Circulating tumor DNA (ctDNA) is not a good proxy for liquid biopsies of tumor tissues for early detection

Clare Fiala; Eleftherios P. Diamandis

doi:10.1515/cclm-2020-0083

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Circulating tumor DNA (ctDNA) is not a good proxy for liquid biopsies of tumor tissues for early detection

Clare Fiala and Eleftherios P. Diamandis

Published/Copyright: March 11, 2020

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From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 58 Issue 10

Abstract

The important conclusion that ctDNA is a mediocre proxy for liquid biopsies of tumor tissues for early detection was reached after new data were published recently in Nature Genetics. These data have shown that most mutations found in ctDNA are not related to tumor tissues but rather to the precancerous condition clonal hematopoiesis. Previously, our group has analyzed the sensitivity of the ctDNA test for early detection of cancer and concluded that the achievable sensitivity, especially for small tumors, is not enough to have clinical value. Now, the new data have shown a serious compromise in specificity. We believe that scientists who are interested in early cancer diagnostics should be aware of the limitations of this test, in both sensitivity and specificity. Our work may prompt further work aiming to alleviate these important issues in the cancer diagnostics field.

Keywords: CA-125: cancer antigen 125; ctDNA: circulating tumor DNA; PSA: prostate-specific antigen

Corresponding author: Eleftherios P. Diamandis, MD, PhD, FRCP(C), FRSC, Head of Clinical Biochemistry, Mount Sinai Hospital and University Health Network, 60 Murray St. Box 32, Floor 6, Rm L6-201, Toronto, ON M5T 3L9, Canada; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; and Department of Clinical Biochemistry, University Health Network, Toronto, ON, Canada, Phone: +(416) 586-8443

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: Dr. Eleftherios P. Diamandis discloses that he holds a consultant/advisory role with Abbott Diagnostics. Miss Clare Fiala has nothing to disclose.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Fiala C, Kulasingam V, Diamandis EP. Circulating tumor DNA for early cancer detection. J Appl Lab Med 2018;4:026393.10.1373/jalm.2018.026393Search in Google Scholar PubMed

2. Diamandis EP, Fiala C. Can circulating tumor DNA be used for direct and early stage cancer detection? F1000Research 2017;6:2129.10.12688/f1000research.13440.1Search in Google Scholar PubMed PubMed Central

3. Fiala C, Diamandis EP. Utility of circulating tumor DNA in cancer diagnostics with emphasis on early detection. BMC Med 2018;14:166.10.1186/s12916-018-1157-9Search in Google Scholar PubMed PubMed Central

4. Liu MC, Maddala T, Aravanis A, Hubbell E, Beausang JF, Filippova D, et al. Breast cancer cell-free DNA (cfDNA) profiles reflect underlying tumor biology. The Circulating Cell-Free Genome Atlas (CCGA) study. J Clin Oncol 2018;36(suppl):536.10.1200/JCO.2018.36.15_suppl.536Search in Google Scholar

5. Oxnard GR, Klein EA, Seiden M, Hubbell E, Venn O, Jamshidi A, et al. Simultaneous multi-cancer detection and tissue of origin (TOO) localization using targeted bisulfite sequencing of plasma cell-free DNA (cfDNA). J Glob Oncol 2019;5(suppl):44.10.1200/JGO.2019.5.suppl.44Search in Google Scholar

6. Razavi P, Li BT, Brown DN, Jung B, Hubbell E, Shen R, et al. High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants. Nat Med 2019;25:1928–37.10.1038/s41591-019-0652-7Search in Google Scholar PubMed PubMed Central

7. Loh PR, Genovese G, Handsaker RE, Finucane HK, Reshef YA, Palamara PF, et al. Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations. Nature 2018;559:350–5.10.1038/s41586-018-0321-xSearch in Google Scholar PubMed PubMed Central

8. Li BT, Janku F, Jung B, Hou C, Madwani K, Alden R, et al. Ultra-deep next-generation sequencing of plasma cell-free DNA in patients with advanced lung cancers: results from the Actionable Genome Consortium. Ann Oncol 2019;30:597–603.10.1093/annonc/mdz046Search in Google Scholar PubMed PubMed Central

9. Keller L, Pantel K. Unravelling tumour heterogeneity by single-cell profiling of circulating tumor cells. Nat Rev Cancer 2019;19:553–67.10.1038/s41568-019-0180-2Search in Google Scholar PubMed

10. Shen SY, Singhania R, Fehringer G, Chakravarthy A, Roehrl MH, Chadwick D, et al. Sensitive tumour detection and classification using plasma cell-free DNA methylomes. Nature 2018;563: 579–83.10.1038/s41586-018-0703-0Search in Google Scholar PubMed

11. Cristiano S, Leal A, Phallen J, Fiksel J, Adleff V, Bruhm DC, et al. Genome-wide cell-free DNA fragmentation in patients with cancer. Nature 2019;570:385–9.10.1038/s41586-019-1272-6Search in Google Scholar PubMed PubMed Central

12. Mouliere F, Chandrananda D, Piskorz AM, Moore EK, Morris J, Ahlborn LB, et al. Enhanced detection of circulating tumor DNA by fragment size analysis. Sci Transl Med 2018;10:eaat4921.10.1126/scitranslmed.aat4921Search in Google Scholar PubMed PubMed Central

13. Tomasetti C. Mutated clones are the new normal. Science 2019;364:938–9.10.1126/science.aax5525Search in Google Scholar PubMed

Received: 2020-01-22

Accepted: 2020-02-19

Published Online: 2020-03-11

Published in Print: 2020-09-25

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Articles in the same Issue

https://doi.org/10.1515/cclm-2020-0083

Keywords for this article

CA-125: cancer antigen 125; ctDNA: circulating tumor DNA; PSA: prostate-specific antigen