{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T23:14:44Z","timestamp":1787786084006,"version":"build-2784847793"},"reference-count":52,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T00:00:00Z","timestamp":1644278400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Circulating tumor DNA (ctDNA) is a promising liquid biopsy (LB) marker to support clinical decisions in precision medicine. For implementation into routine clinical practice, clinicians need precise ctDNA level cutoffs for reporting residual disease and monitoring tumor burden changes during therapy. We clinically validated the limit of blank (LOB) and the limit of quantification (LOQ) of assays for the clinically most relevant somatic variants BRAF p.V600E and KRAS p.G12\/p.G13 in colorectal cancer (CRC) in a study cohort encompassing a total of 212 plasma samples. We prove that residual disease detection using the LOB as a clinically verified cutoff for ctDNA positivity is in concordance with clinical evidence of metastasis or recurrence. We further show that tumor burden changes during chemotherapy and the course of disease are correctly predicted using the LOQ as a cutoff for quantitative ctDNA changes. The high potential of LB using ctDNA for accurately predicting the course of disease was proven by direct comparison to the routinely used carcinoembryonic antigen (CEA) as well as the circulating free DNA (cfDNA) concentration. Our results show that LB using validated ctDNA assays outperforms CEA and cfDNA for residual disease detection and the prediction of tumor burden changes.<\/jats:p>","DOI":"10.3390\/cancers14030851","type":"journal-article","created":{"date-parts":[[2022,2,9]],"date-time":"2022-02-09T01:03:40Z","timestamp":1644368620000},"page":"851","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Clinical Validity of Circulating Tumor DNA as Prognostic and Predictive Marker for Personalized Colorectal Cancer Patient Management"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6503-1874","authenticated-orcid":false,"given":"Ariane","family":"Hallermayr","sequence":"first","affiliation":[{"name":"MGZ\u2014Medizinisch Genetisches Zentrum, 80335 Munich, Germany"},{"name":"Institute for Medical Information Processing, Biometry, and Epidemiology, Pettenkofer School of Public Health LMU Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8491-3234","authenticated-orcid":false,"given":"Verena","family":"Steinke-Lange","sequence":"additional","affiliation":[{"name":"MGZ\u2014Medizinisch Genetisches Zentrum, 80335 Munich, Germany"},{"name":"Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universit\u00e4t M\u00fcnchen, 80336 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9750-8924","authenticated-orcid":false,"given":"Holger","family":"Vogelsang","sequence":"additional","affiliation":[{"name":"Department of General, Visceral, Thoracic and Endocrine Surgery, Klinikum Garmisch-Partenkirchen, Teaching Hospital, Ludwig Maximilian University Munich, 82467 Garmisch-Partenkirchen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Rentsch","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Thorax Surgery, Klinikum Ingolstadt, 85049 Ingolstadt, Germany"},{"name":"Department of General, Visceral, Vascular and Transplant Surgery, University Hospital Munich, Campus Gro\u00dfhadern, Ludwig-Maximilians University of Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maike","family":"de Wit","sequence":"additional","affiliation":[{"name":"Department of Haemaotology, Oncology and Palliative Medicine, Vivantes Klinikum Neukoelln, 12351 Berlin, Germany"},{"name":"Department of Oncology, Vivantes Auguste-Viktoria-Klinikum, 12157 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Haberl","sequence":"additional","affiliation":[{"name":"Department of Oncology and Hematology, Barmherzige Br\u00fcder, Klinikum St. Elisabeth, 94315 Straubing, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elke","family":"Holinski-Feder","sequence":"additional","affiliation":[{"name":"MGZ\u2014Medizinisch Genetisches Zentrum, 80335 Munich, Germany"},{"name":"Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universit\u00e4t M\u00fcnchen, 80336 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9269-5177","authenticated-orcid":false,"given":"Julia M. A.","family":"Pickl","sequence":"additional","affiliation":[{"name":"MGZ\u2014Medizinisch Genetisches Zentrum, 80335 Munich, Germany"},{"name":"Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universit\u00e4t M\u00fcnchen, 80336 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1093\/clinchem\/48.3.421","article-title":"Predominant Hematopoietic Origin of Cell-free DNA in Plasma and Serum after Sex-mismatched Bone Marrow Transplantation","volume":"48","author":"Lui","year":"2002","journal-title":"Clin. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5040","DOI":"10.1038\/s41598-021-84507-z","article-title":"Cell-free DNA concentration and fragment size as a biomarker for prostate cancer","volume":"11","author":"Chen","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1038\/nm.1789","article-title":"Circulating mutant DNA to assess tumor dynamics","volume":"14","author":"Diehl","year":"2008","journal-title":"Nat. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"9085","DOI":"10.1200\/jco.2014.32.15_suppl.9085","article-title":"Correlation of tumor-derived circulating cell free DNA (cfDNA) measured by digital PCR (DigPCR) with tumor burden measured radiographically in patients (pts) with BRAFV600E mutated melanoma (mel) treated with RAF inhibitor (RAFi) and\/or ipilimumab (Ipi)","volume":"32","author":"Momtaz","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5437","DOI":"10.1158\/1078-0432.CCR-17-0510","article-title":"Clinical Implications of Monitoring Circulating Tumor DNA in Patients with Colorectal Cancer","volume":"23","author":"Reinert","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1038\/nm.4239","article-title":"Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer","volume":"23","author":"Carter","year":"2017","journal-title":"Nat. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1038\/s41467-019-10122-2","article-title":"Hydro-Seq enables contamination-free high-throughput single-cell RNA-sequencing for circulating tumor cells","volume":"10","author":"Cheng","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41576-018-0071-5","article-title":"Current and future perspectives of liquid biopsies in genomics-driven oncology","volume":"20","author":"Heitzer","year":"2019","journal-title":"Nat. Rev. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1146\/annurev-pathmechdis-012418-012735","article-title":"Enabling Precision Oncology Through Precision Diagnostics","volume":"15","author":"Brown","year":"2020","journal-title":"Annu. Rev. Pathol."},{"key":"ref_10","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_11","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1200\/JCO.18.02052","article-title":"Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients with Urothelial Bladder Carcinoma","volume":"37","author":"Christensen","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"McDonald, B.R., Contente-Cuomo, T., Sammut, S.-J., Odenheimer-Bergman, A., Ernst, B., Perdigones, N., Chin, S.-F., Farooq, M., Mejia, R., and Cronin, P.A. (2019). Personalized circulating tumor DNA analysis to detect residual disease after neoadjuvant therapy in breast cancer. Sci. Transl. Med., 11.","DOI":"10.1126\/scitranslmed.aax7392"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/s41467-020-14310-3","article-title":"White blood cell and cell-free DNA analyses for detection of residual disease in gastric cancer","volume":"11","author":"Leal","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1016\/j.annonc.2020.09.010","article-title":"5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5)","volume":"31","author":"Cardoso","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"iv192","DOI":"10.1093\/annonc\/mdy275","article-title":"Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"29","author":"Planchard","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1002\/ijc.33312","article-title":"Prognostic significance of postsurgery circulating tumor DNA in nonmetastatic colorectal cancer: Individual patient pooled analysis of three cohort studies","volume":"148","author":"Tie","year":"2020","journal-title":"Int. J. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1016\/j.annonc.2020.06.022","article-title":"Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"31","author":"Tabernero","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4466","DOI":"10.1200\/JCO.2003.99.200","article-title":"Carcinoembryonic Antigen Surge in Metastatic Colorectal Cancer Patients Responding to Oxaliplatin Combination Chemotherapy: Implications for Tumor Marker Monitoring and Guidelines","volume":"21","author":"Dahl","year":"2003","journal-title":"J. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1081\/CNV-58878","article-title":"Carcinoembryonic Antigen in the Staging and Follow-up of Patients with Colorectal Cancer","volume":"23","author":"Goldstein","year":"2005","journal-title":"Cancer Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1093\/jnci\/djp240","article-title":"Analysis of circulating tumor DNA to confirm somatic KRAS mutations","volume":"101","author":"Holdhoff","year":"2009","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16368","DOI":"10.1073\/pnas.0507904102","article-title":"Detection and quantification of mutations in the plasma of patients with colorectal tumors","volume":"102","author":"Diehl","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3761","DOI":"10.1002\/cam4.2219","article-title":"Detection of mutations in circulating cell-free DNA in relation to disease stage in colorectal cancer","volume":"8","author":"Liebs","year":"2019","journal-title":"Cancer Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1093\/clinchem\/hvaa164","article-title":"Generic Protocols for the Analytical Validation of Next-Generation Sequencing-Based ctDNA Assays: A Joint Consensus Recommendation of the BloodPAC\u2019s Analytical Variables Working Group","volume":"66","author":"Godsey","year":"2020","journal-title":"Clin. Chem."},{"key":"ref_24","unstructured":"NCCLS (2004). Protocols for Determination of Limits of Detection and Limits of Quantitation Guideline: Approved Guideline, NCCLS Document EP17-A."},{"key":"ref_25","unstructured":"Wittekind, C., and Meyer, H.-J. (2010). TNM Klassifikation Maligner Tumoren, Wiley-VCH. [7th ed.]."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2198","DOI":"10.1038\/s41375-020-0869-y","article-title":"Prevalence and dynamics of clonal hematopoiesis caused by leukemia-associated mutations in elderly individuals without hematologic disorders","volume":"34","author":"Midic","year":"2020","journal-title":"Leukemia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1093\/clinchem\/hvab124","article-title":"Liquid Biopsy Hotspot Variant Assays: Analytical Validation for Application in Residual Disease Detection and Treatment Monitoring","volume":"67","author":"Hallermayr","year":"2021","journal-title":"Clin. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6985","DOI":"10.1158\/1078-0432.CCR-06-1931","article-title":"Free DNA and carcinoembryonic antigen serum levels: An important combination for diagnosis of colorectal cancer","volume":"12","author":"Flamini","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1309\/AJCP4RK2IHVKTTZV","article-title":"Measurement of circulating cell-free DNA levels by a new simple fluorescent test in patients with primary colorectal cancer","volume":"135","author":"Czeiger","year":"2011","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Berger, A.W., Schwerdel, D., Welz, H., Marienfeld, R., Schmidt, S.A., Kleger, A., Ettrich, T.J., and Seufferlein, T. (2017). Treatment monitoring in metastatic colorectal cancer patients by quantification and KRAS genotyping of circulating cell-free DNA. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174308"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5416","DOI":"10.1158\/1078-0432.CCR-16-3155","article-title":"Early Evaluation of Circulating Tumor DNA as Marker of Therapeutic Efficacy in Metastatic Colorectal Cancer Patients (PLACOL Study)","volume":"23","author":"Garlan","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4437","DOI":"10.1158\/1078-0432.CCR-18-0143","article-title":"False-Positive Plasma Genotyping Due to Clonal Hematopoiesis","volume":"24","author":"Hu","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1001\/jamaoncol.2017.4420","article-title":"Association of Preoperative and Postoperative Serum Carcinoembryonic Antigen and Colon Cancer Outcome","volume":"4","author":"Konishi","year":"2018","journal-title":"JAMA Oncol."},{"key":"ref_34","unstructured":"Weaver, C.H. (2021, March 19). Understanding The CEA Test in Colon Cancer. Available online: https:\/\/news.cancerconnect.com\/colon-cancer\/understanding-the-cea-test-in-colon-cancer-2yuVIMszUkideV0m-kWBwA."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Larrib\u00e8re, L., and Martens, U.M. (2021). Advantages and Challenges of Using ctDNA NGS to Assess the Presence of Minimal Residual Disease (MRD) in Solid Tumors. Cancers, 13.","DOI":"10.3390\/cancers13225698"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1001\/jamaoncol.2019.0528","article-title":"Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients with Stages I to III Colorectal Cancer","volume":"5","author":"Reinert","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1001\/jamaoncol.2019.0512","article-title":"Prognostic Potential of Circulating Tumor DNA Measurement in Postoperative Surveillance of Nonmetastatic Colorectal Cancer","volume":"5","author":"Wang","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref_38","first-page":"CD002200","article-title":"Follow-up strategies for patients treated for non-metastatic colorectal cancer","volume":"11","author":"Jeffery","year":"2016","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_39","first-page":"CD011134","article-title":"Blood CEA levels for detecting recurrent colorectal cancer","volume":"12","author":"Nicholson","year":"2015","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"11631","DOI":"10.1038\/s41598-018-30100-w","article-title":"Utility of targeted deep sequencing for detecting circulating tumor DNA in pancreatic cancer patients","volume":"8","author":"Park","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1038\/s41416-020-0941-4","article-title":"Serial circulating tumour DNA analysis for locally advanced rectal cancer treated with preoperative therapy: Prediction of pathological response and postoperative recurrence","volume":"123","author":"Murahashi","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_42","unstructured":"(2021, January 17). COSMIC Cancer Browser: Large Intestine\u2014Carcinoma\u2014Adenocarcinoma Genes. Available online: https:\/\/cancer.sanger.ac.uk\/cosmic\/browse\/tissue?wgs=off&sn=large_intestine&ss=all&hn=carcinoma&sh=adenocarcinoma&in=t&src=tissue&all_data=n."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1093\/annonc\/mdw235","article-title":"ESMO consensus guidelines for the management of patients with metastatic colorectal cancer","volume":"27","author":"Cervantes","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Huang, X., Gao, P., Song, Y., Sun, J., Chen, X., Zhao, J., Liu, J., Xu, H., and Wang, Z. (2014). Relationship between circulating tumor cells and tumor response in colorectal cancer patients treated with chemotherapy: A meta-analysis. BMC Cancer, 14.","DOI":"10.1186\/1471-2407-14-976"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1007\/s00384-018-03223-9","article-title":"Circulating tumor cells as an independent prognostic factor in advanced colorectal cancer: A retrospective study in 121 patients","volume":"34","author":"Wang","year":"2019","journal-title":"Int. J. Colorectal Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6843180","DOI":"10.1155\/2020\/6843180","article-title":"Perspectives of the Application of Liquid Biopsy in Colorectal Cancer","volume":"2020","author":"Ding","year":"2020","journal-title":"Biomed Res. Int."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Vacante, M., Ciuni, R., Basile, F., and Biondi, A. (2020). The Liquid Biopsy in the Management of Colorectal Cancer: An Overview. Biomedicines, 8.","DOI":"10.3390\/biomedicines8090308"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Lambros, M.B., Gil, V.S., Crespo, M., Fontes, M.S., Neves, R.N., Mahra, N., Fowler, G., Ebbs, B., Flohr, P., and Seed, G. (2017). Abstract 993: Diagnostic leukapheresis (DLA): Molecular characterisation and organoid culture of circulating tumor cells (CTC) from metastatic castration resistant prostate cancer (mCRPC). Cancer Res., 77.","DOI":"10.1158\/1538-7445.AM2017-993"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Schou, J.V., Rossi, S., Jensen, B.V., Nielsen, D.L., Pfeiffer, P., H\u00f8gdall, E., Yilmaz, M., Tejpar, S., Delorenzi, M., and Kruh\u00f8ffer, M. (2014). miR-345 in metastatic colorectal cancer: A non-invasive biomarker for clinical outcome in non-KRAS mutant patients treated with 3rd line cetuximab and irinotecan. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0099886"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1159\/000463387","article-title":"Circulating Exosomal MicroRNA-21 as a Biomarker in Each Tumor Stage of Colorectal Cancer","volume":"92","author":"Tsukamoto","year":"2017","journal-title":"Oncology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.tranon.2017.12.012","article-title":"Circulating Exosomal miR-17-5p and miR-92a-3p Predict Pathologic Stage and Grade of Colorectal Cancer","volume":"11","author":"Fu","year":"2018","journal-title":"Transl. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s00280-019-03867-6","article-title":"A panel of serum exosomal microRNAs as predictive markers for chemoresistance in advanced colorectal cancer","volume":"84","author":"Jin","year":"2019","journal-title":"Cancer Chemother. Pharmacol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/3\/851\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:16:33Z","timestamp":1760134593000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/3\/851"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,8]]},"references-count":52,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["cancers14030851"],"URL":"https:\/\/doi.org\/10.3390\/cancers14030851","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,8]]}}}