循环肿瘤细胞增加作为基线 CTC 计数低的转移性去势抵抗性前列腺癌患者疾病进展的生物标志物。

Circulating tumour cell increase as a biomarker of disease progression in metastatic castration-resistant prostate cancer patients with low baseline CTC counts.

机构信息

Medical Oncology Service, Hospital La Fe, Valencia, Spain; Prostate Cancer Targeted Therapy Group, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Sutton, Surrey.

Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

出版信息

Ann Oncol. 2018 Jul 1;29(7):1554-1560. doi: 10.1093/annonc/mdy172.

DOI:10.1093/annonc/mdy172

PMID:29741566

Abstract

BACKGROUND

The development of treatment response and surrogate biomarkers for advanced prostate cancer care is an unmet clinical need. Patients with baseline circulating tumour cell (BLCTCs) counts <5/7.5 mL represent a good prognosis subgroup but are non-evaluable for response assessment (decrease in CTCs). The aim of the study is to determine the value of any increase in CTCs (CTC progression) as an indicator of progression in prostate cancer patients with low pre-treatment CTCs (<5).

PATIENTS AND METHODS

We carried out a post hoc analysis of patients with BLCTCs < 5 treated in the COU-AA-301 (abiraterone or placebo + prednisone) and IMMC-38 (chemotherapy) trials. The association of CTC progression (increase in CTCs at 4, 8 or 12 weeks) with overall survival (OS) was evaluated in multi-variable Cox regression models. Performance of survival models with and without CTC progression was evaluated by calculating ROC curve area under the curves (AUCs) and weighted c-indices.

RESULTS

Overall, 511 patients with CTCs < 5 (421 in COU-AA-301 and 90 in IMMC-38) were selected; 212 (41.7%) had CTC progression at 4, 8 or 12 weeks after treatment initiation. CTC progression was associated with significantly worse OS [27.1 versus 15.1 m; hazard ratio (HR) 3.4 (95% confidence interval [CI] 2.5-4.5; P < 0.001)], independent of baseline CTCs and established clinical variables. Adding CTC progression to the OS model significantly improved ROC AUC (0.77 versus 0.66; P < 0.001). Models including CTC progression had superior ROC AUC (0.77 versus 0.69; P < 0.001) and weighted c-index [0.750 versus 0.705; delta c-index: 0.045 (95% CI 0.019-0.071)] values than those including CTC conversion (increase to CTCs ≥ 5). In COU-AA-301, the impact of CTC progression was independent of treatment arm.

CONCLUSIONS

Increasing CTCs during the first 12 weeks of treatment are independently associated with worse OS from advanced prostate cancer in patients with baseline CTCs < 5 treated with abiraterone or chemotherapy and improve models with established prognostic variables. These findings must be prospectively validated.

摘要

背景

开发治疗反应和替代生物标志物来满足晚期前列腺癌护理的需求是一个未满足的临床需求。基线循环肿瘤细胞（BLCTCs）计数<5/7.5ml 的患者代表预后良好亚组，但无法评估其反应评估（CTC 减少）。本研究旨在确定任何 CTC 增加（CTC 进展）作为低基线前治疗 CTCs（<5）的前列腺癌患者进展的指标的价值。

患者和方法

我们对 COU-AA-301（阿比特龙或安慰剂+泼尼松）和 IMMC-38（化疗）试验中 BLCTCs<5 的患者进行了事后分析。在多变量 Cox 回归模型中评估 CTC 进展（治疗开始后 4、8 或 12 周 CTC 增加）与总生存（OS）的关联。通过计算 ROC 曲线下面积（AUCs）和加权 c 指数评估具有和不具有 CTC 进展的生存模型的性能。

结果

共有 511 名 CTCs<5 的患者（COU-AA-301 中 421 名，IMMC-38 中 90 名）入选；212 名（41.7%）在治疗开始后 4、8 或 12 周时出现 CTC 进展。CTC 进展与显著更差的 OS 相关[27.1 与 15.1m；风险比（HR）3.4（95%置信区间[CI]2.5-4.5；P<0.001)]，独立于基线 CTCs 和既定的临床变量。将 CTC 进展添加到 OS 模型中显著提高了 ROC AUC（0.77 与 0.66；P<0.001）。包括 CTC 进展的模型具有更好的 ROC AUC（0.77 与 0.69；P<0.001）和加权 c 指数[0.750 与 0.705；Delta c 指数：0.045（95%CI 0.019-0.071）]值，优于包括 CTC 转换（增加至 CTCs≥5）的模型。在 COU-AA-301 中，CTC 进展的影响独立于治疗臂。