Platelet-derived growth factor receptor A (PDGFRA) mutations occur in approximately 10–15% of gastrointestinal stromal tumors (GISTs). These tumors with PDGFRA mutations have a different pathogenesis, clinical characteristics, and treatment response compared to tumors with receptor tyrosine kinase protein (KIT) mutations (60–70%). Many clinical studies have investigated the use of tyrosine kinase inhibitors mainly in patients with KIT mutations; however, there is a lack of attention to the PDGFRA-mutated molecular subtype. The main effective inhibitors of PDGFRA are ripretinib, avapritinib, and crenolanib, and their mechanisms and efficacy in GIST (as confirmed in clinical trials) are described in this review. Some multi-targeted tyrosine kinase inhibitors with inhibitory effects on this molecular subtype are also introduced and summarized in this paper. This review focuses on PDGFRA-mutated GISTs, introduces their clinical characteristics, downstream molecular signaling pathways, and existing resistance mechanisms. We focus on the most recent literature that describes the development of PDGFRA inhibitors and their use in clinical trials, as well as the potential benefits from different combination therapy strategies.
As one of the most common mesenchymal malignancies in the digestive system, gastrointestinal stromal tumors (GISTs) occur throughout the alimentary tract with diversified oncological characteristics. With the advent of the tyrosine kinase inhibitor era, the treatment regimens of patients with GISTs have been revolutionized and GISTs have become the paradigm of multidisciplinary therapy. However, surgery resection remains recognized as the potentially curative management for the radical resection and provided with favorable oncological outcomes. The existing available surgery algorithms in clinical practice primarily incorporate open procedure, and endoscopic and laparoscopic surgery together with combined operation techniques. The performance of various surgery methods often refers to the consideration of risk evaluation of recurrence and metastases; the degree of disease progression; size, location, and growth pattern of tumor; general conditions of selected patients; and indications and safety profile of various techniques. In the present review, we summarize the fundamental principle of surgery of GISTs based on risk assessment as well as tumor size, location, and degree of progress with an emphasis on the indications, strengths, and limitations of current surgery techniques.
Background. With respect to effect of surgery on the therapy of patients with metastatic gastrointestinal stromal tumors (mGISTs), still no consensus has been reached. This research designed to investigate the effect of surgical treatment on prognosis in patients with mGISTs. Methods. The population-based study consisted of 6282 GIST patients diagnosed between 2001 and 2016, from the Surveillance, Epidemiology, and End Results (SEER) database registry. The Kaplan-Meier method and Cox model were employed for the exploration of the effect of surgery on overall survival (OS) and GIST-specific survival (GSS). Results. In total, 6282 patients were diagnosed with GISTs, including 1238 (19.7%) mGIST patients and 5044 (80.3%) non-mGIST patients. Compared with the patients with non-mGISTs, metastatic patients assumed relatively lower proportion of surgical management (756 [61.1%] vs. 4666 [92.5%], P < 0.001 ). Based on unadjusted analysis, mGIST patients with operative management presented higher five years OS together with GSS in comparison with those without operative management (OS: 58.3% vs. 33.1%, P < 0.001 ; GSS: 61.6% vs. 36.7%, P < 0.001 ). Multivariable analysis found that no surgery was correlated to more than 2-fold increased death risk (OS, adjusted HR = 2.27, 95% CI: 1.90-2.71; GSS, adjusted HR = 2.42, 95% CI: 2.00-2.93). Conclusion. Metastatic GIST patients could potentially benefit from operative management with improved GSS and OS.
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