한빛사 논문
Jihoon G. Yoon,1† Min Hwan Kim,2,3† Mi Jang,4,5† Hoguen Kim,4 Ho Kyoung Hwang,3,6 Chang Moo Kang,3,6 Woo Jung Lee,3,6 Beodeul Kang,2,3 Choong-kun Lee,2,3 Min Goo Lee,1 Hyun Cheol Chung,2 Hye Jin Choi,2,3* and Young Nyun Park4*
1Department of Pharmacology, Yonsei University College of Medicine, Seoul, Republic of Korea.
2Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
3Pancreaticobiliary Cancer Clinic, Yonsei Cancer Center, Severance Hospital, Seoul, Republic of Korea.
4Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
5Department of Pathology, National Health Insurance Service Ilsan Hospital, Goyang, Republic of Korea.
6Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
†These authors contributed equally.
*These authors jointly directed this work.
Abstract
Background & 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 & 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 PD‐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 anatomic location. Favorable responses to chemotherapy were observed in the small‐duct type compared with the large‐duct type intrahepatic cholangiocarcinoma, with frequent mutations in BAP1‐IDH1/2 and KRAS‐SMAD4 genes, respectively. The molecular features were further analyzed in BTCs, and TGF‐β and DNA damage response pathway‐altered tumors exhibited poor and favorable chemotherapy responses, respectively. In the 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 did not show 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.
논문정보
관련 링크
연구자 키워드
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기