Multiple ctDNA- based biomarkers predict benefit from selective RET Inhibition in non-small cell lung cancer patients: exploratory analysis of a prospective study.

IF 9.5 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Chang Lu, Chong-Rui Xu, Yi-Chen Zhang, E-E Ke, Yue-Li Sun, Xiao-Yan Bai, Zhi-Hong Chen, Jian Su, Yu Deng, Ting Hou, Fei Zhao, Min Li, Bin-Chao Wang, Hai-Yan Tu, Zhen Wang, Xu-Chao Zhang, Hua-Jun Chen, Jin-Ji Yang, Wen-Zhao Zhong, Qing Zhou, Yi-Long Wu
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引用次数: 0

Abstract

Selective RET inhibitors such as pralsetinib have become the standard of care for patients with RET fusion-positive non-small cell lung cancer (NSCLC). Serial analysis of circulating tumor DNA (ctDNA) has proven effective in monitoring disease control/progression and therapeutic response in NSCLC. In this prospective study, we analyzed longitudinal ctDNA profiles (at baseline, week 8, and at progression) in Chinese patients with advanced RET fusion-positive NSCLC treated with pralsetinib (NCT03037385), utilizing allele frequency-based, cfDNA quantity-normalized, and methylation-based metrics. Associations between ctDNA dynamics, tumor response, and genomic alterations were assessed. A total of 21 patients were enrolled. Baseline PIK3CA co-mutations were associated with inferior progression-free survival (PFS; 3.0 vs. 12.4 months, P < 0.001). Superior PFS was observed in patients with lower baseline ctDNA levels across all metrics: allele frequency-based (HR = 0.24; 95% confidence interval [CI], 0.07-0.80; P = 0.012), cfDNA quantity-normalized (HR = 0.20; 95% CI, 0.05-0.71; P = 0.006), and methylation-based (HR = 0.09; 95% CI, 0.01-0.85; P = 0.010). Early ctDNA clearance at the first radiographic assessment was also associated with prolonged PFS (median PFS not reached vs. 4.8 months; P = 0.002) and enhanced disease control (71.4% vs. 0%). Moreover, three distinct ctDNA dynamic profiles-clearance-rebound, reduction-rebound, and sustained clearance-were associated with different progression patterns (systemic progression, new extrathoracic lesions, new intracranial/intrathoracic lesions). No evidence of histologic transformation was identified at the time of progression. KRAS G12R and other non-canonical alterations emerged in ctDNA-rebound samples. Molecular progression preceded radiographic progression by a mean interval of 2.2 months. These findings suggest that ctDNA-based surveillance using multiple metrics, enables early forecasting of tumor response and progression in RET fusion-positive NSCLC. Early ctDNA clearance and dynamic profiles provide non-invasive biomarkers for early intervention, warranting further validation with ctDNA-guided strategies.

多种基于ctDNA的生物标志物预测非小细胞肺癌患者选择性RET抑制的益处:一项前瞻性研究的探索性分析。
选择性RET抑制剂如普拉塞替尼已成为RET融合阳性非小细胞肺癌(NSCLC)患者的标准治疗。循环肿瘤DNA (ctDNA)的系列分析已被证明在监测非小细胞肺癌的疾病控制/进展和治疗反应方面是有效的。在这项前瞻性研究中,我们利用基于等位基因频率、cfDNA数量归一化和基于甲基化的指标,分析了接受普拉塞替尼(NCT03037385)治疗的中国晚期RET融合阳性NSCLC患者的纵向ctDNA谱(基线、第8周和进展)。评估了ctDNA动态、肿瘤反应和基因组改变之间的关系。共有21名患者入组。基线PIK3CA共突变与较低的无进展生存期(PFS;3.0 vs. 12.4个月,P
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来源期刊
Biomarker Research
Biomarker Research Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
15.80
自引率
1.80%
发文量
80
审稿时长
10 weeks
期刊介绍: Biomarker Research, an open-access, peer-reviewed journal, covers all aspects of biomarker investigation. It seeks to publish original discoveries, novel concepts, commentaries, and reviews across various biomedical disciplines. The field of biomarker research has progressed significantly with the rise of personalized medicine and individual health. Biomarkers play a crucial role in drug discovery and development, as well as in disease diagnosis, treatment, prognosis, and prevention, particularly in the genome era.
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