Bloomberg-Kimmel Institute, Sidney Kimmel Comprehensive Cancer Center, and The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Bloomberg-Kimmel Institute, Sidney Kimmel Comprehensive Cancer Center, and The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Lancet Oncol. 2020 Mar;21(3):e135-e145. doi: 10.1016/S1470-2045(19)30795-8.
Pancreatic ductal adenocarcinoma is the seventh leading cause of cancer death worldwide with an estimated 432 242 deaths occurring in 2018. This estimate, in conjunction with the findings that pancreatic ductal adenocarcinoma incidence is rising and that pancreatic ductal adenocarcinoma has the highest case-fatality rate of any solid tumour, highlights the urgency for designing novel therapeutic strategies to combat this deadly disease. Through the efforts of the global research community, our knowledge of the factors that lead to the development of pancreatic ductal adenocarcinoma, its progression, and the interplay between tumour cells and their surrounding microenvironment have improved substantially. Although these scientific advances have not yet translated into targeted or immunotherapy strategies that are effective for most patients with pancreatic ductal adenocarcinoma, important incremental progress has been made particularly for the treatment of specific molecular subgroups of tumours. Although PD-1 inhibitors for mismatch-repair-deficient tumours and NTRK inhibitors for tumours containing NTRK gene fusions are the most recent targeted agents approved by the US Food and Drug Administration, olaparib for germline BRCA-mutated pancreatic ductal adenocarcinoma is expected to be approved soon in the maintenance setting. These recent advances show the accelerated pace at which pancreatic ductal adenocarcinoma drugs are achieving successful clinical outcomes. Here we review the current understanding of the pathophysiology of pancreatic ductal adenocarcinoma, recent advances in the understanding of the stromal microenvironment, current standard-of-care treatment, and novel therapeutic targets and strategies that hold promise for improving patient outcomes. We predict that there will be major breakthroughs in the treatment of pancreatic ductal adenocarcinoma in the next 5-10 years. These breakthroughs will result from the increased understanding of the treatment barriers imposed by the tumour-associated stroma, and from the development of novel approaches to re-engineer the tumour microenvironment in favour of effective anticancer responses.
胰腺导管腺癌是全球第七大癌症死亡原因，据估计，2018 年有 432242 人因此死亡。这一估计，加上胰腺导管腺癌发病率正在上升的事实，以及胰腺导管腺癌是所有实体瘤中病死率最高的事实，突显了设计新的治疗策略来对抗这种致命疾病的紧迫性。通过全球研究界的努力，我们对导致胰腺导管腺癌发展、进展以及肿瘤细胞与其周围微环境相互作用的因素的认识有了显著提高。尽管这些科学进展尚未转化为针对大多数胰腺导管腺癌患者有效的靶向或免疫治疗策略，但在治疗特定的肿瘤分子亚群方面已经取得了重要的进展。尽管针对错配修复缺陷肿瘤的 PD-1 抑制剂和含有 NTRK 基因融合的肿瘤的 NTRK 抑制剂是美国食品和药物管理局最近批准的靶向药物，但用于治疗种系 BRCA 突变胰腺导管腺癌的奥拉帕利有望很快在维持治疗中获得批准。这些最新进展表明，胰腺导管腺癌药物在取得成功的临床结果方面的步伐正在加快。在这里，我们回顾了对胰腺导管腺癌病理生理学的当前理解、对基质微环境的最新理解、当前的标准治疗方法以及有希望改善患者预后的新的治疗靶点和策略。我们预测，在未来 5-10 年内，胰腺导管腺癌的治疗将取得重大突破。这些突破将来自于对肿瘤相关基质所施加的治疗障碍的理解的增加，以及开发新的方法来重新设计肿瘤微环境，以促进有效的抗癌反应。
