Coexistence of TP53 and KRAS mutations identifies a molecular subset of biliary tract cancer with poor overall survival after first-line immunochemotherapy.

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.