Division of General and Hepatobiliary Surgery, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, University Hospital G.B. Rossi, Verona, Italy.
Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, University of Verona, University Hospital G.B. Rossi, Verona, Italy.
Int J Med Sci. 2023 May 11;20(7):858-869. doi: 10.7150/ijms.82008. eCollection 2023.
Biliary tract cancers (BTCs) are a heterogenous group of malignancies arising from the epithelial cells of the biliary tree and the gallbladder. They are often locally advanced or already metastatic at the time of the diagnosis and therefore prognosis remains dismal. Unfortunately, the management of BTCs has been limited by resistance and consequent low response rate to cytotoxic systemic therapy. New therapeutic approaches are needed to improve the survival outcomes for these patients. Immunotherapy, one of the newest therapeutic options, is changing the approach to the oncological treatment. Immune checkpoint inhibitors are by far the most promising group of immunotherapeutic agents: they work by blocking the tumor-induced inhibition of the immune cellular response. Immunotherapy in BTCs is currently approved as second-line treatment for patients whose tumors have a peculiar molecular profile, such as high levels of microsatellites instability, PD-L1 overexpression, or high levels of tumor mutational burden. However, emerging data from ongoing clinical trials seem to suggest that durable responses can be achieved in other subsets of patients. The BTCs are characterized by a highly desmoplastic microenvironment that fuels the growth of cancer tissue, but tissue biopsies are often difficult to obtain or not feasible in BTCs. Recent studies have hence proposed to use liquid biopsy approaches to search the blood circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) to use as biomarkers in BTCs. So far studies are insufficient to promote their use in clinical management, however trials are still in progress with promising preliminary results. Analysis of blood samples for ctDNA to research possible tumor-specific genetic or epigenetic alterations that could be linked to treatment response or prognosis was already feasible. Although there are still few data available, ctDNA analysis in BTC is fast, non-invasive, and could also represent a way to diagnose BTC earlier and monitor tumor response to chemotherapy. The prognostic capabilities of soluble factors in BTC are not yet precisely determined and more studies are needed. In this review, we will discuss the different approaches to immunotherapy and tumor circulating factors, the progress that has been made so far, and the possible future developments.
胆道癌（BTCs）是一组异质性恶性肿瘤，起源于胆管和胆囊的上皮细胞。这些肿瘤在诊断时往往已经局部晚期或转移，因此预后仍然很差。不幸的是，BTCs 的治疗受到了耐药性的限制，导致细胞毒性全身治疗的反应率较低。需要新的治疗方法来改善这些患者的生存结果。免疫疗法是最新的治疗选择之一，正在改变肿瘤治疗的方法。免疫检查点抑制剂是迄今为止最有前途的免疫治疗药物之一：它们通过阻断肿瘤诱导的免疫细胞反应抑制来发挥作用。免疫疗法在 BTCs 中的应用目前被批准作为肿瘤具有特殊分子特征（如高水平微卫星不稳定性、PD-L1 过表达或高肿瘤突变负担）的二线治疗。然而，正在进行的临床试验的新数据似乎表明，其他亚组的患者也可以获得持久的缓解。BTCs 的特点是高度促纤维化的微环境，促进癌症组织的生长，但组织活检通常很难获得或在 BTCs 中不可行。最近的研究因此提出使用液体活检方法来检测血液中的循环肿瘤细胞（CTCs）或循环肿瘤 DNA（ctDNA），作为 BTCs 的生物标志物。到目前为止，这些研究还不足以促进其在临床管理中的应用，但仍在进行临床试验，结果初步显示有前景。分析血液样本中的 ctDNA，以研究可能与治疗反应或预后相关的肿瘤特异性遗传或表观遗传改变已经是可行的。尽管目前可用的数据仍然很少，但 BTC 中的 ctDNA 分析快速、非侵入性，也可能代表更早诊断 BTC 并监测肿瘤对化疗反应的一种方法。可溶性因素在 BTC 中的预后能力尚未精确确定，需要更多的研究。在这篇综述中，我们将讨论免疫疗法和肿瘤循环因子的不同方法、迄今为止取得的进展以及未来可能的发展。
