NTRK gene fusions in bilio-pancreatic cancers.

Abstract

e16664 Background: Gene fusions involving one of the 3 neurotrophic tyrosine receptor kinases ( NTRK) have been identified in approximately 1% of solid tumors and inhibitors of TRK have been shown to have anti-tumor activity regardless of tumor type. NTRK gene fusions have been previously reported in bilio-pancreatic tumors. It is of interest therefore to determine incidence and molecular characteristics of NTRK gene fusions in these patients. Methods: Formalin-fixed paraffin-embedded archival blocks from surgical resections, biopsies or cytological samples of biliary tract tumors (BTC) including intra-hepatic (IH), extra-hepatic (EH), perihilar cholangiocarcinoma (PH) and gallbladder tumors (G), and pancreatic adenocarcinoma (PA) were retrieved from the tumor bank of CUB Hôpital Erasme between JAN 2010 and OCT 2019. A two-step diagnostic method incorporating immunohistochemistry (IHC) screening followed by NGS analysis was used. Pan–TRK IHC (monoclonal antibody clone EPR17341 [AbCam, Cambridge, MA]) was used for the screening method. Staining intensity (negative, weak, moderate or strong) pattern (diffuse, focal or rare positive cells), and localization (cytoplasmic or nuclear) were evaluated. The presence of at least weak staining tumor cells led to testing by a RNA-based NGS panel (Oncomine Focus Assay ThermoFisher Scientific). Results: For BTC, 162 archival tumors samples have been selected. 149 samples were suitable to perform IHC.17 samples were IHC positive including 9 IH, 3 PH, 2 EH and 3 G tumor samples. Intensity of staining was weak in 16 samples and moderate in one. Staining location was cytoplasmic (14/17), nuclear (2/17), and nuclear+cytoplasmic (1/17). Pattern of staining was rare positive cells (2/17), focal (4/17) and diffuse (11/17). NGS testing of the 17 IHC positive samples revealed a single NTRK3 gene fusion ( ETV6(4)- NTRK3(14)). In this PH tumor, IHC had a weak focal cytoplasmic and nuclear staining. Overall in the patients screened by IHC and confirmed by NGS, percentage of NTRK fusions was 0.67 %. For PA, 319 archival tumor samples have been selected and 297 were suitable for IHC. 19 samples were IHC positive. Intensity of staining was weak in 18 samples and moderate in one. Staining location was cytoplasmic (18/19) and nuclear (1/19). Pattern of staining was focal in 2 cases and diffuse in 17 cases. No fusion was detected by NGS. Conclusions: NTRK gene fusions are rare in bilio-pancreatic cancers but testing is of high interest due to the emergence of possible treatment with specific TRK inhibitors. These results support the use of NGS to confirm positive IHC results during diagnostic screening.

Impact of Endoscopic Ultrasound-Guided Tissue Acquisition on Decision-Making in Precision Medicine for Pancreatic Cancer: Beyond Diagnosis

“…These fusions are found at high frequencies in rare cancer types, such as secretory breast carcinoma [ 166 ] and mammary analogue secretory carcinoma of the salivary gland [ 167 ]. On the other hand, the frequency of NTRK fusion was low, less than 1.0%, in PCs [ 165 , 168 ].…”

PRMT5: An Emerging Target for Pancreatic Adenocarcinoma

“…However, olaparib only confers 3.8 months improvement in progression-free survival (PFS) without any OS benefit, nor improvement in quality of life compared to a truncated course of chemotherapy [58,59]. Although targeting gene fusions involving N-TRK or NRG-1 and using anti-PD1/PDL-1 therapies for microsatellite unstable subtypes have been reported to offer more significant clinical benefits, only limited patients included in the trials/case series had PDAC diagnosis [14,16,18,60,61]. Therefore, some uncertainty remains regarding the true clinical benefit of these therapies for PDAC patients.…”

“…This has led to global pancreatic cancer genomic profiling efforts to gain a better understanding of the root causes and potential therapeutic vulnerabilities in this disease. Unfortunately, finding targeted therapies that benefit a reasonable number of subpopulations living with pancreatic cancer remains elusive [12][13][14][15][16][17][18][19].…”

Next generation sequencing for biliary tract cancers

“…The Rare Oncology Agnostic Research (ROAR) basket trial (NCT02034110) enrolled patients with BRAF V600E-mutant BTC for treatment with the combination of dabrafenib and trametinib and demonstrated a 47% ORR by independent review [17]. While present in <1% of BTC, NTRK fusions serve as another potential therapeutic target following the tissue agnostic approval of entrectinib and larotrectinib for solid tumors with NTRK fusions [18]. Immunotherapy is also being investigated in the treatment of BTC, including pembrolizumab as monotherapy or in combination with chemotherapy in MSI-high or MMR deficient CCA [15].…”