Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, Office 1021, New York, NY, USA.
Internal Medicine, Mount Sinai Morningside West Hospital Center, New York, NY, USA.
Cancer Metastasis Rev. 2021 Sep;40(3):891-908. doi: 10.1007/s10555-021-09983-1. Epub 2021 Aug 17.
Pancreas ductal adenocarcinoma (PDAC) is the third most common cause of cancer death in the USA. While other cancers with historically poor prognoses have benefited from new immunotherapies and targeted agents, the 5-year survival rate for PDAC patients has remained static. The accessibility to genomic testing has improved in recent years, and it is now clear that PDAC is a heterogenous disease, with a subset of patients harboring actionable mutations. There are several targeted therapies approved by the Food and Drug administration (FDA) in PDAC: EGFR inhibitor erlotinib (combined with gemcitabine) in unselected patients, TRK inhibitors larotrectinib and entrectinib for patients with NTRK fusion mutation, the PD-1 inhibitor pembrolizumab for mismatch repair-deficient patients, and the poly-ADP-ribose polymerase (PARP) inhibitor olaparib in patients with germline BRCA mutation as a maintenance therapy. DNA damage repair (DDR) is paramount to genomic integrity and cell survival. The defective repair of DNA damage is one of the hallmarks of cancer, and abnormalities in DDR pathways are closely linked with the development of malignancies and upregulation of these pathways linked with resistance to treatment. The prevalence of somatic and germline mutations in DDR pathways in metastatic PDAC is reported to be approximately 15-25%. Patients with DDR gene alterations benefit from a personalized approach to treatment. Recently, the POLO trial demonstrated a progression-free survival (PFS) benefit in metastatic PDAC patients with a germline BRCA1/2 mutation treated with maintenance olaparib following platinum-based induction chemotherapy. This was the first phase 3 randomized trial to establish a biomarker-driven approach in the treatment of PDAC and establishes a precedent for maintenance therapy in PDAC. The review herein aims to outline the current treatment landscape for PDAC patients with DDR gene-mutated tumors, highlight novel therapeutic approaches focused on surmounting tumor resistance, and explore new strategies which may lead to an expansion in the number of patients who benefit from these targeted treatments.
胰腺导管腺癌 (PDAC) 是美国第三大常见癌症死因。虽然其他历史上预后较差的癌症受益于新的免疫疗法和靶向药物，但 PDAC 患者的 5 年生存率仍然保持不变。近年来，基因组检测的可及性有所提高，现在很明显，PDAC 是一种异质性疾病，其中一部分患者存在可靶向的突变。目前已有几种靶向疗法获得美国食品和药物管理局 (FDA) 的批准：针对未选择的患者的 EGFR 抑制剂厄洛替尼（与吉西他滨联合使用）、针对 NTRK 融合突变患者的 TRK 抑制剂拉罗替尼和恩曲替尼、针对错配修复缺陷患者的 PD-1 抑制剂派姆单抗，以及针对种系 BRCA 突变患者的多聚 ADP-核糖聚合酶 (PARP) 抑制剂奥拉帕利作为维持治疗。DNA 损伤修复 (DDR) 对基因组完整性和细胞存活至关重要。DNA 损伤的修复缺陷是癌症的标志之一，DDR 途径的异常与恶性肿瘤的发展密切相关，这些途径的上调与治疗耐药性有关。转移性 PDAC 中 DDR 途径的体细胞和种系突变的发生率约为 15-25%。DDR 基因突变的患者受益于个性化治疗方法。最近，POLO 试验表明，在接受基于铂类的诱导化疗后，接受维持奥拉帕利治疗的携带种系 BRCA1/2 突变的转移性 PDAC 患者的无进展生存期 (PFS) 得到了改善。这是第一项在 PDAC 治疗中建立基于生物标志物的方法的 III 期随机试验，并为 PDAC 的维持治疗确立了先例。本文旨在概述 DDR 基因突变肿瘤的 PDAC 患者的当前治疗现状，重点介绍克服肿瘤耐药性的新治疗方法，并探讨可能使更多患者受益于这些靶向治疗的新策略。
