Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer: circulating tumor DNA analysis of a randomized phase 3 trial

IF 50 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Nature Medicine Pub Date : 2025-09-04 DOI:10.1038/s41591-025-03935-w

Elisabeth M. Jongbloed, Noor Wortelboer, Vanja de Weerd, Corine M. Beaufort, Kirsten Ruigrok-Ritstier, Mai N. Van, Jaco Kraan, Annette A. van Zweeden, Annemieke van der Padt-Pruijsten, Lisanne C. Hamming, Inge R. Konings, Gabe S. Sonke, Esther Oomen-de Hoop, John W. M. Martens, Agnes Jager, Saskia M. Wilting

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Abstract

CDK4/6 inhibitors (CDK4/6i) improve outcome in patients with advanced estrogen receptor-positive, HER2⁻ breast cancer. The phase 3 SONIA trial compared the addition of CDK4/6i to first- versus second-line endocrine therapy for time to disease progression after second-line treatment (progression-free survival after two lines of treatment (PFS2)), as well as for secondary outcomes overall survival, PFS after one line of treatment (PFS1), health-related quality of life (HRQOL), toxicity and cost-effectiveness. No significant difference in PFS2 was observed; however, on an individual patient level this may be different. Using prespecified circulating tumor DNA analyses, we performed an exploratory study to evaluate whether pretreatment circulating tumor DNA (ctDNA) levels in plasma can identify patients that benefit from CDK4/6i during their first-line treatment. Cell free DNA before start of first-line treatment from 409 female patients participating in SONIA was analyzed with the modified fast aneuploidy screening test-sequencing system. This assay yields a genome-wide aneuploidy score, indicative of ctDNA levels. Cox proportional hazard analyses for PFS1 and PFS2 were performed separately for the ctDNA high group (aneuploidy score ≥ 5) and the ctDNA low group (aneuploidy score < 5). In total, 141 of the 409 included patients had a high genome-wide aneuploidy score at baseline. PFS2 in the first- compared to the second-line CDK4/6i strategy showed hazard ratios of 0.58 (95% confidence interval 0.38–0.88) and 1.36 (95% confidence interval 0.95–1.96) in the high and low aneuploidy group, respectively. A significant interaction was demonstrated between treatment strategy and aneuploidy score for PFS2 (P = 0.004). In conclusion, this study demonstrated that pretreatment ctDNA levels can be used to identify patients that benefit from first-line CDK4/6i treatment. ClinicalTrials.gov registration: NCT03425838.

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CDK4/6抑制剂在晚期乳腺癌中的早期与延迟使用：一项随机3期试验的循环肿瘤DNA分析

CDK4/6抑制剂（CDK4/6i）改善晚期雌激素受体阳性HER2−乳腺癌患者的预后。3期SONIA试验比较了一线与二线内分泌治疗中CDK4/6i的添加对二线治疗后疾病进展的时间（两线治疗后的无进展生存期（PFS2）），以及次要结局——总生存期、一线治疗后的PFS （PFS1）、健康相关生活质量（HRQOL）、毒性和成本效益。两组PFS2无显著差异；然而，在个别患者的水平上，这可能是不同的。使用预先指定的循环肿瘤DNA分析，我们进行了一项探索性研究，以评估血浆中预处理循环肿瘤DNA （ctDNA）水平是否可以识别在一线治疗期间受益于CDK4/6i的患者。采用改进的快速非整倍体筛选测试-测序系统对409例参与索尼娅治疗的女性患者一线治疗开始前的细胞游离DNA进行分析。该分析产生全基因组非整倍性评分，指示ctDNA水平。ctDNA高组（非整倍性评分≥5）和ctDNA低组（非整倍性评分<； 5）分别进行PFS1和PFS2的Cox比例风险分析。总的来说，409名患者中有141名在基线时具有高全基因组非整倍性评分。与二线CDK4/6i策略相比，一线PFS2在高非整倍体组和低非整倍体组的风险比分别为0.58（95%置信区间0.38-0.88）和1.36（95%置信区间0.95-1.96）。治疗策略与PFS2非整倍体评分之间存在显著的相互作用（P = 0.004）。总之，本研究表明，预处理ctDNA水平可用于识别从一线CDK4/6i治疗中获益的患者。ClinicalTrials.gov注册：NCT03425838。

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来源期刊

Nature Medicine 医学-生化与分子生物学

CiteScore

100.90

自引率

0.70%

发文量

525

审稿时长

1 months

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