胆道恶性肿瘤（BTC）包括肝内胆管癌（iCCA）、肝门周围胆管癌（pCCA）、肝外胆管癌（eCCA）和胆囊癌（GBC），约占消化道恶性肿瘤3%［1］。BTC早期即可发生肿瘤转移，预后差，且BTC发病率和死亡率呈上升趋势，主要是由于iCCA的发病率在过去30年内有所上升［2－3］。原发性硬化性胆管炎、先天性胆管扩张症、肝胆管结石和肝吸虫病等是诱发胆管癌的危险因素［4］。手术是目前BTC唯一可能治愈的方法，但大多数患者在诊断时处于晚期，失去手术机会，因此系统治疗成为晚期BTC最主要的治疗手段［5］。现阶段，化疗仍是晚期BTC系统治疗的基础，但随着精准治疗理念的发展和基因检测技术的进步，更多BTC的治疗靶点被发现，为BTC治疗领域带来新的突破。
Courage malignant neoplasms (BTC) include cerebral carcinomas in the liver (iCCA), cerebral carcinomas around the liver (pCCA), hepatocytic carcinomas (eCCA) and cystic carcinomas (GBC), which account for about 3% [1] of the malignant carcinomas in the digestive tract. BTC is expected to undergo tumor transfer early on, and the incidence of morbidity and mortality in the BTC has increased, mainly because of the increase in the incidence of iCCA in the last 30 years[2-3]. Ingenuity sclerosis, congenital chorebular expansion, hepatobolism and hepatocytic insectosis are among the risk factors that induce cerebral cancer [4]. Surgical surgery is currently the only possible cure for BTC, but most patients are late in their diagnosis and have lost their surgical opportunities, thus making systematic treatment the most important treatment of BTC [5].
1BTC的诊断
BTC常见的症状有黄疸、腹痛、恶心、呕吐、上腹部包块等。血清癌胚抗原和糖类抗原19－9在BTC的诊断、疗效和转移复发监测方面有重要的作用，常与腹部超声相结合，用于高危人群的筛查与随访［6］。超声、磁共振胰胆管成像、CT、MRI及PET/CT是诊断BTC的重要手段，术前的影像学分期常依赖于腹部增强CT或增强MRI。但病理组织学和/或细胞学检查仍是确诊BTC的唯一依据和金标准。对于影像学上高度怀疑BTC且认为不可切除时，需要通过经皮肝穿刺活检、胆道镜活检、内镜逆行胰胆管造影下胆道细胞刷检获得标本进行病理确诊。同时，若可获得足够的组织进行基因检测，可用于指导系统治疗药物的选择，达到精准诊疗的目的。此外，液体活检技术通过对患者体液中的生物分子如循环肿瘤DNA、循环游离DNA进行分子分析，对个体化治疗及预后具有一定价值［7－8］。
The symptoms common to BTC are yellow, abdominal abdominal pain, nausea, vomiting, upper abdominal buns, etc. The serum cancer embryos and sugar antigens have an important role in the diagnosis, treatment and transfer monitoring of BTC, often combined with the abdominal ultrasound for screening and follow-up of high-risk populations[6]. Ultrasound, magnetic resonance pancreas, CT, MRI, and PET/CT are important tools for diagnosing BTC, and pre-applemental video stages are often dependent on the abdominal enhancement of CT or MRI.
当前常见的基因检测方法有数字聚合酶链式反应（d－PCR）、荧光原位杂交（FISH）和下一代测序技术（NGS）。d－PCR为三代PCR，是将稀释后的样本DNA分别放入扩增槽进行扩增，适用于含有大量正常细胞而只有少量突变细胞的样本，具有高水平的敏感性和特异性，且价格相对便宜。FISH利用特异分子探针和荧光标志物，对被检样本进行定性、定量或相对定位分析，既能检测DNA，也可检测RNA，实验周期短且特异性良好，但无法检测到实体肿瘤中发生的大多数突变类型。目前基于NGS主要有3类检测方案——目标疾病类捕获测序、全外显子测序、全基因组测序。基于DNA的NGS可以检测任何类型的基因组改变，包括单核苷酸变异、插入缺失、重排、扩增等，在肿瘤精准治疗时代，高度选择性的单基因检测常不作为首选考虑，靶向NGS组合在常规诊断中得到应用，具有更高的灵敏度、更快的检测时间和更低的成本等优势［9］。
Current common methods of genetic detection include digital polymerase chain reactions (d-PCR), fluorescent in situ hybrids (FISH) and next generation sequencing techniques (NGS).d-PCRs are three generations of PCRs that expand the diluted sample DNA into an augmentation tank, applying to samples containing a large number of normal cells with only a small number of mutation cells, with a high level of sensitivity and specificity, and relatively inexpensive. FISH uses special molecule probes and fluorescent markers to characterize, quantify or relative positioning analysis of the tested sample, which can detect both DNA and RNA, with a short experimental cycle and a good quality, but which cannot detect most of the mutations occurring in the entity tumor. Currently, based on NGS's three main types of detection programmes — target disease capture sequences, full-extravisive photo sequences, full-genetic sequence sequences, and a relatively inexpensive sequence.
2常见靶向基因及其靶向药物
2 > common target to genes and their target to drugs
2.1. 成纤维细胞生长因子受体（FGFR）基因
FGFR家族包括4种受体酪氨酸激酶，FGFR1～FGFR4结构类似，参与了包括血管生成、分化、发育、生存、组织修复和增殖在内的关键细胞功能［10－11］。在实体瘤中，FGFR突变率为7.1%，其中大多数是基因扩增（66%），其次是基因突变（26%）和基因重排（8%）［10］。在iCCA中也发现多种FGFR2相关基因改变，包括突变、扩增和基因融合/重排，发生率为15%～20%［12－13］。Pemigatinib和Infigratinib是两个最常见的FGFR2抑制剂，研究［14－15］表明二者具有可观的疗效及可控的不良反应，分别于2020年、2021年被美国食品药品监督管理局（FDA）批准作为晚期BTC患者的二线治疗，且Pemigatinib的客观缓解率（ORR）优于Infigratinib（35.5% vs 23.1%）。此外，有研究［16－17］表明Erdafitinib、Futibatinib等FGFR抑制剂在小样本胆道癌中展示出更优秀的疗效，有望在不久的将来获得更高等级的证据支持。FGFR抑制剂在晚期BTC一线治疗中的疗效以及耐药机制的研究将是未来研究的热点。
FGFR has a mutation rate of 7.1%, mostly genetic expansion (66%), followed by genetic mutation (26%) and retrenchment (8%) [10]. A number of FGFR2-related genetic changes have also been found in iCCA, including mutation, expansion and gene integration/retrenchment of 15% to 20% [12-13] of critical cell functions. Pemigatib and Infigratinib are two of the most common FGFR2 inhibitors, followed by genetic mutation (26%) and genetic retrenchment (8%).
2.2. 异柠檬酸脱氢酶1（IDH1）基因
2.2. genogen
IDH有4类亚型，分别为IDH1～IDH4，可催化异柠檬酸氧化脱羧生成α－酮戊二酸（α－KG），α－KG可作为多种酶的共底物［18］。IDH突变导致IDH异常，产生高水平的肿瘤代谢产物羟戊二酸R对映体［（R）—2HG］，可竞争性地调节表观遗传学、DNA修复、代谢和其他过程［19］。IDH1和IDH2是人类癌症中最常见的突变代谢基因，这些突变绝大多数发生在IDH1（R132）和IDH2（Q140和R172）的氨基酸残基上，其突变常出现在包括低级别胶质瘤、急性髓系白血病、软骨肉瘤和胆管癌在内的多种恶性肿瘤中［20］。在iCCA中IDH突变尤为常见，且欧美人群突变率显著高于亚洲人群［21］。此外，药物抑制IDH突变可以延缓iCCA的进展，进一步表明该致癌基因在肿瘤发生机制中的作用［21］。ClarIDHy试验［20］是首个IDH1抑制剂的多中心、随机、Ⅲ期临床研究，研究结果显示Ivosidenib可提高BTC患者1.3个月无进展生存期（PFS），常见不良反应包括恶心、腹泻、疲劳、咳嗽、腹痛、食欲下降、腹水、呕吐、贫血和便秘。目前该药已被FDA批准用于BTC的二线治疗。鉴于IDH突变在亚洲人群中并不常见，且PFS提高仅1.3个月，虽然已获批二线适应证，但在亚洲人群的应用前景并不乐观。
IDH has four subtypes, IDH1 - IDH4, which can competitively regulate genologic, DNA restoration, metabolic and other processes. IDH1 and IDH2 are the most common mutagenic genes in human cancers. The majority of these mutagenic acids occur on IDH1 (R132) and IDH2 (Q140 and R172), which produce high levels of neoplasmal metabolite hydroxydipic R against magnesium [(R)-2HG, which can be subjected to competitive regulation of transgenic genetics, DNA restoration, metabolism and other processes[19]. IDH1 and IDH2 are the most common mutant genes in human cancers.
2.3. 人表皮生长因子受体2（HER2）基因
HER2是表皮生长因子受体家族的一种蛋白酪氨酸激酶，已明确为非小细胞肺癌、乳腺癌、胃癌、食管癌和结直肠癌的重要治疗靶点［22］。包括BTC在内的含有HER2过表达的实体瘤和/或编码HER2（ERBB2）基因扩增突变的患者中正在积极探索HER2靶向治疗的疗效。5%～15%的BTC患者可发现HER2扩增和突变［12］。Neratinib是一种不可逆的泛HER口服酪氨酸激酶抑制剂，在HER2突变肿瘤中具有活性［23］。SUMMIT是一项单臂、Ⅱ期、“篮式”研究［24］，纳入11例胆管癌、10例GBC、4例壶腹癌，接受Neratinib治疗的ORR为12%，临床获益率为20%，中位PFS为2.8个月，中位总生存期（OS）为5.4个月，常见的治疗相关不良反应是腹泻（56%）和呕吐（48%）；腹泻是最常见的3级事件（24%）。MyPathway是一项非随机、Ⅱa期、多队列“篮式”研究［25］，纳入39例既往接受过治疗的转移性胆管癌伴HER2扩增、HER0过表达或两者兼有的患者，使用Trastuzumab+Pertuzumab双重HER2阻断靶向治疗方案，ORR为23%，最常见的治疗相关不良反应是转氨酶水平升高（5例），未出现与治疗相关的严重不良事件、与治疗相关的4级事件或死亡。抗体－药物偶联物是一类靶向癌症疗法，通过化学接头将单克隆抗体与细胞毒性有效载荷相结合，已被批准用于治疗多种癌症类型，并且正在进行新型构建体的广泛临床开发［26］。曲妥珠单抗——Deruxtecan（DS8201）是一种由抗HER2抗体、可切割的三肽连接子和拓扑异构酶Ⅰ抑制剂组成的抗体－药物偶联物。在HERB试验［27］中，22例HER2阳性的BTC患者，ORR为36.4%，疾病控制率（DCR）为81.8%，中位PFS为4.4个月，中位OS为7.1个月，该联合治疗方案具有较好的疗效及较低的不良反应发生率。HER2靶向药物在非小细胞肺癌、乳腺癌和胃癌等疾病中已被确立为标准治疗方案，BTC中虽然有一定比例的HER2扩增和突变，但HER2靶向单药治疗作用有限，目前的研究表明HER2双靶向治疗及HER2的抗体－药物偶联物显示出更有希望的结果。
Her2 is a protein sulfonic stimulant enzyme in the family of the mesothelioma, which has been identified as an important treatment target for non-small cell lung cancer, breast cancer, stomach cancer, dietary carcinoma and rectum carcinomas. [22], including BTC, among patients with her2 expressed physical tumors and/or codes Her2 (ERB2) genetic expansion, is actively exploring the efficacy of the Her2 target for treatment. 5-15% of BTC patients can find Her2 expansion and mutation [12]. Neratinib, an irreversible transverse HER sulfonic sulfonic stimulant inhibitor, 20% of which is used as an interruptible stimulant in the HER2 mutation tumor [23]. SUMIT is a single arm, II “basket” study [24], incorporating 11 bulge cancers, 10 GBCs, 4 kegs of cancer, 12% of which are used to treat the non-removation of Nerinib, and 20% of which are used to treat the anti-tractive stimulative stimulative sulative stimulative sulative stimulative sulants, 20% of which is used, 28.8 per cent of which is used the total PFS of which is used, 4 saturated saturated saturated.
2.4. BRAF基因
BRAF基因编码细胞质丝氨酸/苏氨酸激酶，构成MAPK/ERK信号传导的三层激酶级联反应，是研究最充分的致癌信号通路之一，信号级联的分层组成包括MAPKKK（例如BRAF）、MAPKK（例如MEK）和MAPK（例如ERK1/2）［28］。BTC中BRAF突变率为5%～7%，最常见的突变之一是BRAF V600E，BRAF突变导致MAPK通路激活，促使肿瘤的发生［29］。ROAR研究［29］是一项Dalafenib（BRAF激酶抑制剂）联合Trimetinib（MEK抑制剂）的Ⅱ期、单臂研究，其中纳入43例BTC，研究者评估的ORR为51%，独立评审委员会评估的ORR为47%，安全性可控。该研究显示BRAF和MEK抑制剂联合可获得高达51%的客观缓解，是BTC靶向治疗的又一重大突破。FDA最近批准Dalafenib联合Trimetinib方案用于治疗BRAF V600E突变的不可切除或转移性实体瘤。但鉴于较低的检出率，其获益群体较为有限。
The BRAF gene code cytostatic sulfonic acid/sultanic acid stimulant enzyme, which constitutes one of the most adequate routes for the study of the three-storey stimulant cascades for MAPK/ERK signal transmission, consists of MAPKKKK (e.g. BRAF), MAPK (e.g. MEK) and MAPK (e.g. ERK1/2) [28]. The BTC has a mutation rate of 5-7%. One of the most common mutagenics is the BRAF V600E, and the BRAF mutation caused by MAPK signal activation, prompting the occurrence of tumours.[29] The ROAR study[29] is a 2nd phase of MAPKK (e.g. BRAF) joint Trimetnib (MEK inhibitors) study, which incorporates 43 cases of BTC, the researcher assessed an ORR of 51% and the Independent Evaluation Committee assessed an ORR of 47%, which is controlled.
3免疫检查点抑制剂（ICI）
3strong> immunosuppressants (ICI)
肿瘤细胞中的免疫检查点通过多种途径抑制T淋巴细胞活化以发挥抗肿瘤作用［30］。靶向细胞毒性T淋巴细胞相关蛋白4、程序性细胞死亡1（PD－1）与配体PD－L1和PD－L2相互作用的ICI已被FDA批准用于恶性肿瘤［31］。在晚期黑色素瘤中，近50%的患者可以实现肿瘤消退和长期持久的癌症控制［32］。我国BTC患者中PD－L1阳性率约为35%，其表达水平与胆管癌的分期和预后密切相关［33］。在两项PD－L1阳性BTC患者的Pembrolizumab单药治疗研究［34］中，ORR分别为5.8%、13.0%，中位OS分别为7.4个月、5.7个月，中位PFS分别为2.0个月、1.8个月。因此，即使是在PD－L1阳性的BTC患者中，Pembrolizumab单药疗效仍然有限。Kim等［35］发表的一项关于Nivolumab的多中心、Ⅱ期研究结果显示，ORR为11%，DCR为50%，意向性治疗人群的中位PFS为3.68个月，中位OS为14.28个月。Nivolumab相对于Pembrolizumab显示出较好的耐受性和疗效，但仍需进一步研究证实。
The ICI, which interacts with the formulations PD-L1 and PD-L2, has been approved by the FDA for malignant tumours. In the late-stage black cancer, nearly 50% of patients are able to achieve tumor decomposition and long-lasting cancer control[32]. The PD-L1 positive rate in BTC patients in the country is about 35%, and its level of expression is closely related to the distribution and prognosis of chorebular cancer[33]. In two PD-L1 positive BTC patients, the Pembrozumab single drug study [34], the ORR 5.8%, 13.0%, the median OS7 months, the median PFS-1 positive is about 2.0 months, 1.8 months, and the medium-sized PFS is still required to conduct a further study, even in the PD-L1 positive BTC patients, of which the Pembuluzab drug treatment & 35% of the medium-use & PV3% of the medium-use of the medium-use of the PV.
4靶向治疗联合化疗
4 >. >...........................................................................................................................
目前，将新型靶向药物与传统化疗药物联用的相关研究取得了一定的进展。在KCSG－HB19－14试验［36］中，纳入了34例吉西他滨联合顺铂化疗方案治疗失败的HER2阳性BTC患者，使用奥沙利铂联合曲妥珠单抗（HER2抗体），ORR为46.3%，DCR为79.4%，中位PFS为5.1个月，中位OS为10.7个月。最常见的与治疗相关的3级或4级不良事件是中性粒细胞减少症（19例）、3级贫血（5例）和3级周围感觉神经病变（4例）。疗效结果较为理想，且药物不良反应可控，但缺乏更高级别证据支持。
At present, some progress has been made in linking new targets to traditional chemotherapy drugs. In the KCSG-HB 19-14 test [36], 34 cases of unsuccessful HER2 positive BTC treatments in the Gisita joint serotherapy therapy programme were included, using the Osali platinum combined vortex (HER2 antibodies), or 46.3 per cent in the ORR, 79.4 per cent in the DCR, or 5.1 months in the medium PFS, or 10.7 months in the middle. The most common treatment-related adverse events are moderate particle cell reduction (19 cases), level 3 anaemia (5 cases) and neuropathological changes around level 3 (4 cases).
5免疫治疗联合化疗
由于BTC的高度异质性，且缺乏肿瘤突变负荷和微卫星不稳定性等免疫生物标志物，单纯应用免疫疗法疗效不满意，因此免疫治疗与化疗药物的联合使用引起广泛关注。TOPAZ－1研究［37］评估了度伐利尤单抗+吉西他滨+顺铂对比安慰剂+吉西他滨+顺铂的安全性和有效性，纳入685例进展期胆道肿瘤患者，研究显示度伐利尤单抗组OS、PFS、ORR较安慰剂组均有明显改善，且无额外的毒副作用。因此，2022年中国临床肿瘤学会BTC指南［38］将度伐利尤单抗+吉西他滨+顺铂作为晚期胆道肿瘤一线化疗推荐的4个标准治疗方案之一。KEYNOTE－966研究［39］对比帕博利珠单抗+吉西他滨+顺铂与帕博利珠单抗单药的疗效，结果显示联合组中位OS为12.7个月，单药组中位OS为10.9个月。因此，此方案可以作为转移或不可切除的BTC的新的治疗方法。鉴于此，多个其他ICI与化疗药物联合的临床研究正在进行中，期待更多疗效更好的联合方案纳入指南，为晚期胆道肿瘤患者带来更好的疗效和安全性，提高患者的生存率。
Given the high heterogeneity of BTC and the lack of immunobiotic markers, such as tumor mutagenic loads and microsatellite instability, the combination of immunotherapy treatments and chemotherapy drugs has caused widespread concern. The TOPAZ-1 study[37] assessed the safety and effectiveness of the Vestiyu monolithal resistance plus gypsies plus cosmopolitan parrotsing + gistiana+synthesis, incorporating 685 cases of aggressive tumours during the progress period. The study showed that the Valium resistance OS, PFS, orrR's better placebots group had significantly improved, with no additional toxic side effects.
6靶免联合治疗
6 >
很多靶向疗法会影响免疫系统所需的信号传导途径，这表明靶向治疗存在优化免疫治疗反应的潜能，即靶免具有协同增效的作用［40］。MEK抑制剂作为单一疗法在BTC中的疗效有限，Yarchoan等［41］发现阿替利珠单抗（抗PD－L1）联合考比替尼（MEK抑制剂）治疗显示出有希望的结果，联合治疗组的中位PFS为3.65个月，而单药治疗组的中位PFS为1.87个月。进一步基因分析显示联合治疗可增强抗原加工和递呈基因以及某些抑制性配体的表达，提示该组合具有潜在的临床益处。小分子靶向药物瑞戈非尼在BTC患者中显示出显著的临床获益，且与免疫检查点抑制存在可能的协同作用。一项Ⅱ期临床试验［42］评估瑞戈非尼联合PD－1抑制剂Avelumab在BTC中的疗效，纳入34例患者，结果显示4例（13.8%）部分缓解，11例（37.9%）疾病稳定，中位PFS和中位OS分别为2.5个月和11.9个月，毒副作用可接受。虽然靶免联合治疗具有协同效应，但其整体疗效仍不理想，且不良反应需要格外注意。
Many of the targets have an impact on the signal transmission path required for the immune system, indicating that the target has the potential to optimize the immune treatment response, i.e. that the target has a synergistic effect [40]. MEK inhibitors have limited efficacy in BTC as a single therapy, Yarchoan et al.[41] find that the Adelijellist (anti-PD-L1) co-depressant (MEK inhibitor) treatment shows promising results, with the combined treatment of 3.65 months for the joint treatment team and 1.87 months for the single treatment group. Further genetic analysis shows that joint treatment can enhance antigen processing and transmission of genes and the expression of certain inhibitors in BTC, suggesting that the combination has potential clinical benefits. Small molecular targets show significant clinical benefits to the drug Rigofoni in BTC patients, with potential synergies with the immuno-censor containment site, and a clinical trial of 3.65 months for the joint treatment group and 1.87 months for the single drug treatment of Averumb for the single treatment group.
7小结
7 > >
尽管晚期BTC的整体预后差，但近年来，随着肿瘤精准诊疗理念的发展，研究者对BTC有了更深层次的认识。目前，针对BTC的治疗正逐步转向靶向、免疫、化疗的联合治疗模式，化疗与靶向药物和ICI的结合可能为BTC患者带来更多的临床获益，但多数临床研究仍处于Ⅱ期临床阶段。今后仍需进行更多Ⅲ期临床试验，以明确一线治疗方案，并筛选出潜在的受益人群。此外，仍需加深对BTC发病机制、分子生物学及耐药机制的研究，促进BTC个体化、精准化的治疗。
Despite the overall prognosis of the late BTC, in recent years there has been a deeper understanding of BTC by researchers as the concept of precision treatment for tumours has evolved. Currently, treatment for BTC is gradually shifting to joint treatment models for target direction, immunization, chemotherapy, and the combination of chemotherapy and target to drugs and ICI may bring additional clinical benefits to BTC patients, but most clinical research is still in phase II. More clinical trials of phase III are still needed to identify first-line treatment options and to identify potential beneficiaries. In addition, there is a need to deepen research on BTC mechanisms, molecular biology and drug resistance, and to promote BTC individualization and precision treatment.
http://www.lcgdbzz.org/cn/article/doi/10.3969/j.issn.1001-5256.2023.09.001
范瑞林, 丁宗仁, 曾永毅 . 胆道恶性肿瘤的精准诊疗[J]. 临床肝胆病杂志, 2023, 39(9): 2025-2030
Farrin, Ding Zongren, Tseng Yong-yi... Exact diagnosis of malignant neoplasms [J]. Clinical liver hysteria magazine, 2023, 39 (9): 2025-2030
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