FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors

Abstract

Background: About 10-15% of adult, and most pediatric, gastrointestinal stromal tumors (GIST) lack mutations in KIT, PDGFRA, SDHx, or RAS pathway components (KRAS, BRAF, NF1). The identification of additional mutated genes in this rare subset of tumors can have important clinical benefit to identify altered biological pathways and select targeted therapies.

Methods: We performed comprehensive genomic profiling (CGP) for coding regions in more than 300 cancer-related genes of 186 GISTs to assess for their somatic alterations.

Results: We identified 24 GIST lacking alterations in the canonical KIT/PDGFRA/RAS pathways, including 12 without SDHx alterations. These 24 patients were mostly adults (96%). The tumors had a 46% rate of nodal metastases. These 24 GIST were more commonly mutated at 7 genes: ARID1B, ATR, FGFR1, LTK, SUFU, PARK2 and ZNF217. Two tumors harbored FGFR1 gene fusions (FGFR1-HOOK3, FGFR1-TACC1) and one harbored an ETV6-NTRK3 fusion that responded to TRK inhibition. In an independent sample set, we identified 5 GIST cases lacking alterations in the KIT/PDGFRA/SDHx/RAS pathways, including two additional cases with FGFR1-TACC1 and ETV6-NTRK3 fusions.

Conclusions: Using patient demographics, tumor characteristics, and CGP, we show that GIST lacking alterations in canonical genes occur in younger patients, frequently metastasize to lymph nodes, and most contain deleterious genomic alterations, including gene fusions involving FGFR1 and NTRK3. If confirmed in larger series, routine testing for these translocations may be indicated for this subset of GIST. Moreover, these findings can be used to guide personalized treatments for patients with GIST. Trial registration NCT 02576431. Registered October 12, 2015.

Trial registration: ClinicalTrials.gov NCT02576431.

Keywords: ETV6–NTRK3; FGFR1; GIST; Gene sequencing; Mutation.

Fig. 1

Types of Genomic Alterations Detected on Broad Genetic Profiling of Wild-Type GIST. Bar graph demonstrates the types of genomic alterations identified in WT GIST as determined by CGP). Percentages and total numbers (N) of mutations are indicated

Fig. 2

Deleterious genomic alterations, genes and tumor sites in Wild-Type GIST. Matrix demonstrating genes recurrently mutated in WT GIST patients, with each column representing an individual patient. VUS missense mutations are displayed only if they are predicted to affect gene function by 2 or more algorithms (see “Methods” section). Genes were prioritized on the basis of predicted damaging effect. The table header indicates GIST tissue of origin (blue), positive node status (red), positive metastic status (purple), qWT status (i.e. tested for SDHx—black) missing data (grey). The number of mutated patients for each gene (red scale in row header) is indicated

Fig. 3

Kinase fusions identified in WT GIST samples. Three separate fusions involving the N-terminus of FGFR1 (a) and the C-terminus of NTRK3 (b) were identified. The FGFR1 fusions (a) were similar in structure to reported fusions and contained exons 2-17 fused with exons 5-22 of HOOK3 or exons 7-13 of TACC1. Intact coiled-coil motifs were present in both fusion partners and likely facilitate dimerization. Note that exon 1 of FGFR1 is non-coding and therefore excluded from the protein diagrams. The NTRK3 fusion (b) contained exons 1-5 of ETV6 and exons 14-19, which included the complete kinase domain. Although the portion of ETV6 present in the fusion lacked the DNA-binding domain, a Pointed (PNT) was conserved. This region is composed of 5-helix bundle involved in protein–protein interactions and may facilitate dimerization of this fusion. All diagrams are drawn to scale

Fig. 4

Radiological response of a GIST possessing an ETV6–NTRK3 fusion following treatment with LOXO-101, a selective TRK inhibitor. A 55-year old male with a T3N0M1 small intestine GIST had progression of disease on five lines of tyrosine kinase inhibitors targeting KIT prior to identification of an ETV6–NTRK3 fusion in the tumor. He was enrolled on a Phase I clinical trial of oral LOXO-101 (Loxo Oncology, Stamford, CT), a selective TRK inhibitor. As compared to baseline PET/CT images (a), the tumors had decreased size and FDG-uptake at week 8 (b). At 4 months, the patient had ongoing partial response (44%) according to RECIST 1.1 criteria