ctDNA for Prognostication and Monitoring in Patients with Metastatic Endometrial Carcinoma Treated with Olaparib: Validation in the GINECO-UTOLA Trial.

experimental_design

This ancillary analysis included patients from the multicenter, randomized, phase II GINECO-UTerin OLAparib (UTOLA) trial (NCT03745950) evaluating olaparib/placebo as maintenance after first-line platinum-based chemotherapy.

这项辅助分析包括了来自多中心、随机、II期的 GINECO-UTerin OLAparib (UTOLA) 试验（NCT03745950）的患者，该试验评估了在一线铂类化疗后使用奥拉帕利/安慰剂作为维持治疗的效果。

Plasma samples were collected at screening after chemotherapy (baseline), 3 months (M3), and progression. ctDNA detection was assessed by a validated methylation-based Droplet Digital PCR (MethddPCR) assay targeting DNA positions universally methylated in endometrial carcinoma.

血浆样本在化疗后筛选期（基线）、3个月（M3）和疾病进展时收集。ctDNA检测通过针对子宫内膜癌普遍甲基化的DNA位点进行验证的基于甲基化的液滴数字PCR（MethddPCR）测定法进行评估。

Results

Among 130 evaluable patients, ctDNA was detected in 25 of 129 (19%, 1 technical fail) at baseline, 15 of 80 (19%) at M3, and 33 of 52 (63%) at progression.

在130名可评估患者中，基线时在129名患者中有25名（19%，1例技术失败）检测到ctDNA，M3时在80名患者中有15名（19%）检测到ctDNA，疾病进展时在52名患者中有33名（63%）检测到ctDNA。

Baseline ctDNA positivity was independently associated with poorer progression-free survival(PFS) [median 1.81 vs. 7.39 months; adjusted HR = 5.33 (3.17-8.97)] and overall survival(OS) [10.3 vs. 24.7 months; adjusted HR = 3.98 (2.28-6.91); adjusted for age, stage IV at diagnosis, p53abn subgroup, and residual measurable lesions after chemotherapy].

基线ctDNA阳性与较差的无进展生存期（PFS）[中位数1.81 vs. 7.39个月；调整后风险比（HR）= 5.33 (3.17-8.97)]和总生存期（OS）[10.3 vs. 24.7个月；调整后HR = 3.98 (2.28-6.91)；根据年龄、诊断时IV期、p53异常亚组和化疗后残余可测量病变进行调整]独立相关。

Patients with baseline ctDNA had median OS of 9.36 months under olaparib versus 19.6 months under placebo (log-rank P = 0.05).

基线ctDNA阳性的患者在使用奥拉帕利治疗下的中位总生存期为9.36个月，而在安慰剂治疗下为19.6个月（对数秩检验P = 0.05）。

Patients with increasing ctDNA at M3 had median PFS of 1.67 months, versus 9.64 months without, and median OS of 18.8 versus 25.8 months. ctDNA rising was predictive of poor postprogression OS under olaparib but not under placebo (interaction test, P < 0.001).

在M3时ctDNA增加的患者中位无进展生存期（PFS）为1.67个月，而没有增加的患者为9.64个月；中位总生存期（OS）分别为18.8个月和25.8个月。ctDNA上升预示着在使用奥拉帕利治疗后进展生存期较差，但在安慰剂组中则没有这种预测性（交互作用检验，P < 0.001）。

Conclusions

MethddPCR-ctDNA is an independent prognostic biomarker for OS in advanced/metastatic endometrial carcinoma.

MethddPCR-ctDNA是晚期/转移性子宫内膜癌总生存期（OS）的独立预后生物标志物。

MethddPCR-ctDNA may identify patients unlikely to benefit from PARP inhibition, guide therapeutic decisions, and should be further evaluated as a new stratification parameter in future endometrial carcinoma trials.

MethddPCR-ctDNA可能识别出不太可能从PARP抑制中受益的患者，指导治疗决策，并应作为未来子宫内膜癌试验中的一个新的分层参数进行进一步评估。