Abstract：
An important subgroup of pancreatic ductal adenocarcinomas (PDACs) harbor pathogenic variants in BRCA1, BRCA2, or PALB2. These tumors are exquisitely sensitive to platinum-based chemotherapy and patients may experience deep and durable responses to this treatment. PARP inhibitors offer potential respite from the cumulative toxicities of chemotherapy as they significantly extend progression-free survival compared to a chemotherapy holiday. Given the lack of proven survival benefit, the decision to use a maintenance PARP inhibitor rather than continue chemotherapy should be individualized. Interestingly, in both published clinical trials of maintenance PARP inhibitors, there is a striking range of interpatient benefit: Even in the platinum-sensitive setting, roughly 25% of tumors appear to be PARP inhibitor refractory (progressive disease within 2 months of starting treatment), 50% sustain moderate benefit (up to 2 years), and 25% are hyper-responsive (more than 2 years of benefit). This finding highlights the need to refine our understanding of which patients will respond to maintenance PARP inhibitors, both by being able to identify biallelic loss and by deepening our knowledge of resistance mechanisms and who develops them. Recent data supports that reversion mutations are common in PARP inhibitor refractory patients, but we have little understanding of the mechanisms that drive delayed resistance and long-term responses. Identifying which patients are more prone to certain mechanisms of resistance and tackling them with specific treatment strategies are areas of active investigation. Additionally, given that PARP inhibitors have limited overall efficacy for most patients, upfront combination strategies are an important future strategy.
摘要：
■胰腺导管腺癌(PDACs)的一个重要亚组在BRCA1、BRCA2或PALB2中具有致病变异。这些肿瘤对基于铂的化疗非常敏感，患者可能会对这种治疗产生深刻而持久的反应。PARP抑制剂为化疗的累积毒性提供了潜在的缓解，因为与化疗假期相比，它们显着延长了无进展生存期。鉴于缺乏经证实的生存益处，使用维持PARP抑制剂而不是继续化疗的决定应个体化.有趣的是,在两项已发表的维持PARP抑制剂临床试验中，有一个惊人的范围的病人间的好处：即使在铂敏感的设置，大约25％的肿瘤似乎是PARP抑制剂难治性（在开始治疗的2个月内进行性疾病），50%的人维持中等效益(长达2年)，和25％是反应过度（超过2年的好处）。这一发现强调了需要完善我们对哪些患者会对维持PARP抑制剂产生反应的理解。通过能够识别双等位基因损失，以及加深我们对抗性机制和发展它们的认识。最近的数据支持逆转突变在PARP抑制剂难治性患者中很常见，但是我们对驱动延迟阻力和长期反应的机制知之甚少。确定哪些患者更容易受到某些抵抗机制的影响，并用特定的治疗策略来解决这些问题是积极研究的领域。此外,鉴于PARP抑制剂对大多数患者的总体疗效有限，前期组合策略是重要的未来策略。
