PO.CL01.16 · 临床研究
ctDNA在转移性葡萄膜黑色素瘤患者中的预后意义
Prognostic significance of ctDNA in patients with metastatic uveal melanoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：循环肿瘤DNA（ctDNA）是实体瘤中一种新兴的预后生物标志物。然而，其在转移性葡萄膜黑色素瘤（mUM）中的独立预后价值仍未完全明确。我们评估了通过Signatera检测测量的基线ctDNA的预后意义，评估了其与已知预后因素（如LDH和肝转移）的关系，以及治疗期间ctDNA清除的影响。
方法：我们回顾性评估了在治疗开始前30天内采集了ctDNA的mUM患者。采用Kaplan-Meier（KM）法和Cox比例风险模型评估OS和PFS。基线ctDNA值分为3个等级：未检出（ND）、低（<5 MTM/mL）和高（>5 MTM/mL）。采用多因素Cox模型对LDH（经log转换）和肝转移进行校正。将ctDNA清除与持续阳性的ctDNA进行比较。作为预先设定的亚组，评估了接受一线tebentafusp治疗的患者。
结果：41例患者在一线治疗前进行了基线ctDNA测量；26例接受了一线tebentafusp治疗，66%的患者ctDNA可检出。较高的ctDNA水平与LDH升高相关。
在全队列中，可检出的ctDNA与较短的PFS相关（HR 3.07，95% CI 1.14-8.30；p=0.027）。在三等级分层中，高ctDNA（>5 MTM/mL）可预测较短的PFS（HR 4.65，95% CI 1.62-13.4；p=0.004），并接近对OS的显著性（HR 4.60，95% CI 0.97-21.8；p=0.055）。在KM分析中，各组之间的PFS（p=0.0048）和OS（p=0.011）均存在显著分离。作为连续变量，较高的ctDNA值（经log转换）强烈预测PFS（HR 2.23，95% CI 1.54-3.23；p<0.001）和OS（HR 3.26，95% CI 1.79-5.92；p<0.001）。在多因素分析中，ctDNA仍是PFS的独立预后因素（HR 1.75，95% CI 1.06-2.87；p=0.028）。
ctDNA清除与PFS改善相关（HR 0.25，95% CI 0.08-0.76；p=0.015）以及OS改善相关，清除组无死亡病例（HR无法计算）。
在仅tebentafusp亚组中，基线ctDNA对OS（HR 2.47，95% CI 1.30-4.66；p=0.005）和PFS（HR 1.83，95% CI 1.22-2.74；p=0.003）仍具有显著意义。该亚组中的清除仍与PFS改善相关（HR 0.21，95% CI 0.06-0.79；p=0.021）以及OS改善相关（无死亡病例）。多因素模型的趋势与全队列一致，但受样本量限制。
结论：使用Signatera检测测量的基线和治疗期间ctDNA在mUM患者中具有预后价值。在tebentafusp亚组中以及在校正LDH和肝转移后，ctDNA结果仍具有预后意义。
查看英文原文 English abstract
Background: Circulating tumor DNA (ctDNA) is an emerging prognostic biomarker in solid tumors. However, the independent prognostic value in metastatic uveal melanoma (mUM) remains incompletely defined. We evaluated the prognostic significance of baseline ctDNA as measured by the Signatera assay, assessed the relationship to known prognostic factors such as LDH and liver metastases, and the impact of ctDNA clearance while on treatment.
Methods: We retrospectively evaluated patients with mUM who had ctDNA collected within 30 days prior to treatment initiation. Kaplan-Meier (KM) and Cox proportional-hazard models were used to evaluate OS and PFS. Baseline ctDNA values were categorized into 3 tiers: Not-detected (ND), Low (<5 MTM/mL), and High (>5 MTM/mL). Multivariate Cox models were used to adjust for LDH (log-transformed) and liver metastases. Clearance of ctDNA was compared to persistently positive ctDNA. Patients treated with front-line tebentafusp were assessed as a prespecified subgroup.
Results: 41 patients had baseline ctDNA measurements taken prior to frontline treatment; 26 received front-line tebentafusp and 66% had detectable ctDNA. Higher ctDNA levels correlated with elevated LDH.
In the full cohort, detectable ctDNA was associated with shorter PFS (HR 3.07, 95% CI 1.14-8.30; p=0.027). In a 3-tiered stratification, high ctDNA (>5 MTM/mL) was predictive of shorter PFS (HR 4.65, 95% CI 1.62-13.4; p=0.004) and approached significance for OS (HR 4.60, 95% CI 0.97-21.8; p =0.055). On KM analysis, there was significant separation between the groups for both PFS (p=0.0048) and OS (p=0.011). As a continuous variable, higher ctDNA values (log-transformed) strongly predicted both PFS (HR 2.23, 95% CI 1.54-3.23; p<0.001) and OS (HR 3.26, 95% CI 1.79-5.92; p<0.001). In multivariate analysis, ctDNA remained independently prognostic of PFS (HR 1.75, 95% CI 1.06-2.87; p=0.028).
Clearance of ctDNA was associated with improved PFS (HR 0.25, CI 95% 0.08-0.76; p=0.015) and OS, with no deaths in the clearance group (HR not calculable).
In the tebentafusp-only subgroup, baseline ctDNA remained significant for OS (HR 2.47, 95% CI 1.30-4.66; p=0.005) and PFS (HR 1.83, 95% CI 1.22-2.74l; p=0.003). Clearance in this subgroup remained associated with improved PFS (HR 0.21, CI 95% 0.06-0.79; p=0.021) and OS (no deaths). Multivariate model trends were consistent with the full cohort but were limited by sample size.
Conclusions: Baseline and on treatment ctDNA measured using the Signatera assay are prognostic in patients with mUM. ctDNA results remained prognostic in the tebentafusp subgroup and after adjusting for LDH and liver metastases.
利益披露 Disclosure
A. D. Knight, None.
E. P. Wehrenberg-Klee,
Boston Scientific Independent Contractor.
Sirtex Independent Contractor.
Delcath Independent Contractor.
Embolx Independent Contractor.
Replimune Other, IDMC.
CytoSite g., Board of Directors, non-salaried role).
Absco Therapeutics g., Board of Directors, non-salaried role).