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

PURPOSE: 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.
MATERIALS AND METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.