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Ref Type Journal Article
PMID (35176488)
Authors Silverman IM, Li M, Murugesan K, Krook MA, Javle MM, Kelley RK, Borad MJ, Roychowdhury S, Meng W, Yilmazel B, Milbury C, Shewale S, Feliz L, Burn TC, Albacker LA
Title Validation and Characterization of FGFR2 Rearrangements in Cholangiocarcinoma with Comprehensive Genomic Profiling.
Journal The Journal of molecular diagnostics : JMD
Vol 24
Issue 4
Date 2022 04
URL
Abstract Text Cholangiocarcinoma (CCA) is a heterogeneous biliary tract cancer with a poor prognosis. Approximately 30% to 50% of patients harbor actionable alterations, including FGFR2 rearrangements. Pemigatinib, a potent, selective fibroblast growth factor receptor (FGFR) FGFR1-3 inhibitor, is approved for previously treated, unresectable, locally advanced or metastatic CCA harboring FGFR2 fusions/rearrangements, as detected by a US Food and Drug Administration-approved test. The next-generation sequencing (NGS)-based FoundationOneCDx (F1CDx) was US Food and Drug Administration approved for detecting FGFR2 fusions or rearrangements. The precision and reproducibility of F1CDx in detecting FGFR2 rearrangements in CCA were examined. Analytical concordance between F1CDx and an externally validated RNA-based NGS (evNGS) test was performed. Identification of FGFR2 rearrangements in the screening population from the pivotal FIGHT-202 study (NCT02924376) was compared with F1CDx. The reproducibility and repeatability of F1CDx were 90% to 100%. Adjusted positive, negative, and overall percentage agreements were 87.1%, 99.6%, and 98.3%, respectively, between F1CDx and evNGS. Compared with evNGS, F1CDx had a positive predictive value of 96.2% and a negative predictive value of 98.5%. The positive percentage agreement, negative percentage agreement, overall percentage agreement, positive predictive value, and negative predictive value were 100% for F1CDx versus the FIbroblast Growth factor receptor inhibitor in oncology and Hematology Trial-202 (FIGHT-202) clinical trial assay. Of 6802 CCA samples interrogated, 9.2% had FGFR2 rearrangements. Cell lines expressing diverse FGFR2 fusions were sensitive to pemigatinib. F1CDx demonstrated sensitivity, reproducibility, and high concordance with clinical utility in identifying patients with FGFR2 rearrangements who may benefit from pemigatinib treatment.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR2 CLIP1 FGFR2 - CLIP1 fusion gain of function FGFR2-CLIP1 results from the fusion of FGFR2 and CLIP1, leading to increased PI3K, MAPK, and FGFR2 signaling (PMID: 31371345), and transformation in culture (PMID: 35176488). FGFR2-CLIP1 has been identified in metastatic cholangiocarcinoma (PMID: 31371345).
FGFR2 KIAA1217 FGFR2 - KIAA1217 fusion gain of function - predicted FGFR2-KIAA1217 results from the fusion of FGFR2 and KIAA1217 (PMID: 30745300), which leads to transformation in culture (PMID: 35176488), and therefore, is predicted to lead to a gain of protein function. FGFR2-KIAA1217 has been identified in cholangiocarcinoma (PMID: 34250419, PMID: 31109923, PMID: 33218975).
FGFR2 NRAP FGFR2 - NRAP fusion gain of function - predicted FGFR2-NRAP results from the fusion of FGFR2 and NRAP, which results in transformation in cultured cells (PMID: 35176488), and therefore, is predicted to lead to a gain of protein function. FGFR2-NRAP has been identified in intrahepatic cholangiocarcinoma (PMID: 31109923).
FGFR2 SHTN1 FGFR2 - SHTN1 fusion gain of function FGFR2-SHTN1 (also referred to as FGFR2-KIAA1598) results from the fusion of FGFR2 and SHTN1, which has been demonstrated to result in increased phosphorylation of recombinant proteins S6, Akt, and mTOR (PMID: 31911531) and is transforming in cultured cells (PMID: 35176488). FGFR2-SHTN1 has been identified in cholangiocarinoma (PMID: 25536104, PMID: 31911531) and non-small cell lung cancer (PMID: 30267839).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 - SHTN1 Advanced Solid Tumor predicted - sensitive Pemigatinib Preclinical - Cell culture Actionable In a preclinical study, Pemazyre (pemigatinib) treatment decreased viability of transformed cells expressing FGFR2-SHTN1 (referred to as FGFR2-KIAA1598) in culture (PMID: 35176488). 35176488
FGFR2 - BICC1 Advanced Solid Tumor sensitive Pemigatinib Preclinical - Cell culture Actionable In a preclinical study, Pemazyre (pemigatinib) treatment decreased viability of transformed cells expressing FGFR2-BICC1 in culture (PMID: 35176488). 35176488
FGFR2 - AHCYL1 Advanced Solid Tumor predicted - sensitive Pemigatinib Preclinical - Cell culture Actionable In a preclinical study, Pemazyre (pemigatinib) treatment decreased viability of transformed cells expressing FGFR2-AHCYL1 in culture (PMID: 35176488). 35176488
FGFR2 - KIAA1217 Advanced Solid Tumor sensitive Pemigatinib Preclinical - Cell culture Actionable In a preclinical study, Pemazyre (pemigatinib) treatment decreased viability of transformed cells expressing FGFR2-KIAA1217 in culture (PMID: 35176488). 35176488
FGFR2 - CLIP1 Advanced Solid Tumor sensitive Pemigatinib Preclinical - Cell culture Actionable In a preclinical study, Pemazyre (pemigatinib) treatment decreased viability of transformed cells expressing FGFR2-CLIP1 in culture (PMID: 35176488). 35176488
FGFR2 - NRAP Advanced Solid Tumor sensitive Pemigatinib Preclinical - Cell culture Actionable In a preclinical study, Pemazyre (pemigatinib) treatment decreased viability of transformed cells expressing FGFR2-NRAP in culture (PMID: 35176488). 35176488