Management of a Patient With PDGFRA-Mutant GIST

Rebecca Ganzon, MS, APRN-CNP, AOCNP, Ohio Health, presents the case of a patient with gastrointestinal stromal tumor (GIST) with a PDGFR-alpha D842V mutation (exon 18). Ganzon notes the critical role of upfront molecular testing for this patient population to identify the driving mutation(s) and properly select the most effective treatment and dose.

Transcript:

Hi, my name is Rebecca Ganzon, and I'm a nurse practitioner at Ohio Health. In this case study, our patient presented with anemia, early satiety, and weight loss which are quite typical presenting symptoms in gastrointestinal stromal tumor, or GIST, where almost 70% of patients are symptomatic at diagnosis. She was found to have an ulcerated bleeding gastric mass near the GE [gastroesophageal] junction. 

Typically, when a patient's diagnosed with GIST, the first move is to proceed with surgery, if surgically resectable. Two of the big exceptions where neoadjuvant therapy would be recommended is if the tumor is unresectable or the surgery would be quite extensive. Usually, if the tumor is encroaching the GE junction and may involve esophageal resection, then neoadjuvant therapy is recommended or if there are other complicating factors that would make surgical resection difficult. 

In this case, neoadjuvant treatment was recommended, and patient was sent to medical oncology and started on imatinib 400 mg PO [per oral] daily with the goal of decreasing the tumor size and increasing the ease of surgical resection. At the same time as that recommendation was made, the patient's tumor and blood was sent for NGS testing to determine molecular subtyping. 

The teaching in this case study that I want to emphasize is the critical role of upfront molecular testing because despite molecular testing being considered a standard of care for GIST patients, as recently as 2010, only 6% of patients have had this testing done according to the Life Raft Group. Every GIST patient really should receive molecular testing to identify the driving mutation for their tumor. This is really critical in selecting the proper medication and the most effective dose. For the majority of GIST patients, the driving mutation is a KIT exon 11 mutation, that's about 70% of cases, or KIT exon 9, which is about 10% of cases, but the remaining 20% of patients may harbor a PDGFR-alpha or even a wild-type mutation.

In this case, we found out later that the patient actually did have this PDGFR-alpha D842V mutation, which is an exon 18 mutation, and the patient was negative for KIT. This is extremely pertinent information as we know that D842V mutant GISTs are de novo resistant to the TKIs [tyrosine kinase inhibitors] that are most commonly used in just treatment like imatinib, sunitinib, and regorafenib. In this case, knowing that the patient harbors this less common mutation, the best option for her would be to discontinue imatinib and start avapritinib. Avapritinib was approved in 2020 and is NCCN recommended as first-line treatment for patients harboring a D842V-mutant GIST.

Sources:

Iwatsuki M, Harada K, Iwagami S, Eto K, Ishimoto T, Baba Y, Yoshida N, Ajani JA, Baba H. Neoadjuvant and adjuvant therapy for gastrointestinal stromal tumors. Ann Gastroenterol Surg. 2018 Sep 27;3(1):43-49. doi: 10.1002/ags3.12211. PMID: 30697609; PMCID: PMC6345649.

Poveda et al. (2017, March 2). GEIS guidelines for gastrointestinal sarcomas (GIST). Cancer Treatment Reviews. Volume 55, pgs 107-119. https://doi.org/10.1016/j.ctrv.2016.11.011.

Sun Y, Yue L, Xu P, Hu W. An overview of agents and treatments for PDGFRA-mutated gastrointestinal stromal tumors. Front Oncol. 2022 Aug 31;12:927587. doi: 10.3389/fonc.2022.927587. PMID: 36119525; PMCID: PMC9471148.

Wang Y, Call J. Mutational Testing in Gastrointestinal Stromal Tumor. Curr Cancer Drug Targets. 2019;19(9):688-697. doi: 10.2174/1568009619666190326123945. PMID: 30914028.