Tumor Genotype Is an Independent Prognostic Factor in Primary Gastrointestinal Stromal Tumors of Gastric Origin: A European Multicenter Analysis Based on ConticaGIST

Abstract

Purpose: Although the mutational status in gastrointestinal stromal tumors (GIST) can predict the response to treatment with tyrosine kinase inhibitors, the role of tumor genotype as a prognostic factor remains controversial. The ConticaGIST study sought to determine the pathologic and molecular factors associated with disease-free survival (DFS) in patients with operable, imatinib-naive GIST.Experimental Design: Clinicopathologic and molecular data from 1,056 patients with localized GIST who underwent surgery with curative intention (R0/R1) and were registered in the European ConticaGIST database were prospectively obtained and reviewed. Risk of tumor recurrence was stratified using the modified NIH criteria. The median follow-up was 52 months.Results: On testing for potential prognostic parameters, the following were associated with inferior DFS on multivariable Cox model analysis: primary nongastric site, size >10 cm, mitotic index >10 mitoses per 50 high power field, and the KIT exon 9 duplication [hazard ratio (HR), 1.47; 95% confidence interval (CI), 0.9-2.5; P ¼ 0.037] and KIT exon 11 deletions involving codons 557 and/or 558 [KITdel-inc557/558; HR, 1.45; 95% CI, 1.0-2.2; P ¼ 0.004]. Conversely, PDGFRA exon 18 mutations were indicators of better prognosis [HR, 0.23; 95% CI, 0.1-0.6; P ¼ 0.002]. KITdel-inc557/558 were an adverse indicator only in GIST localized in the stomach (P < 0.001) but not in tumors with nongastric origin. In gastric GIST, all other mutations presented remarkably superior 5-year DFS.Conclusions: In conclusion, tumor genotype is an independent molecular prognostic variable associated with gastric GIST and should be used for optimizing tailored adjuvant imatinib treatment.

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

“…While there is some correlation between gastric location, larger size and the presence of mutation 557-558 showing a lower RFS, the predominantly high risk nature of our cohort meant that a majority of operable/operated patients were candidates for adjuvant IM, thereby shifting the onus of this analysis to evaluation of performance of the exon 11 cohort on IM. While Contica GIST study (15) showed poorer outcome of gastric GIST patients with mutation 557-558, our study showed trend towards poorer outcome in that group irrespective of location.…”

“…The knowledge of KIT exon 11 mutants having a longer PFS on standard IM and KIT exon 9 mutants potentially benefitting from 800 mg doses of IM has emerged in the advanced setting (19). The Contica GIST study (15), clearly showed that gastric GIST with a KIT del 557-558 had an inferior disease free survival compared to other mutants. A larger study, comprising 11 population based series (n=3,067; mutation analysis-1505), but untreated with IM, concluded that patients with PDGFRA mutations and those with KIT exon 11 duplication/single codon deletion mutations have a favorable recurrence free survival (RFS) with surgery alone (20).…”

“…Operated patients with mutation in codon 557-558 of exon 11 have lower relapse free survival (RFS) rates compared to alterations in other codons, with a majority of the data emerging from studies in patients not treated with IM (15,16). However long term results from the BFR14 trial, in advanced inoperable GIST, have confirmed that the codon 557-558 mutation cohort has greater sensitivity to IM, but also develops secondary resistance rapidly compared to other cohorts (17).…”

PDL1 expression is an independent prognostic factor in localized GIST

“…4,[10][11][12][13] Several tumor cell-intrinsic molecular prognosticators have been suggested, mainly based on proteins [47][48][49][50][51] or gene signatures 52,53 related to cell proliferation. Potential immune prognostic/predictive parameters have been more recently reported.…”

Molecular features and genetic markers of gastrointestinal stromal tumors

“…Изучение прогностической роли мутаций проводится до начала таргетной терапии, либо как ре-троспективное, либо при изучении контрольных групп пациентов, получавших плацебо [73]. У паци-ентов с мутациями PDGFRA выживаемость выше, чем у пациентов с мутациями KIT [1,49,50,74,75]. Точечные мутации и дупликации в 11-м экзоне KIT коррелируют с менее агрессивным поведением ГИ-СО, так же как и опухоли с мутацими PDGFRA.…”