{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T13:56:48Z","timestamp":1790431008935,"version":"4.1.0"},"reference-count":38,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T00:00:00Z","timestamp":1655251200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health (NIH)","doi-asserted-by":"publisher","award":["U01 CA199218"],"award-info":[{"award-number":["U01 CA199218"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health (NIH)","doi-asserted-by":"publisher","award":["U01 CA253911"],"award-info":[{"award-number":["U01 CA253911"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute (NCI)","doi-asserted-by":"publisher","award":["U01 CA199218"],"award-info":[{"award-number":["U01 CA199218"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute (NCI)","doi-asserted-by":"publisher","award":["U01 CA253911"],"award-info":[{"award-number":["U01 CA253911"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Breast cancer screening is associated with harms, such as false-positives and overdiagnoses, and, thus, novel screen tests can be considered. Liquid biopsies have been proposed as a novel method for the early detection of cancer, but low cell-free DNA tumor fraction might pose a problem for the use in population screening. Using breast cancer microsimulation model MISCAN-Fadia, we estimated the outcomes of using liquid biopsies in breast cancer screening in women aged 50 to 74 in the United States. For varying combinations of test sensitivity and specificity, we quantify the impact of the use of liquid biopsies on the harms and benefits of screening, and we estimate the maximum liquid biopsy price for cost-effective implementation in breast cancer screening at a cost-effectiveness threshold of USD 50,000. We investigate under what conditions liquid biopsies could be a suitable alternative to digital mammography and compare these conditions to a CCGA substudy. Outcomes were compared to digital mammography screening, and include mortality reduction, overdiagnoses, quality-adjusted life-years (QALYs), and the maximum price of a liquid biopsy for cost-effective implementation. When liquid biopsies are unable to detect DCIS, a large proportion of overdiagnosed cases is prevented but overall breast cancer mortality reduction and quality of life are lower, and costs are higher compared to digital mammography screening. Liquid biopsies prices should be restricted to USD 187 per liquid biopsy depending on test performance. Overall, liquid biopsies that are unable to detect ductal carcinoma in situ (DCIS) need to be able to detect small, early-stage tumors, with high specificity, at low costs in order to be an alternative to digital mammography. Liquid biopsies might be more suitable as an addition to digital mammography than as an alternative.<\/jats:p>","DOI":"10.3390\/cancers14122951","type":"journal-article","created":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T22:17:01Z","timestamp":1655331421000},"page":"2951","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["The Early Detection of Breast Cancer Using Liquid Biopsies: Model Estimates of the Benefits, Harms, and Costs"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5364-2558","authenticated-orcid":false,"given":"Esm\u00e9e K. J.","family":"van der Poort","sequence":"first","affiliation":[{"name":"Department of Public Health, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands"},{"name":"Department of Biomedical Data Sciences, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3531-466X","authenticated-orcid":false,"given":"Nicolien T.","family":"van Ravesteyn","sequence":"additional","affiliation":[{"name":"Department of Public Health, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeroen J.","family":"van den Broek","sequence":"additional","affiliation":[{"name":"Department of Public Health, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4682-3646","authenticated-orcid":false,"given":"Harry J.","family":"de Koning","sequence":"additional","affiliation":[{"name":"Department of Public Health, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2353","DOI":"10.1056\/NEJMsr1504363","article-title":"Breast-cancer screening--viewpoint of the IARC Working Group","volume":"372","author":"Scoccianti","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"215","DOI":"10.7326\/M15-1536","article-title":"Collaborative Modeling of the Benefits and Harms Associated with Different U.S. Breast Cancer Screening Strategies","volume":"164","author":"Mandelblatt","year":"2016","journal-title":"Ann. Intern. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1093\/jnci\/djq099","article-title":"Overdiagnosis in cancer","volume":"102","author":"Welch","year":"2010","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Li, J., Guan, X., Fan, Z., Ching, L.M., Li, Y., Wang, X., Cao, W.M., and Liu, D.X. (2020). Non-Invasive Biomarkers for Early Detection of Breast Cancer. Cancers, 12.","DOI":"10.3390\/cancers12102767"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1111\/cge.13514","article-title":"Liquid Biopsy in Breast Cancer: A Comprehensive Review","volume":"95","author":"Alimirzaie","year":"2019","journal-title":"Clin. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Nunes, S.P., Moreira-Barbosa, C., Salta, S., Palma de Sousa, S., Pousa, I., Oliveira, J., Soares, M., Rego, L., Dias, T., and Rodrigues, J. (2018). Cell-Free DNA Methylation of Selected Genes Allows for Early Detection of the Major Cancers in Women. Cancers, 10.","DOI":"10.3390\/cancers10100357"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/s41586-018-0703-0","article-title":"Sensitive tumour detection and classification using plasma cell-free DNA methylomes","volume":"563","author":"Shen","year":"2018","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1016\/j.annonc.2021.05.806","article-title":"Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set","volume":"32","author":"Klein","year":"2021","journal-title":"Ann. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1038\/s41416-021-01498-4","article-title":"Estimating the population health impact of a multi-cancer early detection genomic blood test to complement existing screening in the US and UK","volume":"125","author":"Hackshaw","year":"2021","journal-title":"Br. J. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1158\/1055-9965.EPI-20-1134","article-title":"Modeled Reductions in Late-stage Cancer with a Multi-Cancer Early Detection Test","volume":"30","author":"Hubbell","year":"2021","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.ccell.2019.09.003","article-title":"Toward the Early Detection of Cancer by Decoding the Epigenetic and Environmental Fingerprints of Cell-Free DNA","volume":"36","author":"Mouliere","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"IJzerman, M.J., de Boer, J., Azad, A., Degeling, K., Geoghegan, J., Hewitt, C., Hollande, F., Lee, B., To, Y.H., and Tothill, R.W. (2021). Towards Routine Implementation of Liquid Biopsies in Cancer Management: It Is Always Too Early, until Suddenly It Is Too Late. Diagnostics, 11.","DOI":"10.3390\/diagnostics11010103"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"eaat4921","DOI":"10.1126\/scitranslmed.aat4921","article-title":"Enhanced detection of circulating tumor DNA by fragment size analysis","volume":"10","author":"Mouliere","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1126\/science.aar3247","article-title":"Detection and localization of surgically resectable cancers with a multi-analyte blood test","volume":"359","author":"Cohen","year":"2018","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"224ra24","DOI":"10.1126\/scitranslmed.3007094","article-title":"Detection of circulating tumor DNA in early- and late-stage human malignancies","volume":"6","author":"Bettegowda","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Pons-Belda, O.D., Fernandez-Uriarte, A., and Diamandis, E.P. (2021). Can Circulating Tumor DNA Support a Successful Screening Test for Early Cancer Detection? The Grail Paradigm. Diagnostics, 11.","DOI":"10.3390\/diagnostics11122171"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Klein, E.A., Beer, T.M., and Seiden, M. (2022). The Promise of Multicancer Early Detection. Comment on Pons-Belda et al. Can Circulating Tumor DNA Support a Successful Screening Test for Early Cancer Detection? The Grail Paradigm. Diagnostics 2021, 11, 2171. Diagnostics, 12.","DOI":"10.3390\/diagnostics12051243"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"359","DOI":"10.2217\/pgs-2019-0130","article-title":"Liquid biopsy for the detection of clinical biomarkers in early breast cancer: New insights and challenges","volume":"21","author":"Matsutani","year":"2020","journal-title":"Pharmacogenomics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.annonc.2020.02.011","article-title":"Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA","volume":"31","author":"Liu","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4221","DOI":"10.1158\/1078-0432.CCR-21-0417","article-title":"Prognostic Significance of Blood-Based Multi-cancer Detection in Plasma Cell-Free DNA","volume":"27","author":"Chen","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Bredno, J., Lipson, J., Venn, O., Aravanis, A.M., and Jamshidi, A. (2021). Clinical correlates of circulating cell-free DNA tumor fraction. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0256436"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"279","DOI":"10.7326\/M15-2886","article-title":"Screening for Breast Cancer: U.S. Preventive Services Task Force Recommendation Statement","volume":"164","author":"Siu","year":"2016","journal-title":"Ann. Intern. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1093\/jncimonographs\/lgj009","article-title":"The MISCAN-Fadia continuous tumor growth model for breast cancer","volume":"36","author":"Tan","year":"2006","journal-title":"J. Natl. Cancer Inst. Monogr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1056\/NEJMoa050518","article-title":"Effect of screening and adjuvant therapy on mortality from breast cancer","volume":"353","author":"Berry","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3S","DOI":"10.1177\/0272989X17737507","article-title":"Introduction to the Cancer Intervention and Surveillance Modeling Network (CISNET) Breast Cancer Models","volume":"38","author":"Alagoz","year":"2018","journal-title":"Med. Decis. Mak."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9S","DOI":"10.1177\/0272989X17700624","article-title":"Common Model Inputs Used in CISNET Collaborative Breast Cancer Modeling","volume":"38","author":"Mandelblatt","year":"2018","journal-title":"Med. Decis. Mak."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"54S","DOI":"10.1177\/0272989X17711928","article-title":"Simulating the Impact of Risk-Based Screening and Treatment on Breast Cancer Outcomes with MISCAN-Fadia","volume":"38","author":"Heijnsdijk","year":"2018","journal-title":"Med. Decis. Mak."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1148\/radiol.2016161174","article-title":"National Performance Benchmarks for Modern Screening Digital Mammography: Update from the Breast Cancer Surveillance Consortium","volume":"283","author":"Lehman","year":"2017","journal-title":"Radiology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"dju092","DOI":"10.1093\/jnci\/dju092","article-title":"Benefits, harms, and costs for breast cancer screening after US implementation of digital mammography","volume":"106","author":"Stout","year":"2014","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1093\/jnci\/djq495","article-title":"Projections of the cost of cancer care in the United States: 2010\u20132020","volume":"103","author":"Mariotto","year":"2011","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"700","DOI":"10.7326\/M16-0476","article-title":"Tailoring Breast Cancer Screening Intervals by Breast Density and Risk for Women Aged 50 Years or Older: Collaborative Modeling of Screening Outcomes","volume":"165","author":"Kerlikowske","year":"2016","journal-title":"Ann. Intern. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1093\/jnci\/djn103","article-title":"Cost of care for elderly cancer patients in the United States","volume":"100","author":"Yabroff","year":"2008","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_33","first-page":"DS197","article-title":"Panel on cost-effectiveness in health and medicine","volume":"34","author":"Gold","year":"1996","journal-title":"Med. Care"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1056\/NEJMp1405158","article-title":"Updating cost-effectiveness\u2014The curious resilience of the $50,000-per-QALY threshold","volume":"371","author":"Neumann","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1038\/s41586-019-1272-6","article-title":"Genome-wide cell-free DNA fragmentation in patients with cancer","volume":"570","author":"Cristiano","year":"2019","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/s41698-017-0039-5","article-title":"The potential of liquid biopsies for the early detection of cancer","volume":"1","author":"Heitzer","year":"2017","journal-title":"NPJ Precis. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1001\/jama.2015.12783","article-title":"Breast Cancer Screening for Women at Average Risk: 2015 Guideline Update From the American Cancer Society","volume":"314","author":"Oeffinger","year":"2015","journal-title":"JAMA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.jacr.2009.09.022","article-title":"Breast cancer screening with imaging: Recommendations from the Society of Breast Imaging and the ACR on the use of mammography, breast MRI, breast ultrasound, and other technologies for the detection of clinically occult breast cancer","volume":"7","author":"Lee","year":"2010","journal-title":"J. Am. Coll. Radiol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/12\/2951\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:32:01Z","timestamp":1760139121000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/12\/2951"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,15]]},"references-count":38,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["cancers14122951"],"URL":"https:\/\/doi.org\/10.3390\/cancers14122951","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,15]]}}}