A Two-Step Diagnostic Approach for NTRK Gene Fusion Detection in Biliary Tract and Pancreatic Adenocarcinomas

Abstract

Background It is of interest to determine the incidence and molecular characteristics of NTRK gene fusions in patients with bilio-pancreatic cancers, because of possible treatment with TRK inhibitors for advanced tumors. The aim of the present study was to apply the guidelines for NTRK testing algorithm to a series of patients with bilio-pancreatic cancers. Methods Immunohistochemistry screening was applied on formalin-fixed paraffin-embedded archival blocks from surgical resections, biopsies, or cytological samples of biliary tract and pancreatic adenocarcinomas. The presence of at least a weak staining in rare tumor cells led to testing by 2 RNA-based NGS panels. Results For biliary tract tumors, 153 samples have been selected. A total of 140 samples were suitable to perform IHC, and 17 samples were IHC positive. RNA NGS testing of the 17 IHC-positive samples revealed a single NTRK3 gene fusion (ETV6(4)-NTRK3(14)) that was detected by both NGS panels. In this perihilar cholangiocarcinoma, IHC performed on a biopsy showed a weak focal cytoplasmic and nuclear staining. No other NTRK fusion was detected on the 16 other samples with both panels. Overall in the patients screened by IHC and confirmed by NGS, the percentage of NTRK fusions was 0.7%. For pancreatic cancers, 319 samples have been selected and 297 were suitable to perform IHC. Nineteen samples were IHC positive. No fusion was detected by NGS. Conclusion NTRK gene fusions are rare in bilio-pancreatic cancers but testing is of high interest due to possible treatment with specific TRK inhibitors.

Current Status of Targeted Therapy for Biliary Tract Cancer in the Era of Precision Medicine

“…These agents are promising treatment options for BTC patients with NTRK fusion, despite NTRK fusion being reported in only 0.2–0.7% of patients with BTC [ 62 , 63 ].…”

Current and Future Therapeutic Targets for Directed Molecular Therapies in Cholangiocarcinoma

“…Based on these data, both the FDA and EMA approved entrectinib for use in adult and pediatric patients with solid tumors carrying an NTRK gene fusion. However, due to the low prevalence of NTRK gene fusion in CCA (estimated by 0.75%) and the limited representation of patients with CCA in the basket trials, further studies are necessary to evaluate the clinical benefit of larotrectinib and entrectinib in advanced or metastatic CCA with NRTK gene fusion [172] (see Table 12).…”

Targeted Therapies in Advanced Cholangiocarcinoma

“…NTRK fusion, similar in mechanism to FGFR2 fusion, stems from chromosomal rearrangement, resulting in the replacement of the 3 region of NTRK with a binding partner that allows for dimerization of TRK and activation of signaling in the absence of neurotrophins [97]. NTRK fusion may be observed in <1% of solid malignancies, and has been reported in <1% of cases of CCA [96,98,99].…”