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Molecular Characterization of Biliary Tract Cancer Predicts Chemotherapy and Programmed Death 1/Programmed Death-Ligand 1 Blockade Responses

Authors
 Jihoon G Yoon  ;  Min Hwan Kim  ;  Mi Jang  ;  Hoguen Kim  ;  Ho Kyoung Hwang  ;  Chang Moo Kang  ;  Woo Jung Lee  ;  Beodeul Kang  ;  Choong-Kun Lee  ;  Min Goo Lee  ;  Hyun Cheol Chung  ;  Hye Jin Choi  ;  Young Nyun Park 
Citation
 HEPATOLOGY, Vol.74(4) : 1914-1931, 2021-10 
Journal Title
HEPATOLOGY
ISSN
 0270-9139 
Issue Date
2021-10
Abstract
Background and aims: Biliary tract cancer (BTC) exhibits diverse molecular characteristics. However, reliable biomarkers that predict therapeutic responses are yet to be discovered. We aimed to identify the molecular features of treatment responses to chemotherapy and immunotherapy in BTCs. Approach and results: We enrolled 121 advanced BTC patients (68 cholangiocarcinomas [33 intrahepatic, 35 extrahepatic], 41 gallbladder cancers, and 12 Ampulla of Vater cancers) whose specimens were analyzed by clinical sequencing platforms. All patients received first-line palliative chemotherapy; 48 patients underwent programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade therapy after failed chemotherapy. Molecular and histopathological characterization was performed using targeted sequencing and immunohistochemical staining to investigate treatment response-associated biomarkers. Genomic analysis revealed a broad spectrum of mutational profiles according to anatomical location. Favorable responses to chemotherapy were observed in the small-duct type compared with the large-duct type intrahepatic cholangiocarcinoma, with frequent mutations in BRCA1-associated protein-1/isocitrate dehydrogenase 1/2 and KRAS proto-oncogene, GTPase/SMAD family member 4 genes, respectively. The molecular features were further analyzed in BTCs, and transforming growth factor beta and DNA damage response pathway-altered tumors exhibited poor and favorable chemotherapy responses, respectively. In PD-1/PD-L1 blockade-treated patients, KRAS alteration and chromosomal instability tumors were associated with resistance to immunotherapy. The majority of patients (95.0%) with these resistance factors show no clinical benefit to PD-1/PD-L1 blockade and low tumor mutational burdens. Low tumor-infiltrating lymphocyte (TIL) density in tumors with these resistance factors indicated immune-suppressive tumor microenvironments, whereas high intratumoral TIL density was associated with a favorable immunotherapy response. Conclusions: This study proposes predictive molecular features of chemotherapy and immunotherapy responses in advanced BTCs using clinical sequencing platforms. Our result provides an intuitive framework to guide the treatment of advanced BTCs benefiting from therapeutic agents based on the tumors' molecular features.
Full Text
https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.31862
DOI
10.1002/hep.31862
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Beodeul(강버들) ORCID logo https://orcid.org/0000-0001-5177-8937
Kang, Chang Moo(강창무) ORCID logo https://orcid.org/0000-0002-5382-4658
Kim, Min Hwan(김민환) ORCID logo https://orcid.org/0000-0002-1595-6342
Kim, Hogeun(김호근)
Park, Young Nyun(박영년) ORCID logo https://orcid.org/0000-0003-0357-7967
Yoon, Jihoon G.(윤지훈) ORCID logo https://orcid.org/0000-0002-4401-7803
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
Lee, Woo Jung(이우정) ORCID logo https://orcid.org/0000-0001-9273-261X
Lee, Choong-kun(이충근) ORCID logo https://orcid.org/0000-0001-5151-5096
Jang, Mi(장미) ORCID logo https://orcid.org/0000-0002-0153-9847
Chung, Hyun Cheol(정현철) ORCID logo https://orcid.org/0000-0002-0920-9471
Choi, Hye Jin(최혜진) ORCID logo https://orcid.org/0000-0001-5917-1400
Hwang, Ho Kyoung(황호경) ORCID logo https://orcid.org/0000-0003-4064-7776
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/185406
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