Two different KIT mutations may lead to different responses to imatinib in metastatic gastrointestinal stromal tumor

Yim, Eunjung; An, Ho Jung; Cho, Uiju; Kim, Youngwoo; Kim, Seung Hoon; Choi, Yeon-Geun; Shim, Byoung Yong

doi:10.3904/kjim.2015.295

Cited by 7 publications

(8 citation statements)

References 5 publications

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“…The KIT gene encodes the stem cell growth factor receptor, a type III transmembrane receptor tyrosine kinase that has been involved in the pathogenesis of various malignancies, including gastro-intestinal stromal tumours, acute myelogenous leukaemia and testicular seminomas [39][40][41]. KIT signalling is upstream of RAS-MAPK signalling and the PI3K pathway.…”

Section: Identification Of Kit Mutations In Intracranial Germinomasmentioning

confidence: 99%

Molecular exploration of paediatric intracranial germinomas from multi-ethnic Singapore

Low

Zou

et al. 2020

BMC Neurol

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Background Germinomas (IG) account for up to 50% of all intracranial germ cell tumours. These tumours are reputed to be more prevalent in Oriental populations in comparison to Western cohorts. Biological characteristics of IG in other ethnic groups are unknown. Singapore is a multi-ethnic country with diverse cultures. Owing to inter-racial heterogeneity, the authors hypothesize there are molecular differences between paediatric IG patients in our local population. The aims of this study are exploratory: firstly, to identify molecular characteristics in this tumour type and circulating CSF unique to different racial cohorts; and next, to corroborate our findings with published literature. Methods This is a single-institution, retrospective study of prospectively collected data. Inclusion criteria encompass all paediatric patients with histologically confirmed IG. Excess CSF and brain tumour tissues are collected for molecular analysis. Tumour tissues are subjected to a next generation sequencing (NGS) targeted panel for KIT and PDGRA. All CSF samples are profiled via a high-throughput miRNA multiplexed workflow. Results are then corroborated with existing literature and public databases. Results In our cohort of 14 patients, there are KIT exon variants in the tumour tissues and CSF miRNAs corroborative with published studies. Separately, there are also KIT exon variants and miRNAs not previously highlighted in IG. A subgroup analysis demonstrates differential CSF miRNAs between Chinese and Malay IG patients. Conclusion This is the first in-depth molecular study of a mixed ethnic population of paediatric IGs from a Southeast Asian cohort. Validation studies are required to assess the relevance of novel findings in our study.

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Section: Identification Of Kit Mutations In Intracranial Germinomasmentioning

confidence: 99%

Molecular exploration of paediatric intracranial germinomas from multi-ethnic Singapore

Low

Zou

et al. 2020

BMC Neurol

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“…Over 85% of gastrointestinal stromal tumors (GIST) are driven by oncogenic mutations of the genes encoding KIT and/or platelet-derived growth factor receptor A (PDGFRA) receptor tyrosine kinases [ 1 , 2 ]. The most common sites for mutations in GIST are in the juxtamembrane domain (exon 11; 60–70%) and the extracellular domain (exon 9; 5–10%) of KIT ; mutations in PDGFRA (5–10%) are most commonly located in the activation loop (exon 18) and the juxtamembrane domain (exon 12) [ 3 – 6 ].…”

Section: Introductionmentioning

confidence: 99%

Clinical efficacy comparison of avapritinib with other tyrosine kinase inhibitors in gastrointestinal stromal tumors with PDGFRA D842V mutation: a retrospective analysis of clinical trial and real-world data

et al. 2021

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Background Avapritinib, a potent inhibitor of KIT and platelet-derived growth factor receptor A (PDGFRA) tyrosine kinases, has demonstrated unprecedented clinical activity in PDGFRA D842V-mutant gastrointestinal stromal tumors (GIST). Methods This retrospective analysis compared efficacy of avapritinib in patients enrolled in the NAVIGATOR phase 1 trial (NCT02508532) with the efficacy of other tyrosine kinase inhibitors (TKIs) in patients with unresectable/metastatic PDGFRA D842V-mutant GIST enrolled in a retrospective natural history study (Study 1002). The primary endpoint was overall survival (OS) from the start of reference treatment (avapritinib for NAVIGATOR patients or first-line TKI for treatment of unresectable/metastatic GIST for Study 1002 patients); the secondary endpoint was progression-free survival (PFS). Adjusted Kaplan–Meier survival curves were compared by Cox regression. Results Fifty-six (NAVIGATOR) and 19 (Study 1002) patients with PDGFRA D842V-mutant GIST were evaluated; of the 56 patients from NAVIGATOR, a subgroup of patients treated with either 300 mg (recommended phase 2 dose) or 400 mg (maximum tolerated dose) avapritinib starting dose (n = 38) were analyzed separately. Patient characteristics were adjusted for imbalances by propensity score between the study groups. Inverse probability of treatment weighting-adjusted Kaplan–Meier analysis of OS showed median OS was not reached for NAVIGATOR patients treated with any of the avapritinib doses tested and was 12.6 months for Study 1002 patients; OS rate at 6/48 months was 100%/63% in NAVIGATOR and 56%/17% in Study 1002 (P = 0.0001). In the 300/400 mg subgroup, adjusted OS rates at 6/36 months were 100%/73 and 68%/20% in Study 1002 (P = 0.0016). Adjusted median PFS was 29.5 months in NAVIGATOR and 3.4 months in Study 1002. Conclusions In this indirect, retrospective analysis, avapritinib demonstrated more durable survival outcomes compared with other TKIs in patients with unresectable/metastatic PDGFRA D842V-mutant GIST. Trial registration The NAVIGATOR trial was registered at ClinicalTrials.gov as per July 2015, Identifier: NCT02508532.

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Section: Introductionmentioning

confidence: 99%

“…While KIT exon 11 mutations show a better response to Imatinib and contribute to a longer overall-survival, mutations in KIT exon 9 as well as the PDGFRA gene show an inferior response to Imatinib. 11,12 Some adults (10-15%) and most children (85%) with GIST have no mutations in the KIT or PDGFRA genes. These GISTs are referred to as wild-type GISTs with mutations in the succinate dehydrogenase (SDH) gene.…”

Section: Introductionmentioning

confidence: 99%

Gastrointestinal stromal tumor – A review of clinical studies

Khoshnood

2019

J Oncol Pharm Pract

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Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. With the advent of Imatinib, the treatment of gastrointestinal stromal tumor has been revolutionized as both the progression-free and overall survival rates have increased dramatically. Unfortunately, gastrointestinal stromal tumor patients on Imatinib do eventually fail due to resistance. Even though sunitinib and regorafenib have been shown to be highly effective as second- and third-line treatments, both have limited effects. New treatments are highly warranted for this reason. In this present review, 25 registered pharmacological clinical trials at ClinicalTrials.gov have been reviewed and show promising and encouraging results.

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Two different KIT mutations may lead to different responses to imatinib in metastatic gastrointestinal stromal tumor

Cited by 7 publications

References 5 publications

Molecular exploration of paediatric intracranial germinomas from multi-ethnic Singapore

Molecular exploration of paediatric intracranial germinomas from multi-ethnic Singapore

Clinical efficacy comparison of avapritinib with other tyrosine kinase inhibitors in gastrointestinal stromal tumors with PDGFRA D842V mutation: a retrospective analysis of clinical trial and real-world data

Gastrointestinal stromal tumor – A review of clinical studies

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