Genomic pathway alterations and their prognostic impact in biliary tract cancer: Insights from a multinational cohort treated with cisplatin, gemcitabine, and durvalumab.
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Pirrone Chiara, Malapelle Umberto, Pepe Francesco, Lo Prinzi Federica, Nichetti Federico, Saborowski Anna, Antonuzzo Lorenzo, Camera Silvia, Satake Tomoyuki, Peeters Frederik, Vivaldi Caterina, Pressiani Tiziana, Lucchetti Jessica, Kim Jin Won, Abidoye Oluseyi, Rapposelli Ilario Giovanni, Tamberi Stefano, Finkelmeier Fabian, Giordano Guido, Pircher Chiara, Chon Hong Jae, Braconi Chiara, Qaisar Aitzaz, Pastorino Alessandro, Castet Florian, Tamburini Emiliano, Yoo Changhoon, Parisi Alessandro, Diana Anna, Scartozzi Mario, Prager Gerald W, Avallone Antonio, Corallo Salvatore, Schirripa Marta, Kim Il Hwan, Perkhofer Lukas, Oneda Ester, Verrico Monica, Adeva Jorge, Chan Stephen L, Spinelli Gian Paolo, Personeni Nicola, Garajova Ingrid, Rodriquenz Maria Grazia, Leo Silvana, Alvim Cecilia Melo, Roque Ricardo, Farinea Giovanni, Salani Francesca, De Grandis Caterina, Lavacchi Daniele, Persano Mara, Ikeda Masafumi, Dekervel Jeroen, Niger Monica, Balsano Rita, Tonini Giuseppe, Kang Minsu, Bekaii-Saab Tanios, Esposito Luca, Boccaccino Alessandra, Himmelsbach Vera, Landriscina Matteo, De Cobelli Francesco, Ratti Francesca, Daniel Francesca, Tesini Giulia, Masi Gianluca, Vogel Arndt, Lonardi Sara, Rimini Margherita, Fornaro Lorenzo, Rimassa Lorenza, Casadei-Gardini Andrea
Аннотация
METHODS: This retrospective, multicenter study included 735 patients with advanced BTC, of whom 197 underwent comprehensive genomic profiling using the FoundationOne® CDx assay. Pathways were classified based on the presence of key gene alterations, and their association with overall survival (OS) and progression-free survival (PFS) was assessed through univariate and multivariate analyses. Tumor mutational burden (TMB) was also evaluated as a potential biomarker.
RESULTS: HRD/BRCAness pathway alterations were associated with significantly improved OS (23.3 vs. 13.8 months, HR 0.51, 95 % CI 0.27-0.93, p = 0.0295) and PFS (13.2 vs. 8.1 months, HR 0.53, 95 % CI 0.32-0.89, p = 0.0153). TGF-β pathway alterations were linked to longer PFS (16.0 vs. 8.1 months, HR 0.53, 95 % CI 0.28-0.99, p = 0.0473) but did not independently predict OS. High TMB (>10 mut/Mb) was associated with improved OS (NR vs. 11.0 months, HR 0.34, 95 % CI 0.14-0.85, p = 0.0206) and PFS (NR vs. 7.6 months, HR 0.40, 95 % CI 0.13-0.96, p = 0.043). However, no single pathway was significantly correlated with early treatment response.
CONCLUSIONS: HRD/BRCAness and TGF-β pathway alterations, along with high TMB, emerged as potential prognostic biomarkers in patients with BTC treated with chemo-immunotherapy. These findings, if prospectively confirmed and validated, support the integration of molecular profiling into routine clinical practice to improve patient stratification and treatment outcomes in this challenging tumor type.