PO.PR02.02 · 预防研究
动态监测并识别可预测bireociclib联合氟维司群疗效的可靠生物标志物：BRIGHT-2研究的探索性ctDNA分析
Dynamic monitoring and identification of reliable biomarkers to predict efficacy of bireociclib and fulvestrant: An exploratory ctDNA analysis of the BRIGHT-2 study
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摘要 Abstract
中文摘要
背景 尽管新型细胞周期蛋白依赖性激酶4和6（CDK4/6）抑制剂bireociclib在BRIGHT-2研究（NCT05077449）中对激素受体阳性、人表皮生长因子受体2（HER2）阴性的晚期乳腺癌显示出强效疗效，但患者在治疗疗效上表现出显著的异质性——部分患者呈现高度敏感，而另一些患者则迅速产生耐药。因此，一个关键的研究目标是在治疗开始前确定敏感性，并界定能够比影像学更早动态检测治疗结果的生物标志物。
方法 基于BRIGHT-2研究，在基线、治疗中和治疗结束时间点，采用1021基因panel进行纵向循环肿瘤DNA（ctDNA）分析。识别体细胞突变并计算分子肿瘤负荷指数（mTBI）。生存分析采用Kaplan-Meier曲线结合log-rank检验及Cox比例风险模型，而治疗与基因改变之间的交互分析采用错误发现率（FDR）方法。所有分析均使用R软件进行，统计学显著性设定为p<0.05。
结果 bireociclib组在三个时间点分别采集了197、139和86份ctDNA样本，而安慰剂组分别为79、46和49份。突变频率最高的基因为PIK3CA（48%）、TP53（37%）和ESR1（23%）。ctDNA阳性或高mTBI的患者与ctDNA阴性或低mTBI的患者相比，无进展生存期（PFS）和总生存期（OS）明显更短。CCND1和FGF19的基因改变与bireociclib相较于安慰剂的更大PFS获益相关（FDR校正后P值分别为0.030和0.002）。在bireociclib组中，gBRCA及同源重组修复基因突变较野生型提示预后更差。ctDNA或特定基因突变的动态清除与CDK4/6抑制剂改善的疗效和生存结局相关。
结论 对于接受bireociclib联合氟维司群治疗的激素受体阳性、HER2阴性乳腺癌患者，ctDNA的基线监测和动态监测均展现出对治疗反应和生存结局的显著预测价值。这些潜在生物标志物有待通过更大规模的临床试验和基础研究进一步验证。
关键词：CDK4/6抑制剂，晚期乳腺癌，生物标志物，bireociclib，预后。
查看英文原文 English abstract
Background Although the novel cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor bireociclib demonstrated potent efficacy for hormone receptor -positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in the BRIGHT-2 study (NCT05077449), patient exhibited substantial heterogeneity in therapeutic efficacy-some demonstrated high sensitivity, while others rapidly developed resistance. Consequently, a critical research aim is to ascertain sensitivity before treatment initiation and define biomarkers that can dynamically detect therapeutic outcomes earlier than imaging.
Methods Based on the BRIGHT-2 study, longitudinal circulating tumor DNA (ctDNA) analysis was performed using a 1021-gene panel at baseline, on-treatment, and end-of-treatment timepoints. Somatic mutations were identified and molecular tumor burden index (mTBI) was calculated. Survival analyses employed Kaplan-Meier curves with log-rank tests and Cox proportional hazards models, while the interaction analysis between treatment and gene alternations were conducted using False Discovery Rate (FDR) method. All the analyses were performed using R software, with statistical significance set at p<0.05.
Results The bireociclib group collected 197, 139, and 86 ctDNA samples from three timepoints, compared with 79, 46, and 49 from placebo group. The most frequently mutated genes were PIK3CA (48%), TP53 (37%), and ESR1 (23%). Patients with ctDNA-positive or high mTBI had conspicuously shorter progression-free survival (PFS) and overall survival (OS) than those with ctDNA-negative or low mTBI. The gene alterations in CCND1 and FGF19 were associated with a greater PFS benefit with bireociclib versus placebo (FDR-adjusted P values of 0.030 and 0.002, respectively). The gBRCA and homologous recombination repair genes mutation indicated poorer prognosis compared to wild-type in bireociclib group. Dynamic clearance of ctDNA or specific gene mutations was correlated with improved efficacy and survival outcomes for CDK4/6 inhibitor.
Conclusions Both baseline and dynamic monitoring of ctDNA demonstrated salient predictive value for treatment response and survival outcomes in hormone receptor-positive, HER2-negative breast cancer patients receiving bireociclib plus fulvestrant. These potential biomarkers warrant further validation through larger clinical trials and basic researches.
Key words: CDK4/6 inhibitor, advanced breast cancer, biomarkers, bireociclib, prognosis.
利益披露 Disclosure
Y. Wang, None..
H. Xu, None..
Y. Zhou, None..
L. Cui, None..
Q. Sa, None..
H. Cheng, None..
R. Gao, None..
Q. Zhang, None..
Z. Tong, None..
Q. Ouyang, None..
X. Tan, None..
J. Bai, None..
L. Wang, None..
X. Duan, None..
F. Yang, None..
J. Wang, None..
B. Xu, None.