European journal of cancer (Oxford, England : 1990) · 2026
Coexistence of TP53 and KRAS mutations identifies a molecular subset of biliary tract cancer with poor overall survival after first-line immunochemotherapy.
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Ishikawa Shiori, Ouchi Kota, Wakayama Shonosuke, Oyamada Shunsuke, Iwasaki Tomoyuki, Numakura Ryunosuke, Yoshida Yuya, Taniguchi Sakura, Kasahara Yuki, Komine Keigo, Saijo Ken, Shirota Hidekazu, Kawakami Hisato
Аннотация
BACKGROUND: Biliary tract cancer (BTC) is a biologically heterogeneous malignancy with a poor prognosis. Although the combination of an immune checkpoint inhibitor (ICI) with gemcitabine plus cisplatin (GC) is now a standard first-line therapy for advanced BTC, the genomic determinants of treatment outcome have remained unclear.
METHODS: We investigated the relation between genomic alterations and overall survival (OS) in BTC patients treated with first-line GC or GC + ICI using data from the Japanese Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database.
RESULTS: Among 1875 BTC patients with available OS data, genomic alterations of TP53 (53.3%), CDKN2A (25.4%), and KRAS (21.0%) were the most frequently identified and were significantly associated with inferior OS in both GC and GC + ICI groups. TP53 and KRAS mutations showed numerically higher hazard ratios (HRs) in the GC + ICI group than in the GC group (HR of 1.53 [95% confidence interval (CI), 1.25-1.88] vs. 1.29 [95% CI, 1.03-1.61] for TP53; HR of 1.78 [95% CI, 1.45-2.17] vs. 1.40 [95% CI, 1.07-1.83] for KRAS), whereas CDKN2A alterations showed similar effects across treatments. The TP53/KRAS double-mutant subgroup showed the poorest survival outcome, with shorter median OS on GC + ICI than on GC (11.8 vs. 15.9 months; HR, 1.47 [95% CI, 0.99-2.18]), although no significant interaction between treatment and double-mutant status was observed (interaction P = 0.1655).
CONCLUSION: TP53 and KRAS co-mutation may identify a molecular subset of BTC with poor prognosis in the context of GC + ICI.
METHODS: We investigated the relation between genomic alterations and overall survival (OS) in BTC patients treated with first-line GC or GC + ICI using data from the Japanese Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database.
RESULTS: Among 1875 BTC patients with available OS data, genomic alterations of TP53 (53.3%), CDKN2A (25.4%), and KRAS (21.0%) were the most frequently identified and were significantly associated with inferior OS in both GC and GC + ICI groups. TP53 and KRAS mutations showed numerically higher hazard ratios (HRs) in the GC + ICI group than in the GC group (HR of 1.53 [95% confidence interval (CI), 1.25-1.88] vs. 1.29 [95% CI, 1.03-1.61] for TP53; HR of 1.78 [95% CI, 1.45-2.17] vs. 1.40 [95% CI, 1.07-1.83] for KRAS), whereas CDKN2A alterations showed similar effects across treatments. The TP53/KRAS double-mutant subgroup showed the poorest survival outcome, with shorter median OS on GC + ICI than on GC (11.8 vs. 15.9 months; HR, 1.47 [95% CI, 0.99-2.18]), although no significant interaction between treatment and double-mutant status was observed (interaction P = 0.1655).
CONCLUSION: TP53 and KRAS co-mutation may identify a molecular subset of BTC with poor prognosis in the context of GC + ICI.