胰腺癌精准治疗的现状和展望
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中国人民解放军海军军医大学附属长海医院 肝胆胰脾外科,上海 200433

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金钢,中国人民解放军海军军医大学附属长海医院主任医师,主要从事胰腺、肝胆肿瘤精准医学方面的研究。

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上海申康医院发展中心促进市级医院临床技能与临床创新能力三年行动计划资助项目(SHDC2020CR2001A)。


Current status and future perspective of precision medicine in pancreatic cancer treatment
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Department of Hepatobiliary and Pancreatic Surgery, Changhai Hospital, Navy Military Medical University, Shanghai 200433, China

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    摘要:

    胰腺癌恶性程度高,预后差,目前群体研究证据所提供的治疗方案对改善胰腺癌的预后效果有限。究其原因,还是由于胰腺癌高度恶性的生物学行为以及个体间的异质性造成了其治疗效果的差异。精准治疗模式在癌症领域的蓬勃发展也为胰腺癌的治疗带来了新的希望。目前胰腺癌在靶向治疗、分子分型、个体化肿瘤模型等方面都有了一些进展,为精准治疗模式在胰腺癌治疗领域的应用提供了基础。胰腺癌的四大驱动突变(KRAS、TP53、CDKN2A、SMAD4)在胰腺癌的发生发展中起着重要作用,但目前还缺乏相对应的靶向药物。II期临床试验证实AMG510对有KRAS G12C突变的实体瘤患者治疗效果显著,但KRAS G12C突变在胰腺癌患者中占比较低。POLO试验结果提示奥拉帕利可以提高BRCA基因胚系突变的转移性胰腺癌患者的无进展生存期,基于此结果,NCCN指南已推荐奥拉帕利用于BRCA1/2基因胚系突变晚期胰腺癌的维持治疗。此外,KEYNOTE-158 II期临床试验提示存在错配修复缺陷相关基因(MLH1、MSH2等)突变以及高度微卫星不稳定的胰腺癌患者可能从PD-1抑制剂的治疗中获益。总体上看,目前胰腺癌可干预靶点较少,针对四大高频突变及其相关通路靶向药物的研发是胰腺癌精准治疗的重要方向。相对于传统的病理学分型,转录组学分型从胰腺癌患者的基因表达差异对患者进行分型,为精准治疗的实施提供更多有价值的信息。从2011年首个胰腺癌转录组学分型被提出后,已有多个研究从不同角度提出了新的转录组学分型标准。综合来看,根据转录组学特征可以将胰腺癌大致分为两型:经典型和基底样型。相对于经典型胰腺癌,基底样型胰腺癌对化疗的反应不佳,预后也更差。未来的研究中,表观遗传学和蛋白组学的发展可能会为胰腺癌的分子分型和临床转化提供新的路径。个体化肿瘤模型可以为癌症患者筛选潜在有效的治疗药物,是胰腺癌个体化治疗的又一重要途径。相对于传统的肿瘤细胞系,人源肿瘤异种移植模型(PDX)和类器官更好地保留了肿瘤的分子特征和生物学行为特征。我中心的研究实践证实了胰腺癌PDX和类器官有相对较高的建模成功率,其中类器官模型可以准确预测患者对化疗药物的敏感性。但是PDX和类器官在肿瘤微环境上与人体有较大差别,同时建模方法和药敏检测也缺乏统一标准,限制了其推广和应用。总体上看,胰腺癌的精准治疗还处于探索阶段。未来胰腺癌精准治疗的发展应侧重于借助多组学探索胰腺癌治疗的新靶点、建立生物样本库加速药物的临床前研究、开展前瞻性临床试验促进基础研究成果的临床转化。随着基础医学的进步以及精准医疗实践的深入,精准医疗模式一定能为胰腺癌的治疗带来更多的希望。

    Abstract:

    Pancreatic cancer is highly malignant with a dismal outcome. Current treatment protocols based on cohort studies have limited efficacy in improving its prognosis. This may be caused by the heterogeneity of pancreatic cancer among individuals, which leads to different biological properties and different therapeutic outcomes. The rapid development of precision medicine may bring hope for pancreatic cancer. In recent years, some progress has been made in in areas such as targeted therapy, molecular subtyping and personalized tumor model for pancreatic cancer, which enable the application of precision treatment strategies in pancreatic cancer. The four major driver mutations (KRAS/TP53/CDKN2A/SMAD4) play an important role in the development of pancreatic cancer, but there are no targeted drugs available in clinical practice. A phase II clinical trial demonstrated that AMG510 was effective in solid tumor patients with KRAS G12C mutation, but the KRAS G12C mutation frequency was relatively low in pancreatic cancer. The POLO trial suggested that olaparib can improve progression-free survival in metastatic pancreatic cancer patients with germline BRCA mutations. Based on this result, NCCN guideline recommended olaparib for maintenance treatment of advanced pancreatic cancer with germline BRCA1/2 mutations. In addition, the phase II KEYNOTE-158 study suggested that pancreatic cancer patients who were deficient in DNA mismatch repair (dMMR) and have high microsatellite instability may benefit from anti-programmed death-1 therapy with pembrolizumab. In general, the actionable targets for pancreatic cancer are inadequate. Therefore, researches on drugs that targeting the four high frequency mutations and their related pathways are important for precision treatment of pancreatic cancer. Compared with traditional pathological subtyping, transcriptomic subtyping uses mRNA (transcriptome) profiling to define intrinsic molecular subtypes, which can provide more valuable information for the implementation of precision therapy. The first transcriptome subtyping system for pancreatic cancer was proposed in 2011. After that, several studies have proposed new transcriptome subtyping systems. In general, according to the transcriptome profiling, pancreatic cancer can be defined as two subtypes: the classical and basal-like subtypes. The basal-like subtypes seem more resistant to chemotherapy and have a worse prognosis than the classical subtypes. In the future, advances in epigenetics and proteomics may provide new avenues for the clinical application of molecular subtyping.Personalized tumor model can screen potential effective drugs for cancer patients, which is an important approach for individual treatment. Compared with traditional tumor cell lines, patient-derived tumor xenograft (PDX) and organoid retain the molecular and biological characteristics of pancreatic cancer. Our center's practices on PDX and organoid research have confirmed that these two models have high success rate of cultivation, and organoid model can accurately predict patient response to chemotherapy. However, PDX and organoid have different tumor microenvironment from patients, and there is no standard for modeling methods and drug sensitivity test, which limits their application. Overall, the precision medicine approach for pancreatic cancer is still in the preliminary stage. The future researches should focus on finding new therapeutic targets for pancreatic cancer by means of multi-omics, establishing biobanks to accelerate preclinical researches of new drugs, and conducting prospective clinical trials to promote clinical translation of basic scientific achievements. In the future, the precision medicine will certainly offer more options for the treatment of pancreatic cancer.

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王欢,金钢.胰腺癌精准治疗的现状和展望[J].中国普通外科杂志,2021,30(9):997-1005.
DOI:10.7659/j. issn.1005-6947.2021.09.001

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  • 收稿日期:2021-07-28
  • 最后修改日期:2021-08-27
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  • 在线发布日期: 2021-10-09