Reference Detail

Ref Type

Journal Article

PMID

(18628470)

Authors

Mussi C, Schildhaus HU, Gronchi A, Wardelmann E, Hohenberger P

Title

Therapeutic consequences from molecular biology for gastrointestinal stromal tumor patients affected by neurofibromatosis type 1.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	14	14	2008 Jul 15	4550-5	Clin Cancer Res

URL

Abstract Text

Patients affected by neurofibromatosis type 1 (NF-1) have an increased risk of developing gastrointestinal stromal tumors (GIST). NF-1-associated GISTs are usually wild type for c-KIT and platelet-derived growth factor receptor-alpha (PDGFR-alpha) mutations and harbor a different oncogenic molecular mechanism. The lack of data on imatinib activity raises the question whether to enroll these patients in clinical trials. We analyzed a large series of NF-1 related GISTs to discuss the therapeutic implications.Clinical, pathologic (IHC to CD34, S100, bcl-2, PDGFRA), and molecular features (exons 9, 11, 13, 14, 17 in c-kit and exons 12, 14, 18 in PDGFRA) of 28 patients were analyzed.The most common site of primary lesions was the small bowel (75%). Twelve patients (43%) had multiple tumors. Most tumors belonged to the high (30.5%) or intermediate risk group for malignant behavior (39%). Three patients developed peritoneal and liver metastases; another four had peritoneal spread only. All tumors were immunohistochemically strongly positive for CD117. Three primary KIT/PDGFRA activating mutations were found. Three metastatic patients treated with imatinib experienced progression, and only one had temporary stable disease. Median survival after starting treatment with imatinib was 21 months.This study is the largest series available and confirms that KIT/PDGFRA mutations in NF-1-associated GISTs are sporadic. Prognosis of metastatic tumors is poor, and imatinib response rate is low. Patients with NF-1-GIST of high or intermediate risk should not be eligible for adjuvant trials of imatinib. Imatinib should not be used in a neoadjuvant intent in these patients, and molecular analysis of activating mutations is strongly recommended.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
KIT	D820N	missense	unknown	KIT D820N lies within the protein kinase domain of the Kit protein (UniProt.org). D820N has been identified as a secondary mutation associated with imatinib-resistance (PMID: 18628470), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Nov 2024).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KIT D820N	gastrointestinal stromal tumor	predicted - resistant	Imatinib	Case Reports/Case Series	Actionable	In a clinical study, KIT D820N was identified as a secondary mutation in the metastatic lesions from a gastrointestinal stromal tumor patient whose disease progressed on Gleevec (imatinib) (PMID: 18628470).	18628470