Targeted oncology · 2024
Different Genomic Clusters Impact on Responses in Advanced Biliary Tract Cancer Treated with Cisplatin Plus Gemcitabine Plus Durvalumab.
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Rimini Margherita, Loi Eleonora, Rizzato Mario Domenico, Pressiani Tiziana, Vivaldi Caterina, Gusmaroli Eleonora, Antonuzzo Lorenzo, Martinelli Erika, Garajova Ingrid, Giordano Guido, Lucchetti Jessica, Schirripa Marta, Cornara Noemi, Rossari Federico, Vitiello Francesco, Amadeo Elisabeth, Persano Mara, Piva Vittoria Matilde, Balsano Rita, Salani Francesca, Pircher Chiara, Cascinu Stefano, Niger Monica, Fornaro Lorenzo, Rimassa Lorenza, Lonardi Sara, Scartozzi Mario, Zavattari Patrizia, Casadei-Gardini Andrea
Аннотация
BACKGROUND: The results reported in the TOPAZ-1 phase III trial led to the approval of the combination of cisplatin and gemcitabine with durvalumab as the new first-line standard of care for patients with locally advanced or metastatic cholangiocarcinoma.
OBJECTIVE: We performed a clustering analysis to classify patients into different groups based on their mutation profile, correlating the results of the analysis with clinical outcomes.
METHODS: We selected 51 patients with cholangiocarcinoma who were treated with the combination of chemotherapy and durvalumab and who were screened using the next-generation sequencing-based FoundationOne gene panel. We conducted mutation-based clustering of tumors and a survival analysis.
RESULTS: Three main clusters were identified. Cluster 1 is mostly characterized by mutations in genes belonging to the chromatin modification pathway, altered in 100% of patients. Cluster 2 is characterized by the alteration of several pathways, among which DNA damage control, chromatin modification, RTK/RAS, cell-cycle apoptosis, TP53, and PI3K were the most affected. Finally, most altered pathways in cluster 3 were RTK/RAS and cell-cycle apoptosis. Overall response rate was 4/13 (31%), 12/24 (50%), and 0/10 (0%) in cluster 1, cluster 2, and cluster 3, respectively, and the difference between the three clusters was statistically significant (p = 0.0188).
CONCLUSIONS: By grouping patients into three clusters with distinct molecular and genomic alterations, our analysis showed that patients included in cluster 2 had higher overall response rates, whereas patients included in cluster 3 had no objective response. Further investigations on larger and external cohorts are needed in order to validate our results.
OBJECTIVE: We performed a clustering analysis to classify patients into different groups based on their mutation profile, correlating the results of the analysis with clinical outcomes.
METHODS: We selected 51 patients with cholangiocarcinoma who were treated with the combination of chemotherapy and durvalumab and who were screened using the next-generation sequencing-based FoundationOne gene panel. We conducted mutation-based clustering of tumors and a survival analysis.
RESULTS: Three main clusters were identified. Cluster 1 is mostly characterized by mutations in genes belonging to the chromatin modification pathway, altered in 100% of patients. Cluster 2 is characterized by the alteration of several pathways, among which DNA damage control, chromatin modification, RTK/RAS, cell-cycle apoptosis, TP53, and PI3K were the most affected. Finally, most altered pathways in cluster 3 were RTK/RAS and cell-cycle apoptosis. Overall response rate was 4/13 (31%), 12/24 (50%), and 0/10 (0%) in cluster 1, cluster 2, and cluster 3, respectively, and the difference between the three clusters was statistically significant (p = 0.0188).
CONCLUSIONS: By grouping patients into three clusters with distinct molecular and genomic alterations, our analysis showed that patients included in cluster 2 had higher overall response rates, whereas patients included in cluster 3 had no objective response. Further investigations on larger and external cohorts are needed in order to validate our results.