Molecular determinants of outcome to gemcitabine, cisplatin, and nab-paclitaxel in patients with advanced biliary tract cancer
- Author:
Daeseong KIM
1
;
Nam Suk SIM
;
Seonjeong WOO
;
Min Hwan KIM
;
Choong-kun LEE
;
Seung Soo HONG
;
Sung Hyun KIM
;
Ho Kyoung HWANG
;
Chang Moo KANG
;
Woo Jung LEE
;
Jung Hyun JO
;
Taek CHUNG
;
Sohyun HWANG
;
Beodeul KANG
;
Jung Sun KIM
;
Chang-Il KWON
;
Sangwoo KIM
;
Hong Jae CHON
;
Chang Gon KIM
;
Young Nyun PARK
;
Hye Jin CHOI
Author Information
- Publication Type:Original Article
- From:Clinical and Molecular Hepatology 2026;32(2):721-736
- CountryRepublic of Korea
- Language:English
-
Abstract:
Background/Aims:Biliary tract cancer (BTC) is a rare malignancy with poor prognosis. We investigated genomic determinants of clinical benefit from gemcitabine, cisplatin, and nab-paclitaxel (GAP) versus gemcitabine and cisplatin (GC) in advanced BTC.
Methods:Clinical and genomic data using TruSight Oncology 500 were analyzed from patients treated with GAP (N=198) or GC (N=89) as first-line therapy.
Results:With a median follow-up of 33.0 months, GAP modestly improved progression-free survival (PFS) (hazard ratio [HR] 0.764; 95% confidence interval [CI] 0.591–0.989) without significant overall survival (OS) difference compared to GC. Genomic profiling revealed frequent alterations in TP53 (35.2%), KRAS (16.4%), SMAD4 (10.5%), and TNFRSF14 (10.5%), involving RTK/RAS (44.3%), TP53 (41.8%), and PI3K (20.2%) pathways. Single-gene mutations did not predict treatment benefit. However, pathway-level analysis identified PI3K pathway activation as significantly associated with inferior PFS (HR 2.148; 95% CI 1.478–3.124) and OS (HR 2.096; 95% CI 1.413–3.109) in patients receiving GAP, an effect not observed with GC. Importantly, GAP conferred clinical benefit only in patients without PI3K pathway activation, while no survival advantage was seen in those with such alterations (Pinteraction=0.023 for PFS, Pinteraction=0.003 for OS). Similar results were obtained in the independent validation cohort treated with GAP (N=103) or GC (N=64) for BTC.
Conclusions:Genomic profiling using next-generation sequencing identified PI3K pathway activation as key molecular determinant that differentiates patient outcomes between GAP and GC treatments in advanced BTC.
