BEECH 试验中早期 ctDNA 动力学作为晚期乳腺癌无进展生存期的替代指标。
Early ctDNA dynamics as a surrogate for progression-free survival in advanced breast cancer in the BEECH trial.
机构信息
Breast Cancer Now Research Centre, The Institute of Cancer Research, London, UK.
Breast Cancer Now Research Centre, The Institute of Cancer Research, London, UK; Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
出版信息
Ann Oncol. 2019 Jun 1;30(6):945-952. doi: 10.1093/annonc/mdz085.
BACKGROUND
Dynamic changes in circulating tumour DNA (ctDNA) levels may predict long-term outcome. We utilised samples from a phase I/II randomised trial (BEECH) to assess ctDNA dynamics as a surrogate for progression-free survival (PFS) and early predictor of drug efficacy.
PATIENTS AND METHODS
Patients with estrogen receptor-positive advanced metastatic breast cancer (ER+ mBC) in the BEECH study, paclitaxel plus placebo versus paclitaxel plus AKT inhibitor capivasertib, had plasma samples collected for ctDNA analysis at baseline and at multiple time points in the development cohort (safety run-in, part A) and validation cohort (randomised, part B). Baseline sample ctDNA sequencing identified mutations for longitudinal analysis and mutation-specific digital droplet PCR (ddPCR) assays were utilised to assess change in ctDNA abundance (allele fraction) between baseline and 872 on-treatment samples. Primary objective was to assess whether early suppression of ctDNA, based on pre-defined criteria from the development cohort, independently predicted outcome in the validation cohort.
RESULTS
In the development cohort, suppression of ctDNA was apparent after 8 days of treatment (P = 0.014), with cycle 2 day 1 (4 weeks) identified as the optimal time point to predict PFS from early ctDNA dynamics. In the validation cohort, median PFS was 11.1 months in patients with suppressed ctDNA at 4 weeks and 6.4 months in patients with high ctDNA (hazard ratio = 0.20, 95% confidence interval 0.083-0.50, P < 0.0001). There was no difference in the level of ctDNA suppression between patients randomised to capivasertib or placebo overall (P = 0.904) nor in the PIK3CA mutant subpopulation (P = 0.071). Clonal haematopoiesis of indeterminate potential (CHIP) was evident in 30% (18/59) baseline samples, although CHIP had no effect on tolerance of chemotherapy nor on PFS.
CONCLUSION
Early on-treatment ctDNA dynamics are a surrogate for PFS. Dynamic ctDNA assessment has the potential to substantially enhance early drug development.
CLINICAL REGISTRATION NUMBER
NCT01625286.
背景
循环肿瘤 DNA（ctDNA）水平的动态变化可能预测长期预后。我们利用来自 I/II 期随机试验（BEECH）的样本，评估 ctDNA 动态作为无进展生存期（PFS）的替代指标和药物疗效的早期预测指标。
患者和方法
BEECH 研究中，接受紫杉醇联合安慰剂或紫杉醇联合 AKT 抑制剂卡培西他滨治疗的雌激素受体阳性晚期转移性乳腺癌（ER+ mBC）患者，在开发队列（安全入组，A 部分）和验证队列（随机，B 部分）中采集基线和多个时间点的血浆样本进行 ctDNA 分析。基线样本 ctDNA 测序确定了用于纵向分析的突变，并且使用突变特异性数字液滴 PCR（ddPCR）检测来评估基线和 872 个治疗样本之间 ctDNA 丰度（等位基因分数）的变化。主要目的是评估基于开发队列的预定义标准，早期 ctDNA 抑制是否独立预测验证队列的结果。
结果
在开发队列中，治疗 8 天后 ctDNA 抑制明显（P=0.014），第 2 周期第 1 天（4 周）被确定为从早期 ctDNA 动力学预测 PFS 的最佳时间点。在验证队列中，ctDNA 抑制的患者中位 PFS 为 11.1 个月，而 ctDNA 高的患者为 6.4 个月（风险比=0.20，95%置信区间 0.083-0.50，P<0.0001）。总体而言，随机分配至卡培西他滨或安慰剂的患者之间的 ctDNA 抑制水平没有差异（P=0.904），PIK3CA 突变亚群也没有差异（P=0.071）。在 30%（18/59）的基线样本中存在不确定潜能的克隆性造血（CHIP），尽管 CHIP 对化疗的耐受性或 PFS 没有影响。
结论
早期治疗 ctDNA 动力学是 PFS 的替代指标。动态 ctDNA 评估有可能大大增强早期药物开发。
临床试验注册号
NCT01625286。
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