1516 - Mutational Analysis Before and After Neoadjuvant Imatinib Mesylate for Locally Advanced Gastrointestinal Stromal Tumours

Abstract

ABSTRACT Background The majority of gastrointestinal stromal tumours (GISTs) express gain-of-function mutations in the tyrosine kinase receptor KIT, and less often in platelet derived growth factor receptor α (PDGFRα). Imatinib mesylate is an effective therapy for GISTs, especially in patients with Exon 11 mutations, but has less response in Exon 9 mutation patients. Imatinib is least effective in patients expressing wild-type (WT) KIT and PDGFRα mutations. When used in the neoadjuvant setting, patients typically experience maximal tumor response within a year of initiation and surgical resection is required for potential cure. In this study, we characterized the mutational status in paired samples before and after neoadjuvant imatinib therapy. Methods All patients receiving neoadjuvant imatinib (at a single academic institution), to improve surgical resectability were reviewed retrospectively. Patients were treated with imatinib until deemed to be appropriate surgical candidates at a multidisciplinary case conference. All tumours were sent for molecular analysis before and after resection when possible. Results 17 patients were identified from 2007 to 2012. The time on neoadjuvant imatinib therapy ranged from 31-135 weeks, with a median time of 57 weeks. At time of diagnosis, mutational analysis was possible on 7 samples, all of which were found to have a mutation: 5 in Exon 11, 2 in Exon 9. Of the 6 patients where mutational analysis was possible both prior to imatinib therapy and following surgical resection, 5 retained identical mutations. 1 patient with a jejunal GIST found to express an Exon 9 mutation at diagnosis was found to have WT KIT following imatinib therapy. The greatest median reduction in maximum tumour dimension (MR-MTD) was in the patient with the Exon 9 mutation (54.55%) compared to 9 patients with Exon 11 mutations (39.2%) and 2 patients with WT KIT/PDGFRα (38.0%). Patients with Exon 11 mutations showed the greatest variation in MR-MTD, one growing by 6.7% to another shrinking by 79.4%. Conclusions Most tumors retain the same mutations after neaoadjuvant therapy with imatinib. We identified one patient who had a different non-imatinib sensitive mutation after treatment. In the neoadjuvant setting, the duration of imatinib therapy may be too short for imatinib resistant clones to appear. Disclosure All authors have declared no conflicts of interest.