Genotyping was performed on 10 of these patient cases, which represents the largest group of such tumors for which imatinib treatment outcomes are available. Consistent with previous studies, kinase mutations were identified in eight of the 10 CD117-negative patient cases,17,18 and kinase inhibitor Perifosine KIT exon 11 mutations were present in six of these patient cases. The apparent absence of CD117 staining in these patient cases could reflect false-negative immunohistochemistry as a consequence of poor tumor fixation. Alternatively, the levels of KIT protein in these tumors may have been sufficient for oncogenic signal transduction but may have been less than the limit of detection by standard immunohistochemistry. Two of the CD117-negative patient cases contained PDGFRA exon 18 mutations (D842V and deletion IMHD842-846).

Four of the six patients with KIT exon 11�Cmutant GISTs had CR (n = 1) or PR (n = 3) as the best objective response to therapy. The remaining two patients had SD or were nonassessable for response, respectively. None of the four patients with PDGFRA-mutant or WT CD117-negative GISTs had objective responses (PD, n = 3; NA, n = 1). The TTP and OS of patients with CD117-negative GIST were compared with our main study population of CD117-positive tumors (Fig 4). The median TTP for CD117-negative GISTs was 18.3 months versus 20.5 months for CD-117 positive GISTs (P = .46). The median OS for the genotyped CD117-negative GISTs was 25.8 months versus 57.1 months for CD117-positive GISTs (P = .01). The median TTP and OS for the exon 11�Cmutant, CD117-negative GISTs were 31.9 and 44.

9 months, respectively. These results are comparable to those seen for KIT exon 11�Cmutant, CD117-positive GISTs: 24.7 and 60.0 months, respectively (P = .81 and .42 for TTP and OS, respectively). Fig 4. Comparison of time to progression and overall survival for patients with CD117-positive and CD117-negative gastrointestinal stromal tumors. DISCUSSION This prospective biomarker study of 397 patients who had genotyped CD117-positive tumors represents the largest genotyped collection of patients with GIST enrolled on a clinical study. The North American intergroup phase III trial was written in conjunction with another international phase III study (EORTC 62005) to determine the optimal imatinib dose for treating patients who have advanced GIST.

Results from the EORTC trial have been published and will be compared with our current results.13,15 The frequency and spectrum of KIT and PDGFRA mutations that were identified match well with the EORTC phase III trial and with other series. Similar to previous studies, these results confirm the favorable Entinostat impact of the KIT exon 11 genotype on the response to imatinib therapy compared with GISTs that have KIT exon 9�Cmutant or WT genotypes. This is evidenced by the following: superior objective CR/PR rates (71.7%, 44.4%, and 44.