Findings confirmed the most frequently mutated genes within the wild-type GIST cohort were TP53 (17%), NTRK1 (13%), TET2 (13%), APC (9%), CTNNB1 (9%), ERBB2 (9%), MED12 (9%), and SPEN (9%). Additionally, potentially targetable alterations found were ERBB2 (9%), BRAF (4%), NRAS (4%), PIK3CA (4%), and EGFR (4%).

“We found BRAF V600E and NRAS Q61K which can be targeted by BRAF or MEK inhibitors. ERBB2 driver mutations were seen in 2 patients including V8421 and R190W. These two patients were good candidates for HER2-targeted therapy clinical trials,” continued Dr Zhang, et al.

Further observations found one activating PIK3CA mutation (D549N) which has potential sensitivity to mTOR inhibitors and one targetable gene mutation of EGFR T790M. One patient had an activating ZFYVE26-ALK fusion gene. Notably, this is the first report of ALK fusion detected in GIST patients.

In 6 patients with available MSI status, none showed microsatellite instability. The median tumor mutational burden (TMB) of 8 patients was 3.3 mutations/Mb. Four deleterious germline mutations were present with two for PTCH2, one for SDHA and SDHB.

Conclusively, 18 (78%) patients in the cohort presented actionable genetic mutations.

“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,” concluded Dr Zhang, et al. – Alexa Stoia