Abstract 353: The translocations of FGFR2 and NTRK1 in intrahepatic cholangiocarcinoma and their discordance in status by FISH and IHC
Authors: Zou Yining , Ji Yuan 
Published: July 2021

Abstract
Objectives Intrahepatic cholangiocarcinoma(ICC) is a subtype of primary liver cancer lacking effective therapeutic agents. Chromosomal translocations of the neurotrophic tyrosine receptor kinase (NTRK) and fibroblast growth factor receptor 2 (FGFR2) have become promising therapeutic targets in several kinds of malignancies, but their incidence and optimum testing standards have not been fully assessed in ICC. The current study investigated the status of FGFR2 and NTRK1 genes in ICCs by different methods, and their correlation with clinicopathological features.
Methods We examined FGFR2 and NTRK protein expression by immunohistochemistry (IHC), FGFR2 and NTRK1 gene translocation by fluorescence in situ hybridization (FISH). Samples were collected from 160 patients who underwent surgical resection for ICC. Break-apart probes were employed and the ratios of FGFR2 or NTRK1/chromosome enumeration probe (CEP) 10 double-color probes were determined. Furthermore, we analyzed the clinicopathological significances of the patients.
Results FGFR2-positive status was detected in 13.2% of ICCs. Twenty-one patients (13.2%) were detected FGFR2 translocation. Compared with the patients with normal FGFR2, FGFR2-positivity tended to correlate with low histological grade, less mucus(P=0.024), and lower preoperative serum CA199 level, showed(P&lt;0.01)in certain tumors, and were accompanied by hepatitis B virus infection more frequently (P&lt;0.01). Histologically, tumors with FGFR2 translocation had a tendency to manifest small-duct subtype. The Kaplan-Meier survival analysis showed that patients with FGFR2 translocation had better prognosis in 5-year survival than those with normal FGFR2 (P=0.007),( median overall survival, 57 months vs 33 months). With regard to the NTRK1 translocated ICCs, 5.6% (9/160) were detected to have NTRK1 translocation, 5 cases were female, 4 were with hepatitis B virus infection, and 6 showed histologically large-duct subtype. Interestingly, two patients demonstrated both FGFR2 and NTRK1 translocation by FISH. However, among the 9 cases with NTRK1 translocation, only 2 cases showed moderately positive on IHC, with the remaining 7 cases weak or negative. Similarly, only 14.3% (3/21) FGFR2 translocation FISH-positive cases showed moderate to strong positive by IHC. Concordance rates between IHC and FISH were 22.2% for NTRK1 and 14.3% for FGFR2. The positive rate by IHC is significantly lower than that by FISH on both NTRK1 (2.5% vs 5%) and FGFR2 (3.7% vs 13%) according to our cohort.
Conclusions The positive rate by IHC is significantly lower than that by FISH on both genes. The findings of this study suggest that a large subgroup of FGFR2-positive and NTRK-positive cases can be considered for targeted therapy. Moreover, the FGFR2 and NTRK status in ICCs should be determined carefully using a sensitive approach toward larger cancer tissues.
Citation Format: Yining Zou, Yuan Ji. The translocations of FGFR2 and NTRK1 in intrahepatic cholangiocarcinoma and their discordance in status by FISH and IHC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 353.