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Molecular Diagnostics

Incidental pathogenic germline alterations detected through liquid biopsy in patients with solid tumors: prevalence, clinical utility and implications

British Journal of Cancer (2024)Cite this article

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Abstract

Liquid biopsy, a minimally invasive approach for detecting tumor biomarkers in blood, has emerged as a leading-edge technique in cancer precision medicine. New evidence has shown that liquid biopsies can incidentally detect pathogenic germline variants (PGVs) associated with cancer predisposition, including in patients with a cancer for which genetic testing is not recommended. The ability to detect these incidental PGV in cancer patients through liquid biopsy raises important questions regarding the management of this information and its clinical implications. This incidental identification of PGVs raises concerns about cancer predisposition and the potential impact on patient management, not only in terms of providing access to treatment based on the tumor molecular profiling, but also the management of revealing genetic predisposition in patients and families. Understanding how to interpret this information is essential to ensure proper decision-making and to optimize cancer treatment and prevention strategies. In this review we provide a comprehensive summary of current evidence of incidental PGVs in cancer predisposition genes identified by liquid biopsy in patients with cancer. We critically review the methodological considerations of liquid biopsy as a tool for germline diagnosis, clinical utility and potential implications for cancer prevention, treatment, and research.

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Fig. 1: Proposed algorithm in the event of incidental pathogenic germline variants (PGV) detection in cfDNA analysis, and clinical implications for patients and families.
Fig. 2: Clinical utility for patients and their families if a PGV is confirmed.

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Acknowledgements

We thank Ainara Arcocha, Jessica González and Laura Alcolea for the administrative support and Sarah Mackenzie PhD, for language editing.

Funding

The authors received no specific funding for this work. Juan Carlos Laguna received support from Contractes Clínic de Recerca “Emili Letang-Josep Font” 2023; Hospital Clínic Barcelona, 2023. Laura Mezquita received support from the Contrato Juan Rodes 2020 (ISCIII, Ministry of Health; JR20/00019); Ayuda de la Acción Estratégica en Salud- ISCIII FIS 2021 (PI21/01653); Ayuda SEOM Juan Rodés 2020 and Beca SEOM Grupo emergente 2022.

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Authors and Affiliations

  1. Medical Oncology Department, Hospital Clinic of Barcelona, Barcelona, Spain

    Juan Carlos Laguna, Belén Pastor, Irene Nalda & Laura Mezquita

  2. Laboratory of Translational Genomics and Targeted Therapies in Solid Tumors, IDIBAPS, Barcelona, Spain

    Juan Carlos Laguna, Irene Nalda, Cristina Teixido & Laura Mezquita

  3. Preclinical and Experimental Research in Thoracic Tumors (PRETT), Oncobell, Bellvitge Biomedical Research Institute (IDIBELL), l’Hospitalet de Llobregat, Barcelona, Spain

    Sara Hijazo-Pechero

  4. Department of Medicine, University of Barcelona, Barcelona, Spain

    Cristina Teixido & Laura Mezquita

  5. Department of Pathology, Hospital Clinic of Barcelona, Barcelona, Spain

    Cristina Teixido

  6. Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, IDIBAPS, Barcelona, Spain

    Miriam Potrony

  7. CIBER of Rare Diseases (CIBERER), Barcelona, Spain

    Miriam Potrony & Joan Antón Puig-Butillé

  8. Molecular Biology CORE, Hospital Clínic of Barcelona, IDIBAPS, Barcelona, Spain

    Joan Antón Puig-Butillé

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  1. Juan Carlos Laguna
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Contributions

JCL, BP and LM: Conceived and designed the review. All: Drafted and reviewed the manuscript. All: Approved the final version.

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Correspondence to Laura Mezquita.

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JCL: Lectures and educational activities: Kyowa Kirin; Travel, Accommodations, Expenses: Rovi, Pierre-Fabre. BP: The author declares no conflict of interest. IN: The author declares no conflict of interest. SH: The author declares no conflict of interest. CT: Lectures and educational activities: AstraZeneca, Roche, Janssen Oncology, Pfizer, Biocartis, Merck Sharp & Dohme; Consulting, advisory role: Novartis, AstraZeneca; Research Grants: Novartis, AstraZeneca; Travel, Accommodations, Expenses: Bristol-Myers Squibb, Lilly, Merck Sharp & Dohme, Pfizer. MP: Educational activities: ISDIN. JAP: The author declares no conflict of interest. LM: Lectures and educational activities: Bristol-Myers Squibb, AstraZeneca, Roche, Takeda, Janssen, Pfizer, MSD; Consulting, advisory role: Roche, Takeda, Janssen; Research Grants: Bristol-Myers Squibb, Boehringer Ingelheim, Amgen, Stilla, Inivata, AstraZeneca; Travel, Accommodations, Expenses: Bristol-Myers Squibb, Roche, Takeda, AstraZeneca, Janssen.

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Laguna, J.C., Pastor, B., Nalda, I. et al. Incidental pathogenic germline alterations detected through liquid biopsy in patients with solid tumors: prevalence, clinical utility and implications. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02607-9

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