Early outcomes of exon 11 mutants in GIST treated with standard dose Imatinib

Abstract

Background: The exon 11 KIT mutant gastrointestinal stromal tumors (GIST) is a heterogeneous cohort with variable biological behavior based on different mutational subtypes. Methods:Patients with histologically proven GIST with KIT exon 11 mutations were selected from a prospectively maintained database, and evaluated for clinical characteristics and event free survival (EFS). Patients were divided into mutations upstream to codon 557 (G1), mutations involving codon 557-558 (G2) and mutation downstream to codon 558 (G3).Results: A total of 90 patients satisfied the inclusion criteria for study. Substitutions, indels and duplications were seen in 23 patients. Deletions were seen in 67 patients, of which 44 patients had large deletions (>6 base pairs), while 23 has small deletions (<6 base pairs). Complex mutations were seen in 15 patients. G2 mutations were noted in 33 patients, while G1 and G3 mutations were seen 32 and 25 patients respectively. With a median follow-up of 26 months, estimated median EFS for the entire cohort was 55 months. The G2 cohort had an inferior EFS compared to the G1 and G3 cohorts (46 vs. 55 months), but this did not achieve statistical significance (univariate analysis: P=0.075). On multivariate analysis, patients undergoing radical intent surgery vs. no surgery (58 vs. 55 months; P=0.005) and G1 or G3 vs. G2 cohort (P=0.058) showed trend towards improved EFS. Conclusions:In patients with GIST exon 11 codon 557-558 mutation subset there is a trend towards an inferior survival even when treated with imatinib mesylate (IM).

Gastrointestinal stromal tumors: a comprehensive review

“…In patients with early detection of exon 11 mutations, a low dose of imatinib (400 mg/day) is adequate (11,13,35). Ramaswamy and colleagues showed that CD117 exon 9 mutations have 38 months of overall survival compared to CD117 exon 11 mutation with a survival rate of 66 months (36). Patients with exon 13 or 14 mutations benefit from sunitinib and exon 17 mutations benefit from ponatinib ( Table 6) (11)(12)(13).…”

Tumor-targeting Salmonella typhimurium A1-R suppressed an imatinib-resistant gastrointestinal stromal tumor with c-kit exon 11 and 17 mutations

“…Accumulative evidence suggests the effectiveness of imatinib in both the adjuvant and metastatic GISTs in patients with KIT or PDGFRA mutations [ 64 , 65 , 66 , 67 ]. However, imatinib was not effective in all patients, because it was found that GIST patients with mutations in the exon 9 of the KIT gene have lower effectiveness compared to mutations in exon 11 [ 41 , 67 , 68 ].…”

“…Since exon-11-mutant KIT GIST is heterogeneous, it was advisable to plan treatment strategies based on individual mutant cohorts [68] . Imatinib can improve the prognosis of advanced GIST patients [ 68 , 69 ].…”

“…Since exon-11-mutant KIT GIST is heterogeneous, it was advisable to plan treatment strategies based on individual mutant cohorts [68] . Imatinib can improve the prognosis of advanced GIST patients [ 68 , 69 ]. However, almost all such cases become resistant to these drugs due to secondary mutations in c-kit or PDGFRα [ 68 , 69 ].…”

“…Imatinib can improve the prognosis of advanced GIST patients [ 68 , 69 ]. However, almost all such cases become resistant to these drugs due to secondary mutations in c-kit or PDGFRα [ 68 , 69 ]. The present case also had a secondary mutation in exon 17 and failed neoadjuvant therapy using imatinib.…”