Cancer Res Treat.  2023 Oct;55(4):1291-1302. 10.4143/crt.2022.1450.

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

• Lee SH
• Cheon J
• Lee S
• Kang B
• Kim C
• Shim HS
• Park YN
• Jung S
• Choi SH
• Choi HJ
• Lee Ck
• Chon HJ

• KMID: 2547803
• DOI: http://doi.org/10.4143/crt.2022.1450

Abstract

Purpose
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.
Results
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.
Conclusion
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.

Keyword

Biliary tract neoplasms; High-throughput nucleotide sequencing; Chemotherapy

Figure

• 

  Fig. 1 Genomic alteration associated with anatomic locations of biliary tract cancer. Oncoplot showing non-silent mutation counts for individual tumors (top), frequently mutated top 40 genes (middle), and other clinical factors including center, sex, age, sequencing panel, and MMR status (bottom). CCA, cholangiocarcinoma; dMMR, deficient mismatch repair; EHC, extrahepatic cholangiocarcinomar; GB, gallbladder cancer; MMR, mismatch repair; MSI, microsatellite instability; MSS, microsatellite stable; NGS, next generation sequencing.

• 

  Fig. 2 Alteration pattern associated with anatomic locations of biliary tract cancer. (A) Bar plot showing the relative fraction of alterations for ERBB2 amplification and IDH1. p-value was calculated using the chi-square test. (B) Stacked bap plot for single nucleotide changes for KRAS according to the anatomic location. (C) Circos plot representing fusion events. Red color indicates extrahepatic while green color indicates intrahepatic location. (D) Diagram for pathway alteration presenting the percentage of samples for each anatomic location with respect to DNA damage response, ErbB/HER signaling, Wnt/β-catenin, TGF-β signaling, fibroblast growth factor and AMPK pathways, as well as the SWI/SNF complex, respectively. CCA, cholangiocarcinoma; GB, gallbladder cancer.

• 

  Fig. 3 Prediction of clinical outcomes according to prognostic genes. (A) Forest plot showing significant genes, for predicting disease progression (ARID1A, BRCA2, and STK11) after first-line chemotherapy from multivariate logistic regression. (B) Kaplan-Meier plot demonstrating survival difference for progression-free survival according to ARID1A in total biliary tract cancer patients. (C) Stacked bar plot indicating optimal response after first-line chemotherapy according to ARID1A mutation in EHC. (D) Kaplan-Meier plot presenting survival difference for progression-free survival according to ARID1A in EHC. p-value was estimated using the log-rank test. CCA, cholangiocarcinoma; CI, confidence interval; EHC, extrahepatic cholangiocarcinomar; OR, odds ratio; PD, progressive disease; PR, partial response; SD, stable disease.

• 

  Fig. 4 Drug sensitivity of cancer cells according to ARID1A mutation. (A) Volcano plot presenting sensitive or resistant drugs according to ARID1A mutation. p-value was estimated using the student’s t test. (B) Grouped bar plot showing ARID1A-specific drug sensitivity for cisplatin according to cancer types. p-value was calculated using the Wilcoxon signed-rank test. DMSO, dimethyl sulfoxide; NA, not available.

Reference

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