Affordable Access

Publisher Website

ARID1A Mutation from Targeted Next-Generation Sequencing Predicts Primary Resistance to Gemcitabine and Cisplatin Chemotherapy in Advanced Biliary Tract Cancer.

Authors
  • Lee, Sung Hwan1
  • Cheon, Jaekyung2, 3
  • Lee, Seoyoung4
  • Kang, Beodeul3
  • Kim, Chan3
  • Shim, Hyo Sup5
  • Park, Young Nyun5
  • Jung, Sanghoon6
  • Choi, Sung Hoon1
  • Choi, Hye Jin4
  • Lee, Choong-Kun4
  • Chon, Hong Jae3
  • 1 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea. , (North Korea)
  • 2 Division of Medical Oncology, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea. , (North Korea)
  • 3 Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea. , (North Korea)
  • 4 Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea. , (North Korea)
  • 5 Department of Pathology, Yonsei University College of Medicine, Seoul, Korea. , (North Korea)
  • 6 Department of Radiology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea. , (North Korea)
Type
Published Article
Journal
Cancer research and treatment
Publication Date
Oct 01, 2023
Volume
55
Issue
4
Pages
1291–1302
Identifiers
DOI: 10.4143/crt.2022.1450
PMID: 37139666
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

There are clinical unmet needs in predicting therapeutic response and precise strategy for the patient with advanced biliary tract cancer (BTC). We aimed to identify genomic alterations predicting therapeutic response and resistance to gemcitabine and cisplatin (Gem/Cis)-based chemotherapy in advanced BTC. Genomic analysis of advanced BTC multi-institutional cohorts was performed using targeted panel sequencing. Genomic alterations were analyzed integrating patients' clinicopathologic data, including clinical outcomes of Gem/Cis-based therapy. Significance of genetic alterations was validated using clinical next-generation sequencing (NGS) cohorts from public repositories and drug sensitivity data from cancer cell lines. 193 BTC patients from three cancer centers were analyzed. Most frequent genomic alterations were TP53 (55.5%), KRAS (22.8%), ARID1A (10.4%) alterations, and ERBB2 amplification (9.8%). Among 177 patients with BTC receiving Gem/Cis-based chemotherapy, ARID1A alteration was the only independent predictive molecular marker of primary resistance showing disease progression for 1st-line chemotherapy in the multivariate regression model (odds ratio, 3.12; p=0.046). In addition, ARID1A alteration was significantly correlated with inferior progression-free survival on Gem/Cis-based chemotherapy in the overall patient population (p=0.033) and in patients with extrahepatic cholangiocarcinoma (CCA) (p=0.041). External validation using public repository NGS revealed that ARID1A mutation was a significant predictor for poor survival in BTC patients. Investigation of multi-OMICs drug sensitivity data from cancer cell lines revealed that cisplatin-resistance was exclusively observed in ARID1A mutant bile duct cancer cells. Integrative analysis with genomic alterations and clinical outcomes of the first-line Gem/Cis-based chemotherapy in advanced BTC revealed that patients with ARID1Aalterations showed a significant worse clinical outcome, especially in extrahepatic CCA. Well-designed prospective studies are mandatory to validate the predictive role of ARID1Amutation.

Report this publication

Statistics

Seen <100 times