Synapse - Concordance in oncogenic alterations between the primary tumor and advanced disease: Insights into the heterogeneity of intrahepatic cholangiocarcinoma

Concordance in oncogenic alterations between the primary tumor and advanced disease: Insights into the heterogeneity of intrahepatic cholangiocarcinoma Journal Article

Authors:	McIntyre, S. M.; Preston, W. A.; Walch, H.; Sharib, J.; Kundra, R.; Sigel, C.; Lidsky, M. E.; Allen, P. J.; Morse, M. A.; Chen, W.; Cercek, A.; Harding, J. J.; Abou-Alfa, G. K.; O'Reilly, E. M.; Park, W.; Balachandran, V. P.; Drebin, J.; Soares, K. C.; Wei, A.; Kingham, T. P.; D'Angelica, M. I.; Iacobuzio-Donahue, C.; Jarnagin, W. R.
Article Title:	Concordance in oncogenic alterations between the primary tumor and advanced disease: Insights into the heterogeneity of intrahepatic cholangiocarcinoma
Abstract:	PURPOSEIntrahepatic cholangiocarcinoma (ICCA) is characterized by significant phenotypic and clinical heterogeneities and poor response to systemic therapy, potentially related to underlying heterogeneity in oncogenic alterations. We aimed to characterize the genomic heterogeneity between primary tumors and advanced disease in patients with ICCA.METHODSBiopsy-proven CCA specimens (primary tumor and paired advanced disease [metastatic disease, progressive disease on systemic therapy, or postoperative recurrence]) from two institutions were subjected to targeted next-generation sequencing. Overall concordance (oncogenic driver mutations, copy number alterations, and fusion events) and mutational concordance (only oncogenic mutations) were compared across paired samples. A subgroup analysis was performed on the basis of exposure to systemic therapy. Patients with extrahepatic CCA (ECCA) were included as a comparison group.RESULTSSample pairs from 65 patients with ICCA (n = 54) and ECCA (n = 11) were analyzed. The median time between sample collection was 19.6 months (range, 2.7-122.9). For the entire cohort, the overall oncogenic concordance was 49% and the mutational concordance was 62% between primary and advanced disease samples. Subgroup analyses of ICCA and ECCA revealed overall/mutational concordance rates of 47%/58% and 60%/84%, respectively. Oncogenic concordance was similarly low for pairs exposed to systemic therapy between sample collections (n = 50, 53% overall, 68% mutational). In patients treated with targeted therapy for IDH1/2 alterations (n = 6) or FGFR2 fusions (n = 3), there was 100% concordance between the primary and advanced disease specimens. In two patients, FGFR2 (n = 1) and IDH1 (n = 1) alterations were detected de novo in the advanced disease specimens.CONCLUSIONThe results reflect a high degree of heterogeneity in ICCA and argue for reassessment of the dominant driver mutations with change in disease status.
Keywords:	chemotherapy; multicenter; open-label; primary liver-cancer; single-arm; metastatic cholangiocarcinoma
Journal Title:	JCO Precision Oncology
Volume:	8
ISSN:	2473-4284
Publisher:	American Society of Clinical Oncology
Date Published:	2024-10-01
Language:	English
ACCESSION:	WOS:001282879800012
DOI:	10.1200/po.23.00534
PROVIDER:	wos
PMCID:	PMC10901433
PUBMED:	38394469
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: William R. Jarnagin -- Source: Wos