Longitudinal profiling of hormone receptor positive, HER2 negative metastatic breast cancer through droplet digital PCR-based circulating tumor DNA fragmentomics

IF 5 2区医学 Q2 Medicine

Translational Oncology Pub Date : 2025-06-26 DOI:10.1016/j.tranon.2025.102456

Lorenzo Foffano , Alessandra Franzoni , Elisabetta Molteni , Fabiola Giudici , Arianna Dri , Debora Basile , Linda Cucciniello , Silvia Buriolla , Claudia Noto , Stefania Russo , Elena Nascimbeni , Silvia Bolzonello , Brenno Pastò , Serena Della Rossa , Lorenzo Allegri , Marta Bonotto , Alessandro Marco Minisini , Barbara Belletti , Giuseppe Damante , Lorenzo Gerratana , Fabio Puglisi

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引用次数: 0

Abstract

Background

In the context of hormone receptor positive, HER2 negative Metastatic breast cancer (MBC), CDK 4/6 inhibitors (CDK4/6i) combined with endocrine therapy represent the standard first-line treatment, improving Progression-Free Survival (PFS) and Overall Survival (OS). Despite these benefits, resistance to treatment develops, necessitating early risk classification to guide clinical management. This study explores the potential of cell-free DNA (cfDNA) fragmentomics, specifically ACTB fragments, in predicting tumor dynamics and treatment outcomes in luminal MBC, based on the principle that shorter DNA fragments are generally indicative of circulating tumor DNA (ctDNA) from tumor cells, while longer fragments are associated with leukocyte lysis.

Methods

In the MAGNETIC.1 study, 141 women with luminal-like MBC were enrolled between January 2018 and January 2023. Blood samples were collected at baseline (BL), and after 3 (T3) and 6 (T6) months of treatment. cfDNA was extracted and analyzed using droplet digital PCR (ddPCR) to quantify ACTB fragments (136 bp, 420 bp, and 2,000 bp). Continuous variables were compared using the Mann–Whitney test and Kruskall Wallis test depending on data distribution and number of groups. Categorical variables were compared using the Chi-square test or Fischer’s exact test whenever appropriate. Differences in survival were tested by log-rank test and uni- and multivariable Cox regression.

Results

By categorizing the values of actinic fragments into interquartiles (Q1, Q2, and Q3), ACTB_short Q3 at baseline was significantly associated with negative PR expression (RRR 0.27, P = 0.012) and a higher frequency of liver metastasis (RRR = 3.75, P = 0.009). In terms of clinical outcomes, regarding PFS a significant role was observed for baseline ACTB_short Q3 (HR 1.92, P = 0.041) and ACTB_medium Q3 (HR 0.47, P = 0.043), the latter maintaining significance in multivariable analysis (HR 0.33, 95 %, P = 0.012). For OS, ACTB_short Q3 demonstrated a significant impact in both univariable (HR 3.94, P = 0.003) and multivariable analyses (HR 3.25, P = 0.023).

Conclusions

This study demonstrates the feasibility of employing a fragmentomics mutation agnostic approach in luminal MBC. Baseline and longitudinal changes in ACTB fragments were significantly associated with clinical outcomes, suggesting their potential as non-invasive biomarkers for early risk classification and monitoring tumor dynamics.

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基于微滴数字pcr的循环肿瘤DNA片段组学对激素受体阳性、HER2阴性转移性乳腺癌的纵向分析

在激素受体阳性，HER2阴性的转移性乳腺癌（MBC）的背景下，cdk4 /6抑制剂（CDK4/6i）联合内分泌治疗代表了标准的一线治疗，改善了无进展生存期（PFS）和总生存期（OS）。尽管有这些好处，但对治疗的耐药性仍在发展，需要早期风险分类以指导临床管理。基于较短的DNA片段通常表明来自肿瘤细胞的循环肿瘤DNA (ctDNA)，而较长的片段与白细胞溶解相关的原理，本研究探索了游离DNA （cfDNA）片段组学，特别是ACTB片段，在预测腔内MBC肿瘤动力学和治疗结果方面的潜力。方法：在2018年1月至2023年1月期间，141名患有luminal-like MBC的女性加入了这项研究。在基线（BL）、治疗3个月（T3）和6个月（T6）后采集血样。提取cfDNA，采用液滴数字PCR （ddPCR）对ACTB片段（136 bp、420 bp和2000 bp）进行定量分析。根据数据分布和组数，采用Mann-Whitney检验和Kruskall Wallis检验比较连续变量。分类变量的比较使用卡方检验或Fischer精确检验。生存率差异采用log-rank检验、单变量和多变量Cox回归进行检验。结果ACTBshort Q3与PR负表达（RRR = 0.27, P = 0.012）及肝转移发生率增高（RRR = 3.75, P = 0.009）有显著相关性。在临床结果方面，基线ACTBshort Q3 （HR 1.92, P = 0.041）和基线ACTBmedium Q3 （HR 0.47, P = 0.043）对PFS有显著作用，后者在多变量分析中保持显著性（HR 0.33, 95%, P = 0.012）。对于OS， ACTBshort Q3在单变量分析（HR 3.94, P = 0.003）和多变量分析（HR 3.25, P = 0.023）中均表现出显著影响。结论本研究证明了采用片段组学突变不可知论方法诊断腔内MBC的可行性。ACTB片段的基线和纵向变化与临床结果显著相关，表明它们具有作为早期风险分类和监测肿瘤动态的非侵入性生物标志物的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Translational Oncology ONCOLOGY-

CiteScore

8.40

自引率

2.00%

发文量

314

审稿时长

54 days

期刊介绍： Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.