Genomic alterations predict clinical response to systemic chemotherapy and immune checkpoint blockade in biliary tract cancer

医学 内科学 肿瘤科 免疫检查点 免疫疗法 胆道癌 癌症研究 化疗 无容量 免疫系统 阿替唑单抗 癌症 封锁 彭布罗利珠单抗
作者
Min Kim,Jung Hyun Yoon,Mi Jang,H.J. Kim,Young Nyun Park,Min Geol Lee,Ho Kyoung Hwang,Chang Moo Kang,Woonhyoung Lee,Byunghag Kang,H.C. Chung,Hoseung Choi
出处
期刊:Annals of Oncology [Elsevier BV]
卷期号:30
标识
DOI:10.1093/annonc/mdz247.008
摘要

Abstract Background Previous studies have identified several targetable oncogenic mutations in biliary tract cancer (BTC). However, reliable predictors of clinical response to therapeutic agents have not been established. This study aimed to identify predictors of clinical response to chemotherapy and immune checkpoint blockade in advanced BTC patients. Methods Genomic alterations in 54 patients with recurrent or metastatic BTC were investigated by targeted deep-sequencing for 524 key cancer genes using pre-treatment tumor tissues. The predictive value of genomic alterations, including mutational signatures, on response to chemotherapy and anti-PD-1/PD-L1 therapy, was assessed. Results Frequently altered genes included TP53 (50.0%), NOTCH1 (31.5%), KRAS (24.1%), KMT2C (22.2%), BAP1 (22.2%), and ERBB2 (22.2%). BAP1 deletion and NOTCH1 mutation were associated with a favorable response to chemotherapy. The homologous recombination deficiency (HRD)-associated signature (signature 3) was significantly higher in the responding patients to chemotherapy and a positive correlation between the HRD-signature and BAP1 deletion was observed, suggesting that HRD caused by BAP1 deletion may contribute to a favorable response to chemotherapy. A high proportion of signature 12 was associated with favorable overall and progression-free survival after chemotherapy. Among 19 patients treated with anti-PD-1/PDL1 therapy, the mismatch repair (MMR) deficiency–associated signatures (signatures 6, 15, 20, and 26) were significantly higher in the responding patients. Conclusions This study identified several predictors on therapeutic response of advanced BTC. BAP1 deletion and NOTCH1 mutation were predictors of a favorable response to chemotherapy. Furthermore, the mutational signatures associated with HRD and MMR significantly correlated with the response to chemotherapy and anti-PD-1/PD-L1 therapy, respectively. Legal entity responsible for the study The authors. Funding National R&D Program for Cancer Control, Republic of Korea. Disclosure All authors have declared no conflicts of interest.
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