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Updated: Sep 3, 2025
Detection and Monitoring of Tumor Associated Circulating DNA in Patient Biofluids
Published on: June 8, 2019
Subtyping of metastatic breast cancer based on plasma circulating tumor DNA alterations: An observational,
Zhe-Yu Hu1,2, Yu Tang1,2, Liping Liu1,2
1Department of Breast Cancer Medical Oncology, Hunan Cancer Hospital, Changsha, 410013, China.
Background:
After multiple lines of therapies, no guideline or consensus is currently available for the treatment of patients with metastatic breast cancer. This study aims to evaluate the efficacy of a novel re-subtyping and treatment strategy based on ctDNA alterations.
Methods:
This observational, multicentre study recruited 223 patients with metastatic breast cancer intending to receive late-line therapy from Dec 1, 2016, to June 31, 2019. This study took place in Hunan Cancer Hospital, the Forth Hospital of Changsha and Zhuzhou Central Hospital in China. ctDNA alterations were assessed by next-generation sequencing (NGS). Patients with druggable ctDNA alterations were treated with corresponding targeted drugs which are clinically available. Other patients received physician-chosen treatment. This study was registered with ClinicalTrials.gov, NCT05079074.
Findings:
The progression-free survival (hazard ratio: 0.45, 95% Confidence Interval (CI): 0.33-0.62, P < 0.0001) and disease control rate (89.4% vs. 65.9%, P < 0.0001) were significantly improved in patients who received druggable ctDNA alteration-guided therapy compared with those of patients who received physician-chosen treatment. ctDNA alterations with top rank and high clustering scores were classified into four subtypes based on their functions as follows: 1) extracellular function (ECF), 2) cell proliferation (CP), 3) nuclear function (NF), and 4) cascade signaling pathway (CSP). A significant benefit from ctDNA alteration-guided treatment was observed in patients with NF and CSP ctDNA alterations, with hazard ratios of 0.39 (95% CI: 0.24-0.65, P = 0.0003) and 0.14 (95% CI: 0.04-0.46, P < 0.0001), respectively.
Interpretation:
After multiline traditional pathological HR/HER2 subtype-guided therapies, ctDNA testing could identify druggable ctDNA alterations to guide late-line therapy for patients with metastatic breast cancer.
Funding:
This work was supported by Key Grants of Research and Development in Hunan Province (2018SK2124, 2018SK2120), Natural Science Foundation of Hunan (2019JJ50360), Hunan Provincial Health Commission Project (B2019085, B2019089 and C2019070), and Changsha Science and Technology Project (kq2004125 and kq2004137).
Insights
Liquid biopsy using circulating tumor DNA (ctDNA) alterations can guide late-line therapy for metastatic breast cancer patients, improving progression-free survival and disease control rates.
Area of Science:
- Oncology
- Genomics
- Translational Medicine
Background:
- Metastatic breast cancer lacks treatment guidelines for patients after multiple therapies.
- Circulating tumor DNA (ctDNA) analysis offers a novel approach for personalized treatment strategies.
Purpose of the Study:
- To evaluate the efficacy of a re-subtyping and treatment strategy based on ctDNA alterations in metastatic breast cancer.
- To identify specific ctDNA alteration subtypes that benefit most from targeted therapies.
Main Methods:
- An observational, multicenter study of 223 metastatic breast cancer patients receiving late-line therapy.
- Next-generation sequencing (NGS) to assess ctDNA alterations.
- Treatment guided by actionable ctDNA alterations versus physician's choice.
Main Results:
- ctDNA-guided therapy significantly improved progression-free survival (HR: 0.45) and disease control rate (89.4%) compared to physician's choice (65.9%).
- Specific ctDNA subtypes, nuclear function (NF) and cascade signaling pathway (CSP), showed significant benefit from targeted treatment.
- Hazard ratios for NF and CSP subtypes were 0.39 and 0.14, respectively.
Conclusions:
- ctDNA testing can identify actionable alterations for guiding late-line therapy in metastatic breast cancer.
- This strategy enhances treatment efficacy beyond traditional pathological subtypes.
- Personalized therapy based on ctDNA analysis represents a promising approach for refractory metastatic breast cancer.
