Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
Penn Center for Cancer Care Innovation, University of Pennsylvania, Philadelphia, Pennsylvania.
Clin Cancer Res. 2023 Dec 15;29(24):5207-5216. doi: 10.1158/1078-0432.CCR-23-1467.
PARP inhibitors (PARPi) provide an effective maintenance option for patients with BRCA- or PALB2-mutated pancreatic cancer. However, mechanisms of PARPi resistance and optimal post-PARPi therapeutic strategies are poorly characterized.
We collected paired cell-free DNA samples and post-PARPi clinical data on 42 patients with advanced, platinum-sensitive pancreatic cancer who were treated with maintenance rucaparib on NCT03140670, of whom 32 developed progressive disease.
Peripherally detected, acquired BRCA or PALB2 reversion variants were uncommon (5/30; 16.6%) in patients who progressed on rucaparib. Reversions were significantly associated with rapid resistance to PARPi treatment (median PFS, 3.7 vs. 12.5 months; P = 0.001) and poor overall survival (median OS, 6.2 vs. 23.0 months; P < 0.0001). All patients with reversions received rechallenge with platinum-based chemotherapy following PARPi progression and experienced faster progression on this therapy than those without reversion variants (real-world time-to-treatment discontinuation, 2.4 vs. 5.8 months; P = 0.004). Of the patients who progressed on PARPi and received further chemotherapy, the OS from initiation of second-line therapy was significantly lower in those with reversion variants than in those without (5.5 vs. 12.0 months, P = 0.002). Finally, high levels of tumor shedding were independently associated with poor outcomes in patients who received rucaparib.
Acquired reversion variants were uncommon but detrimental in a population of patients with advanced BRCA- or PALB2-related pancreatic ductal adenocarcinoma who received maintenance rucaparib. Reversion variants led to rapid progression on PARPi, rapid failure of subsequent platinum-based treatment, and poor OS of patients. The identification of such variants in the blood may have both predictive and prognostic value. See related commentary by Tsang and Gallinger, p. 5005.
聚腺苷二磷酸核糖聚合酶（PARP）抑制剂（PARPi）为 BRCA 或 PALB2 突变的胰腺癌患者提供了一种有效的维持治疗选择。然而，PARPi 耐药的机制和最佳的 PARPi 后治疗策略尚未得到充分描述。
我们收集了 42 名接受 NCT03140670 方案中维持治疗鲁卡帕尼的晚期铂类敏感胰腺癌患者的配对游离 DNA 样本和 PARPi 后临床数据，其中 32 名患者疾病进展。
在鲁卡帕尼进展的患者中，外周检测到的获得性 BRCA 或 PALB2 回复变异很少见（5/30；16.6%）。回复与 PARPi 治疗的快速耐药显著相关（中位 PFS，3.7 与 12.5 个月；P=0.001）和总体生存不良（中位 OS，6.2 与 23.0 个月；P<0.0001）。所有出现回复的患者在 PARPi 进展后接受了铂类化疗的再挑战，并且在这种治疗中比没有回复变异的患者更快进展（实际治疗停止时间，2.4 与 5.8 个月；P=0.004）。在 PARPi 进展并接受进一步化疗的患者中，具有回复变异的患者从二线治疗开始的 OS 明显低于没有回复变异的患者（5.5 与 12.0 个月，P=0.002）。最后，高水平的肿瘤脱落与接受鲁卡帕尼治疗的患者的不良结局独立相关。
在接受维持治疗鲁卡帕尼的晚期 BRCA 或 PALB2 相关胰腺导管腺癌患者中，获得性回复变异虽然少见，但却有害。回复变异导致 PARPi 快速进展、随后的铂类治疗迅速失败以及患者的总体生存不良。在血液中识别这些变异可能具有预测和预后价值。有关评论见 Tsang 和 Gallinger 的文章，第 5005 页。
