Type and Gene Location of KIT Mutations Predict Progression-Free Survival to First-Line Imatinib in Gastrointestinal Stromal Tumors: A Look into the Exon

Abstract

In previous studies on localized GISTs, KIT exon 11 deletions and mutations involving codons 557/558 showed an adverse prognostic influence on recurrence-free survival. In the metastatic setting, there are limited data on how mutation type and codon location might contribute to progression-free survival (PFS) variability to first-line imatinib treatment. We analyzed the type and gene location of KIT and PDGFRA mutations for 206 patients from a GIST System database prospectively collected at an Italian reference center between January 2005 and September 2020. By describing the mutational landscape, we focused on clinicopathological characteristics according to the critical mutations and investigated the predictive role of type and gene location of the KIT exon 11 mutations in metastatic patients treated with first-line imatinib. Our data showed a predictive impact of KIT exon 11 pathogenic variant on PFS to imatinib treatment: patients with deletion or insertion/deletion (delins) in 557/558 codons had a shorter PFS (median PFS: 24 months) compared to the patients with a deletion in other codons, or duplication/insertion/SNV (median PFS: 43 and 49 months, respectively) (p < 0.001). These results reached an independent value in the multivariate model, which showed that the absence of exon 11 deletions or delins 557/558, the female gender, primitive tumor diameter (≤5 cm) and polymorphonuclear leucocytosis (>7.5 109/L) were significant prognostic factors for longer PFS. Analysis of the predictive role of PDGFRA PVs showed no significant results. Our results also confirm the aggressive biology of 557/558 deletions/delins in the metastatic setting and allow for prediction at the baseline which GIST patients would develop resistance to first-line imatinib treatment earlier.

Keywords: GIST; KIT; gastrointestinal stromal tumors; imatinib; mutations; predictive biomarkers.

Figure 1

The mutational landscape of gastrointestinal stromal tumor (GIST) patients according to pathogenic variant (PV) gene location. The most common tyrosine kinase (KIT) exon 11 PVs are classified into deletions involving codons 557/558, deletions upstream of codons 557/558, deletions downstream of codons 557/558 and deletions/insertions affecting codons 557 and/or 558.

Figure 2

Codon location of the PVs in the population of metastatic KIT exon 11 patients treated with first-line imatinib. The different colors indicate the PVs positions as related to 557/558 critical codons: PVs involving codons upstream of codon 557; PVs involving codon 557; PVs involving codons 557 and 558; PVs involving codon 558; and PVs involving codons downstream of codon 558. The length of the line indicates the number of codons involved in each KIT exon 11 mutation.

Figure 3

Progression-free survival (PFS) and overall survival (OS) curves according to prognostic factors that resulted statistically significantly from multivariable analyses. PFS according to: (A) KIT Exon 11 deletion and delins in codons 557/558 or other PV types (p < 0.001); (B) KIT Exon 11 deletion and delins in codons 557/558, deletion in other codons or other PV types (duplication, insertion and single nucleotide variant (SNV)) (p = 0.002); (C) primitive tumor diameter (p = 0.017); (D) polymorphonuclear (PMN) leucocyte (p = 0.006); (E) gender (p < 0.001); (F) OS according to performance status (p = 0.029).

Figure 3

Progression-free survival (PFS) and overall survival (OS) curves according to prognostic factors that resulted statistically significantly from multivariable analyses. PFS according to: (A) KIT Exon 11 deletion and delins in codons 557/558 or other PV types (p < 0.001); (B) KIT Exon 11 deletion and delins in codons 557/558, deletion in other codons or other PV types (duplication, insertion and single nucleotide variant (SNV)) (p = 0.002); (C) primitive tumor diameter (p = 0.017); (D) polymorphonuclear (PMN) leucocyte (p = 0.006); (E) gender (p < 0.001); (F) OS according to performance status (p = 0.029).