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Cancer Research and Treatment > Epub ahead of print
doi: https://doi.org/10.4143/crt.2022.1450    [Epub ahead of print]
ARID1A Mutation from Targeted Next-Generation Sequencing Predicts Primary Resistance to Gemcitabine and Cisplatin Chemotherapy in Advanced Biliary Tract Cancer
Sung Hwan Lee1 , Jaekyung Cheon2,3 , Seoyoung Lee4 , Beodeul Kang3, Chan Kim3, Hyo Sup Shim5, Young Nyun Park5, Sanghoon Jung6, Sung Hoon Choi1, Hye Jin Choi4, Choong-kun Lee4 , Hong Jae Chon3
1Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
2Division of Medical Oncology, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
3Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
4Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
5Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
6Department of Radiology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
Correspondence  Choong-kun Lee ,Tel: 82-2-2228-8130, Fax: 82-2-2227-8073, Email: cklee512@yuhs.ac
Hong Jae Chon ,Tel: 82-31-780-7590, Fax: 82-31-780-3929, Email: minidoctor@cha.ac.kr
Received: November 3, 2022;  Accepted: April 25, 2023.  Published online: May 3, 2023.
*Sung Hwan Lee, Jaekyung Cheon and Seoyoung Lee contributed equally to this work.
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.
Materials and Methods
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.
Key words: Biliary tract neoplasms, High-throughput nucleotide sequencing, Chemotherapy, ARID1A
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