Twelve to fourteen percent of GIST patients have primary this website resistance to imatinib while 40-50% develop secondary resistance with progression of disease within 2-3 years (6,7). Resistance to tyrosine kinase inhibitors is of special consideration in exon

17 mutations in both the primary and secondary settings (8). Imatinib has been demonstrated to be more effective in juxtamembrane mutations like KIT exon 11 and Inhibitors,research,lifescience,medical PDGFR exon 12 and less effective in those mutations affecting activation loops like KIT exon 17 and PDGFR exon 18 (8). Exon 17 mutants have also been shown to develop cross-resistance to sunitinib. Sunitinib has been approved as second line treatment following development of resistance or treatment failure with imatinib (9). A 2012 retrospective analysis of sorafenib as third or fourth line therapy Inhibitors,research,lifescience,medical in advanced GIST demonstrated a median overall survival of 13.5 months (10). Sorafenib, with its antagonism of the activation loop in exon 17 mutants, has provided rationale for its use in imatinib-resistant patients (11). Studies have suggested a role for intermittent imatinib in exon 17 mutant GIST (12). Liegl et Inhibitors,research,lifescience,medical al. reported on the heterogeneity of kinase inhibitors resistance mechanism in GIST, in a study of 53 GIST

metastases in 14 patients, 6 out of 14 patients had two to five different secondary mutations in separate metastases. Furthermore, three patients were found to have two secondary KIT mutations within the same metastasis thus potentially raising the question Inhibitors,research,lifescience,medical of a consideration for studies evaluating combining TKI monotherapies if deemed tolerable and beneficial (13). Inhibitors,research,lifescience,medical While our patient developed resistance to

imatinib six months after initiating therapy, he has had quite durable responses to sorafenib plus imatinib lasting more than two years. Recently, regorafenib has been approved for 3rd line treatment of GIST following progression after imatinib and sunitinib. GRID—a randomized phase 3 trial of 133 patients treated with regorafenib 160 mg once daily three out of four Parvulin weeks showed a significantly improved PFS of 4.8 versus 0.9 months in the placebo arm (n=66) (14). Further studies are warranted to understand the role of regorafenib in patients with exon 17 mutations. Acknowledgements Disclosure: The authors declare no conflict of interest.
The liver is the most frequent site of metastasis from colorectal cancer. In patients with resectable colorectal liver metastases (CLM), the efficacy of hepatic resection (HR) has been established. HR is associated with low peri-operative mortality and morbidity (1,2) and 5-year survival rates ranging from 25% to 58% (3-8). Traditionally, only 10-15% of patients with CLM were considered as candidates for HR (9).