Therapeutic Consequences fromMolecular Biology for Gastrointestinal StromalTumor Patients Affected by Neurofibromatosis Type1 ChiaraMussi,

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-KITand platelet-derived growth factor receptor-a (PDGFR-a) 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-1related 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 exons12, 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%) hadmultiple tumors.Most tumors belonged to thehigh (30.5%)or intermediate riskgroup 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 21months. Conclusions:This study is the largest series available and confirms that KIT/PDGFRAmutations in NF-1^ associated GISTs are sporadic. Prognosis of metastatic tumors is poor, and imatinib response rate is low. Patients with NF-1^ GISTof high or intermediate risk should not be eligible for adjuvant trials of imatinib. Imatinib shouldnot be used in a neoadjuvant intent in these patients, and molecular analysis of activating mutations is strongly recommended. The exciting results obtained in metastatic gastrointestinal stromal tumors (GIST) treated with imatinib mesylate (STI571; Gleevec/Glivec, Novartis Pharma) and its low toxicity profile have prompted the development of several international prospective trials to evaluate its therapeutic effect also in the neoadjuvant/cytoreductive and adjuvant setting (1–6). Nevertheless, it is known that the likelihood of imatinib response is strictly related to the mutational pattern of the tumor: KIT mutations on exon 11 are associated with a response rate of f80% to 85%, whereas the response rate of tumors containing exon 9 KIT mutations is roughly 50% and only occasional responses have been observed in patients with no detectable mutations (wild-type tumors; refs. 7–11). Among KIT wildtype tumors, GISTs arising in patients affected by neurofibromatosis type 1 (NF-1) occupy a remarkable position, but little is known about their pathogenesis and their sensitivity to imatinib. NF-1, also known as von Recklinghausen disease, is a fairly common genetic syndrome, affecting approximately 1 in 3,000 individuals. NF-1 is caused by mutations of the NF-1 gene on chromosome 17 (17q11.2), which encodes neurofibromin, a negative regulator of RAS activation. Although inherited in an autosomal dominant pattern, a family history is reported only in about half of all newly diagnosed cases. Owing to its variable penetrance, the phenotype is wide, but clinical diagnostic features are multiple neurofibromas, café au lait macules, skinfold freckles, and iris hamartomas (Lisch nodules). Many other complications may accompany the neurofibromatosis, such as mental disabilities, precocious or delayed puberty, skeletal deformities, and an increased risk of developing several tumors, including multiple GISTs. Although data available are scant, reported cases suggest that NF-1–associated GISTs manifest at a younger age than sporadic GISTs, are more common in the Cancer Therapy: Clinical Authors’ Affiliations: Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, Medical Faculty Mannheim, University of Heidelberg, Germany ; Melanoma and Sarcoma Unit, Department of Surgery, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; and Department of Pathology, University of BonnMedical School, Bonn, Germany Received1/10/08; revised 4/3/08; accepted 4/16/08. Grant support: Conticanet (Connective Tissue Cancer Network) Mobility Program 2007. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Note: C. Mussi and H-U. Schildhaus contributed equally to themanuscript. Preliminary data were presented during the 13th Annual CTOSMeeting, (Seattle, November1-3, 2007, abstract no. 862). Requests for reprints: Peter Hohenberger, Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68135, Mannheim, Germany. Phone: 49-621-383-2609; Fax: 49-621-383-1479; E-mail: [email protected]. F2008 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-08-0086 www.aacrjournals.org Clin Cancer Res 2008;14(14) July15, 2008 4550 Research. on April 30, 2017. © 2008 American Association for Cancer clincancerres.aacrjournals.org Downloaded from small bowel than in the stomach, and are often multiple and a little female predominance was noticed (12). Most interestingly, the molecular analysis of main published series indicates that GISTs in NF-1 are usually wild type, although they usually stain positive for c-KIT by immunohistochemistry. The almost uniform negativity for KIT/platelet-derived growth factor receptor A (PDGFRA) mutations in these patients is very likely due to a different mechanism of tumorigenesis based on the neurofibromin gene disorder. The lack of data on imatinib activity in this different setting raises the question whether to enroll these patients in the ongoing trials of imatinib and whether this decision should be driven by the molecular analysis. To get insights into this matter, we analyzed the clinicopathologic features, survival, and response to imatinib in a series of 28 patients with NF-1– associated GISTs. On the basis of both present results and the literature review, this paper provides an updated discussion on the therapeutic implications from the NF-1–related GIST molecular profile. Materials andMethods This study has been carried out on 28 patients affected by GISTs and NF-1. Clinical data were retrospectively reviewed from the databases of the University Hospitals of the Medical Faculties of Mannheim and Bonn and Istituto Nazionale Tumori. All data had been gathered