Circulating Tumor Biomarkers Laboratory, Inserm CIC-BT 1428, Institut Curie, PSL Research University, 26 rue d'Ulm, 75005, Paris, France.
Department of Surgical Oncology, Institut Curie, Paris, France.
Breast Cancer Res. 2021 Mar 6;23(1):31. doi: 10.1186/s13058-021-01411-0.
Following the PALOMA-3 study results, the combination of palbociclib, a CDK4/6 inhibitor, with fulvestrant, a selective estrogen receptor degrader, has become a standard therapy in women with estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer (MBC). Palbociclib has been shown to increase the progression-free survival (PFS) overall but no predictive biomarker of palbociclib efficacy has been validated so far. We thus evaluated whether early changes of circulating tumor DNA (ctDNA) levels are associated with palbociclib plus fulvestrant efficiency.
ER+ HER2- MBC patients were included in a prospective observational cohort before treatment initiation. Tumor response was assessed by radiological evaluation (RECIST v1.1) every 3 months. Plasma samples were collected before treatment (baseline), at day 15 (D15), at day 30 (D30), and at disease progression. We searched for somatic mutations from archived tumor tissues by targeted deep sequencing. For patients with somatic mutations identified, circulating tumor DNA (ctDNA) was tracked using digital droplet PCR. Ratios of ctDNA levels ([D15/baseline] and [D30/baseline]) were then correlated with prospectively registered patient characteristics and outcomes.
Twenty-five of the 61 patients enrolled had a somatic mutation testable in plasma (N = 21, N = 2, N = 2). At baseline, 84% of patients had detectable ctDNA levels but ctDNA levels had no prognostic impact on PFS (p = 0.10). Among those patients, ctDNA was still detected in 82% at D15 and 68% at D30. ctDNA clearance observed at day 30 was associated with longer PFS (HR = 7.2, 95% CI = 1.5-32.6, p = 0.004). On the contrary, a [D30/baseline] ctDNA ratio > 1 was associated with a shorter PFS (HR = 5.1, 95% CI = 1.4-18.3, p = 0.02) and all 5 patients with increased ctDNA levels at D30 showed disease progression after 3 months under palbociclib-fulvestrant. Finally, at the time of radiological tumor progression, ctDNA was detected in all patients tested.
Our study demonstrates that the efficiency of palbociclib and fulvestrant can be monitored by serial analyses of ctDNA before radiological evaluation and that early ctDNA variation is a prognostic factor of PFS.
PALOMA-3 研究结果公布后，CDK4/6 抑制剂帕博西利与选择性雌激素受体降解剂氟维司群的联合用药方案已成为雌激素受体阳性（ER+）、人表皮生长因子受体 2 阴性（HER2-）转移性乳腺癌（MBC）患者的标准治疗方案。帕博西利已被证实可提高无进展生存期（PFS），但迄今为止，尚无预测帕博西利疗效的生物标志物得到验证。因此，我们评估了循环肿瘤 DNA（ctDNA）水平的早期变化是否与帕博西利联合氟维司群的疗效相关。
在开始治疗前，我们纳入了一项 ER+ HER2- MBC 患者的前瞻性观察队列。每 3 个月通过影像学评估（RECIST v1.1）评估肿瘤反应。在治疗前（基线）、第 15 天（D15）、第 30 天（D30）和疾病进展时采集血浆样本。我们通过靶向深度测序从存档的肿瘤组织中寻找体细胞突变。对于检测到体细胞突变的患者，使用数字液滴 PCR 追踪循环肿瘤 DNA（ctDNA）。然后，将 ctDNA 水平的比值（[D15/基线]和[D30/基线]）与前瞻性登记的患者特征和结局相关联。
在纳入的 61 名患者中，有 25 名患者可进行血浆中的体细胞突变检测（N=21，N=2，N=2）。基线时，84%的患者可检测到 ctDNA 水平，但 ctDNA 水平对 PFS 无预后影响（p=0.10）。在这些患者中，82%的患者在 D15 时仍可检测到 ctDNA，68%的患者在 D30 时仍可检测到 ctDNA。在第 30 天观察到的 ctDNA 清除与更长的 PFS 相关（HR=7.2，95%CI=1.5-32.6，p=0.004）。相反，D30 时的[D30/基线]ctDNA 比值>1 与更短的 PFS 相关（HR=5.1，95%CI=1.4-18.3，p=0.02），并且 D30 时 ctDNA 水平升高的所有 5 名患者在接受帕博西利-氟维司群治疗后 3 个月内均出现疾病进展。最后，在影像学肿瘤进展时，所有接受检测的患者均检测到 ctDNA。
我们的研究表明，在进行影像学评估之前，通过连续分析 ctDNA 可以监测帕博西利和氟维司群的疗效，并且 ctDNA 的早期变化是 PFS 的预后因素。
