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tient was offered a multi kinase inhibitor that did not target BRAF,or a MEK inhibitor.Nevertheless,it should be noted that both of these agents had been experimental,and as a result their therapeutic value has not however been totally validated.Treaent with dabrafenib,which targets BRAF directly,resulted in tumor regression Combretastatin A-4 following 6 weeks,and continued decreasing in size until week 24,followed by a plateau and after that progression at 8 months.Entire exome sequencing did not reveal secondary BRAF or RAS mutations but did demonstrate a somatic gain of function PIK3CA mutation,that has previously been reported in other human cancers.We speculate that the PIK3CA mutation may be the cause on the acquired BRAF inhibitor resistance in lesion 1.This obtaining is notable,mainly because to the very best of our expertise this is only the second PIK3CA mutation ever reported in GIST.
Furthermore,despite the fact that PIK3CA mutations have not previously been reported as a cause of acquired resistance to BRAF inhibitors in melanoma or other malignancies,low PTEN Combretastatin A-4 expression as well as other PTEN alterations are related with reduced response rate and shorter progression free of charge survival in BRAF mutant melanoma patients treated with BRAF inhibitors.We further speculate that dysregulation of cell cycle control by the homozygous CDKN2A mutation in lesion 2 may well also be a molecular basis for resistance of this lesion.No apparent explanation for resistance to BRAF inhibitor treaent was seen in lesion 3.We further tested RNA from all three lesions and had been unable to detect aberrant BRAF splicing as a basis for drug resistance.
The differences in sequencing among the three lesions highlight the prevalence of intratumor OAC1 heterogeneity along with the potential relevance to treaent outcomes.In conclusion,we present the very first patient with GIST plus a V600E BRAF mutation whose tumor showed regression even though receiving treaent with a BRAF inhibitor.To our expertise,the efficacy of BRAF inhibitors in BRAF mutant GIST has not been reported,but our case suggests that further studies and possibly a global clinical trial are warranted.Entire exome capture was performed with a SeqCap EZ Human Exome v2.0 kit,and sequencing was carried out on a HiSeq 2000 instrument.Sequence alignment and variant calling had been performed with DNAnexus software program.Tumor certain variants had been identified based on a minimum variant allele ratio of 20%,a minimum read depth of 20,and absence on the variant inside a matched normal specimen.
Nucleotide variants had been translated,and non synonymous variants had been identified making use of Extispicy SIFT,PolyPhen2,and Mutation Assessor.Variants of interest had been confirmed by Sanger sequence analysis.Gastrointestinal stromal tumor OAC1 is often a malignancy of mesenchymal origin that arises within the gastrointestinal tract and is resistant to conventional cytotoxic chemotherapy agents.KIT and platelet derived growth element receptor mutations are present in 80% and 8% of GISTs,respectively.Approximately 13% of KIT and PDGFRA wild type GISTs contain BRAF mutations.Although receptor tyrosine kinase inhibitors,for example imatinib or sunitinib,are therapeutically active antagonists of KIT and PDGFRA in KIT or PDGFRA mutated GIST,productive treaents for patients with advanced BRAF mutant GIST have not been reported.
Clinical trials of Combretastatin A-4 tyrosine kinase inhibitors which can be highly selective for V600 BRAF mutations have demonstrated high response rates in BRAF mutant melanoma,as well as improvement in general survival and OAC1 progression free of charge survival.Lately,we've shown that the BRAF inhibitor dabrafenib is also active in several non melanoma BRAF mutated cancers.Herein,we report antitumor activity within the very first patient with BRAF mutated GIST who was treated with a BRAF inhibitor.Entire exome sequencing of tumor obtained at time of progressive disease did not reveal secondary BRAF or RAS mutations,but did demonstrate a somatic gain of function PIK3CA mutation as well as a CDKN2A aberration,which may have been responsible for dabrafenib resistance.
A 60 year old man initially presented in September 2007 with abdominal pain plus a palpable mass.Computed tomography revealed Combretastatin A-4 a 10 cm heterogeneous mass,plus a subsequent biopsy demonstrated GIST,spindled cell histology,optimistic for CD34 and CD117 by immunohistochemistry with 6 mitoses per 10 high powered fields.The patient underwent surgical resection revealing a 15 cm mass.DNA was extracted from formalin fixed paraffin embedded tumor tissue and subjected to polymerase chain reaction amplifications of KIT exons 9,11,13,and 17 as well as PDGFRA exons 12 and 18.Sanger sequencing did not identify mutations in either the KIT or PDGFRA genes.The patient OAC1 presented with a new 14 cm mass at the dome on the bladder following 10 months of adjuvant imatinib therapy.The imatinib dose was improved to 800 mg daily,followed by surgical resection on the mass.The patient received adjuvant sunitinib,a many tyrosine kinase inhibitor,at a dose of 50 mg on a schedule of when daily for four weeks,then off for two weeks.Nineteen mont