Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY.
JCO Precis Oncol. 2024 Feb;8:e2300534. doi: 10.1200/PO.23.00534.
Intrahepatic cholangiocarcinoma (ICCA) is characterized by significant phenotypic and clinical heterogeneities and poor response to systemic therapy, potentially related to underlying heterogeneity in oncogenic alterations. We aimed to characterize the genomic heterogeneity between primary tumors and advanced disease in patients with ICCA.
Biopsy-proven CCA specimens (primary tumor and paired advanced disease [metastatic disease, progressive disease on systemic therapy, or postoperative recurrence]) from two institutions were subjected to targeted next-generation sequencing. Overall concordance (oncogenic driver mutations, copy number alterations, and fusion events) and mutational concordance (only oncogenic mutations) were compared across paired samples. A subgroup analysis was performed on the basis of exposure to systemic therapy. Patients with extrahepatic CCA (ECCA) were included as a comparison group.
Sample pairs from 65 patients with ICCA (n = 54) and ECCA (n = 11) were analyzed. The median time between sample collection was 19.6 months (range, 2.7-122.9). For the entire cohort, the overall oncogenic concordance was 49% and the mutational concordance was 62% between primary and advanced disease samples. Subgroup analyses of ICCA and ECCA revealed overall/mutational concordance rates of 47%/58% and 60%/84%, respectively. Oncogenic concordance was similarly low for pairs exposed to systemic therapy between sample collections (n = 50, 53% overall, 68% mutational). In patients treated with targeted therapy for alterations (n = 6) or fusions (n = 3), there was 100% concordance between the primary and advanced disease specimens. In two patients, (n = 1) and (n = 1) alterations were detected de novo in the advanced disease specimens.
The results reflect a high degree of heterogeneity in ICCA and argue for reassessment of the dominant driver mutations with change in disease status.
肝内胆管癌（ICCAs）的表型和临床异质性显著，对全身治疗反应不佳，这可能与致癌改变的潜在异质性有关。我们旨在描述 ICCA 患者的原发肿瘤与晚期疾病之间的基因组异质性。
对来自两个机构的经活检证实的 CCA 标本（原发肿瘤和配对的晚期疾病[转移性疾病、全身治疗进展性疾病或术后复发]）进行靶向下一代测序。比较配对样本之间的总体一致性（致癌驱动突变、拷贝数改变和融合事件）和突变一致性（仅致癌突变）。根据是否接受全身治疗进行亚组分析。将肝外胆管癌（ECCA）患者作为对照组纳入。
对 65 例 ICCA 患者（n=54）和 11 例 ECCA 患者（n=11）的样本对进行了分析。样本采集的中位时间为 19.6 个月（范围：2.7-122.9）。对于整个队列，原发和晚期疾病样本之间的总体致癌一致性为 49%，突变一致性为 62%。对 ICCA 和 ECCA 的亚组分析显示，整体/突变一致性分别为 47%/58%和 60%/84%。在样本采集之间接受全身治疗的配对中，致癌一致性也较低（n=50，总体一致性为 53%，突变一致性为 68%）。在接受针对 改变（n=6）或 融合（n=3）的靶向治疗的患者中，原发和晚期疾病标本之间存在 100%的一致性。在两名患者中，在晚期疾病标本中检测到新的 （n=1）和 （n=1）改变。
这些结果反映了 ICCA 存在高度的异质性，这表明在疾病状态发生变化时需要重新评估主要驱动突变。
