IRCCS San Raffaele Scientific Institute Hospital, Vita-Salute San Raffaele University, Milan, Italy.
Department of Oncology, IRCCS San Raffaele Hospital, Via Olgettina n. 60, Milan, Italy.
Target Oncol. 2024 Mar;19(2):223-235. doi: 10.1007/s11523-024-01032-5. Epub 2024 Feb 12.
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.
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.
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.
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).
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.
TOPAZ-1 三期临床试验的结果导致顺铂和吉西他滨联合度伐利尤单抗被批准为局部晚期或转移性胆管癌患者的新一线治疗标准。
我们进行聚类分析，根据患者的突变情况将其分为不同的组，并将分析结果与临床结果相关联。
我们选择了 51 名接受化疗联合度伐利尤单抗治疗的胆管癌患者，并使用基于下一代测序的 FoundationOne 基因面板对其进行了筛选。我们对肿瘤进行了基于突变的聚类分析和生存分析。
确定了三个主要的聚类。聚类 1 主要特征是染色质修饰途径中的基因突变，100%的患者都发生了改变。聚类 2 的特点是多个途径的改变，其中 DNA 损伤控制、染色质修饰、RTK/RAS、细胞周期凋亡、TP53 和 PI3K 受到的影响最大。最后，聚类 3 中改变最明显的途径是 RTK/RAS 和细胞周期凋亡。在聚类 1、聚类 2 和聚类 3 中，总缓解率分别为 4/13（31%）、12/24（50%）和 0/10（0%），三组之间的差异具有统计学意义（p=0.0188）。
通过将患者分为具有不同分子和基因组改变的三个聚类，我们的分析表明，聚类 2 中的患者总缓解率更高，而聚类 3 中的患者没有客观缓解。需要进一步在更大的外部队列中进行研究以验证我们的结果。
