Liquid Biopsy-Based Biomolecular Alterations for the Diagnosis of Triple-Negative Breast Cancer in Adults: A Scoping Review

  1. Orieta Navarrete-Fernández
  2. Eddy Mora
  3. Josue Rivadeneira
  4. Víctor Herrera
  5. Ángela L. Riffo-Campos

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Abstract

Background/Objectives: Triple-negative breast cancer (TNBC) is an aggressive subtype, with limited diagnostic options and no targeted early detection tools. Liquid biopsy represents a minimally invasive approach for detecting tumor-derived molecular alterations in body fluids. This scoping review aimed to comprehensively synthesize all liquid biopsy-derived molecular biomarkers evaluated for the diagnosis of TNBC in adults. Methods: This review followed the Arksey and O’Malley framework and PRISMA-ScR guidelines. Systematic searches of PubMed, Scopus, Embase, and Web of Science identified primary human studies evaluating circulating molecular biomarkers for TNBC diagnosis. Non-TNBC, non-human, hereditary, treatment-response, and nonmolecular studies were excluded. Data on study design, patient characteristics, biospecimen type, analytical platforms, biomarker class, and diagnostic performance were extracted and synthesized descriptively by biomolecule class. Results: Thirty-two studies met the inclusion criteria, comprising 15 protein-based, 12 RNA-based, and 6 DNA-based studies (one reporting both protein and RNA). In total, 1532 TNBC cases and 3137 participants in the comparator group were analyzed. Protein biomarkers were the most frequently studied, although only APOA4 appeared in more than one study, with conflicting results. RNA-based biomarkers identified promising candidates, particularly miR-21, but validation cohorts were scarce. DNA methylation markers showed promising diagnostic accuracy yet lacked replication. Most studies were small retrospective case–control designs with heterogeneous comparators and inconsistent diagnostic reporting. Conclusions: Evidence for liquid biopsy-derived biomarkers in TNBC remains limited, heterogeneous, and insufficiently validated. No biomarker currently shows reproducibility suitable for clinical implementation. Robust, prospective, and standardized studies are needed to advance liquid biopsy-based diagnostics in TNBC.

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  1. PREreview

    This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/19035631.

    Does the introduction explain the objective of the research presented in the preprint? Yes It gives a comprehensive overview of the current level of breast cancer management with Liquid biopsy as a potential diagnostic technique, and states the objective of the scoping review To synthesize the available evidence on all types of liquid biopsy–derived molecular biomarkers evaluated for the diagnosis of TNBC. This establishes the rationale for conducting a scoping review to map the current research landscape.
    Are the methods well-suited for this research? Highly appropriate The scoping review was stated to be conducted in accordance with the methodological framework of Arksey and O'Malley and reported following the PRISMA-Scr checklist. Multiple major databases-PubMed (Medline), Scopus, Embase, and Web of Science-were searched using both controlled vocabulary and free-text terms related to TNBC, liquid biopsy, body fluids, and molecular biomarkers. This broad search strategy improves coverage of relevant studies and reduces the risk of missing important literature The study includes primary human studies evaluating molecular biomarkers in liquid biopsy specifically for TNBC diagnosis, while excluding non-diagnostic studies, animal/in vitro research, reviews, and studies without TNBC-specific data. These criteria help ensure that the included evidence directly addresses the research question. The review employed independent screening by multiple reviewers, with disagreements resolved by a third reviewer, which strengthens methodological rigor and reduces selection bias.
    Are the conclusions supported by the data? Highly supported
    Are the data presentations, including visualizations, well-suited to represent the data? Somewhat appropriate and clear The visualizations are limited and could be improved with additional figures or clearer graphical summaries of biomarker types and diagnostic findings to enhance readability and comparison across studies
    How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research? Somewhat clearly The discussion section was clear and sequential in its approach, with the terminology appropriate for the subject matter; however, the discussion lacks deeper critical analysis and detailed guidance on future research directions, which makes the interpretation clear but not fully comprehensive
    Is the preprint likely to advance academic knowledge? Somewhat likely This indicates the manuscript makes important contributions, but does not rise to the level of "significant" or "substantial" advancements in the synthesis of literature
    Would it benefit from language editing? No
    Would you recommend this preprint to others? Yes, but it needs to be improved
    Is it ready for attention from an editor, publisher or broader audience? Yes, after minor changes

    Competing interests

    The authors declare that they have no competing interests.

    Use of Artificial Intelligence (AI)

    The authors declare that they did not use generative AI to come up with new ideas for their review.

  2. Version published to 10.3390/diagnostics16020360
  3. Version published to 10.20944/preprints202512.1096.v1