Kasi Anup, Al-Jumayli Mohammed, Park Robin, Baranda Joaquina, Sun Weijing
Division of Medical Oncology, Department of Medicine, Kansas University Cancer Center, Kansas City, Kansas, USA.
Department of Medicine, MetroWest Medical Center/Tufts University School of Medicine, Framingham, Massachusetts, USA.
J Pancreat Cancer. 2020 Dec 4;6(1):107-115. doi: 10.1089/pancan.2020.0010. eCollection 2020.
Pancreatic ductal adenocarcinoma (PDAC) is the most common cancer found in the pancreas. It has a dismal prognosis and current therapeutic options, including surgical resection, provide only a temporary or limited response due to the development of treatment resistance. A narrative review of studies investigating poly (ADP-ribose) polymerase (PARP) pathway inhibitors in metastatic PDAC to highlight recent advances. Mutations in BRCA genes confer a higher risk of PDAC, while germ line mutations are found in 4-7% of individuals harboring pancreatic cancer. Although solid tumors with defective DNA damage repair defect (DDR) genes such as BRCA show heightened sensitivity to platinum agents, tumors can exploit the PARP pathway as salvage pathways. Therefore, blocking this pathway will trigger cell death in vulnerable tumor cells with BRCA/DNA repair deficiency. Several drugs with inhibitory activity on the PARP pathway have been approved for breast and ovarian tumors harboring germ line or somatic BRCA mutations. Based on these results, the phase III POLO study showed a significant improvement in progression-free survival compared with placebo in BRCA mutant pancreatic tumors and highlighted the importance of germ line testing in everyone diagnosed with pancreatic cancer. In addition, expansion of the PARP inhibitor indication beyond BRCA mutations to other genes involved in DDR such as ATM and PALB2 merits attention. PARP inhibitors represent a safe and efficacious treatment for a subset of PDAC patients with BRCA mutations. Ongoing trials are evaluating PARP inhibitors in PDAC patients with non-BRCA DDR gene deficiencies as well as PARP inhibitors in combination with other agents, notably immune checkpoint inhibitors to expand the group of patients that derive benefit from this treatment.
胰腺导管腺癌（PDAC）是胰腺中最常见的癌症。其预后不佳，目前的治疗选择，包括手术切除，由于治疗耐药性的出现，仅能提供暂时或有限的缓解。对转移性PDAC中研究聚（ADP - 核糖）聚合酶（PARP）途径抑制剂的研究进行叙述性综述，以突出近期进展。BRCA基因突变会增加患PDAC的风险，在4 - 7%的胰腺癌患者中发现有胚系突变。虽然具有缺陷DNA损伤修复缺陷（DDR）基因（如BRCA）的实体瘤对铂类药物表现出更高的敏感性，但肿瘤可以利用PARP途径作为挽救途径。因此，阻断该途径将触发具有BRCA/DNA修复缺陷的脆弱肿瘤细胞死亡。几种对PARP途径具有抑制活性的药物已被批准用于患有胚系或体细胞BRCA突变的乳腺癌和卵巢癌。基于这些结果，III期POLO研究表明，与安慰剂相比，BRCA突变型胰腺肿瘤的无进展生存期有显著改善，并突出了对所有确诊为胰腺癌的患者进行胚系检测的重要性。此外，将PARP抑制剂的适应症从BRCA突变扩展到其他参与DDR的基因，如ATM和PALB2，值得关注。PARP抑制剂对一部分具有BRCA突变的PDAC患者是一种安全有效的治疗方法。正在进行的试验正在评估PARP抑制剂在具有非BRCA DDR基因缺陷的PDAC患者中的疗效，以及PARP抑制剂与其他药物（特别是免疫检查点抑制剂）联合使用，以扩大从这种治疗中获益的患者群体。
