Journal of Modern OncologyJournal of Modern Oncology1815-14341815-1442LLC Obyedinennaya Redaktsiya24121510.26442/18151434.2023.1.202179Research ArticleDiagnostic significance of CA-62 cancer antigen for early detection and differential diagnosis of non-small cell lung cancer: results of the blind clinical trialsTcherkassovaJanneta R.<p>Cand. Sci. (Chem.), JVS Diagnostics LLC</p>janneta_tcherkassova@yahoo.comhttps://orcid.org/0000-0002-9074-7233ProstyakovaAnna I.<p>Cand. Sci. (Chem.), Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry</p>prostyakova@gmail.comhttps://orcid.org/0000-0001-5922-6600TsurkanSergei A.<p>Cand. Sci. (Pharmaceut.), JVS Diagnostics LLC</p>sergeitsurkan@gmail.comhttps://orcid.org/0000-0002-0030-1802SuganovNikolai V.<p>Surgeon, Medical advisor at JVS Diagnostics LLC</p>nickol699@gmail.comBorodaAlexander M.<p>Res. Officer, Sechenov First Moscow State Medical University (Sechenov University)</p>boroda_a_m@staff.sechenov.ruhttps://orcid.org/0000-0002-4196-6042ZhilenkovaAngelina V.<p>Res. Assist., Sechenov First Moscow State Medical University (Sechenov University)</p>zhilenkova_a_v@staff.sechenov.ruhttps://orcid.org/0000-0002-0060-2197PirogovaJuliya N.<p>Res. Assist., Sechenov First Moscow State Medical University (Sechenov University)</p>pirogova_yu_n@staff.sechenov.ruSangadzhievaZaiana D.<p>Res. Assist., Sechenov First Moscow State Medical University (Sechenov University)</p>sangadzhieva_z_d@staff.sechenov.ruhttps://orcid.org/0000-0003-0780-5277RusanovAleksandr S.<p>Res. Assist., Sechenov First Moscow State Medical University (Sechenov University)</p>rusanov_a_s@staff.sechenov.ruRozhkovAleksandr A.<p>Res. Assist., Sechenov First Moscow State Medical University (Sechenov University)</p>rozhkov_a_a@staff.sechenov.ruhttps://orcid.org/0000-0002-6520-3031FatyanovaAnastasia S.<p>Assoc. Prof., Sechenov First Moscow State Medical University (Sechenov University)</p>prostyakova@gmail.comhttps://orcid.org/0000-0002-5004-8307NikitinaNatalia M.<p>Res. Assist., Sechenov First Moscow State Medical University (Sechenov University)</p>nikitina_n_m@staff.sechenov.ruBagmetNikolay N.<p>D. Sci. (Med.), Petrovsky National Research Centre of Surgery</p>bagmetn@mail.ruhttps://orcid.org/0000-0001-8325-4409SekachevaMarina I.<p>D. Sci. (Med.), Prof., Sechenov First Moscow State Medical University (Sechenov University)</p>sekacheva_m_i@staff.sechenov.ruhttps://orcid.org/0000-0003-0015-7094JVS Diagnostics LLCShemyakin and Ovchinnikov Institute of Bioorganic ChemistrySechenov First Moscow State Medical University (Sechenov University)Petrovsky National Research Centre of Surgery17052023251829028022023Copyright © 2023, Consilium Medicum2023<p><strong>Background</strong>. The combination of several diagnostic methods is used to predict treatment outcomes, assess overall survival, and increase the positive predictive value of detecting malignant lung and bronchial tumors.</p>
<p><strong>Aim</strong>. To evaluate the diagnostic value of the CLIA-СА-62 chemiluminescence immunoassay reagent kit for the detection of early (IaIIb) and advanced (IIIac) stages of lung cancer (LC) in a double-blind clinical study and to assess the use of the CA-62 cancer antigen as a supportive decision-making tool in LC diagnosis in patients with suspicious changes on the tomogram or as a tool for pre-screening of LC prior to computed tomography (CT) to increase diagnostic sensitivity in the detection of early (I and II) stages of LC.</p>
<p><strong>Materials and methods</strong>. A blinded clinical study was conducted on 304 clinically verified serum samples, including 141 samples from patients with non-small cell LC (NSCLC), 133 healthy volunteers, and 30 chronic obstructive pulmonary disease patients. Quantification of other well-known tumor markers used in the diagnosis of LC (CEA, CA-125, CA 15-3, CA 19-9, CYFRА 21-1, NSE, and SCC), as well as the CA-62 marker in all serum samples was performed using electrochemiluminescent immunoassay Elecsys CA-125, ELECSYS CA 19-9, ELECSYS CYFRА 21-1 and ELECSYS SCC (COBAS, Roche Diagnostics GmbH, Germany, EU), enzyme-linked immunoassay CA 15-3-ELISA-BEST, CEA-ELISA-BEST, NSE-ELISA-BEST (AO Vector-Best, Russia) and chemiluminescent immunoassay CLIA-СА-62 (JVS Diagnostics, Skolkovo, Moscow, Russia).</p>
<p><strong>Results</strong>. CA-62 glycoprotein showed the highest level of expression at stage I NSCLC (12 745 U/mL) compared to other tumor markers studied and remained very high at the later stages of cancer: stage II (11 261 U/mL) and stage III (10 220 U/mL). A comparative analysis of the ROC curves of the most promising tumor markers CEA, CYFRA 21-1, SCC, and CA-62 for the entire NSCLC cohort versus all healthy volunteers and patients with chronic obstructive pulmonary disease showed a significant difference in the area under the curve between CA-62 (AUC 0.981) and other markers: CEA (AUC 0.84) CYFRA 21-1 (AUC 0.753)SCC (AUC 0.682). When detecting early stages (I and II) of NSCLC, a comparison of the sensitivity of the studied tumor markers showed the following pattern: CA-62 (92%)CEA (37%)CYFRA 21-1 (9%) and SCC (9%)NSE (4.5%)CA-125 (3%)CA 15-3 (1.5%)CA 199 (1%). In contrast to the CEA, CA 15-3, CA-125, NSE, CA 19-9, CYFRA 21-1, and SCC tumor markers, which are expressed proportionally to tumor growth, the epithelial carcinoma marker CA-62 showed the highest diagnostic indicators in the detection of LC early stages (III): sensitivity 92.5%, specificity 96.3%, positive predictive value 91.2%, NPV 97%, with 95% accuracy of LC detection with biopsy.</p>
<p><strong>Conclusion</strong>. The study results showed that in order to increase the specificity of computed tomography in diagnosing LC in patients with suspicious lesion on the CT scan on the tomogram, the use of the carcinoma-specific marker CA-62 can improve the interpretation of the localized focus visualized and increase the accuracy of differential diagnosis at the early stages of LC to 96%, thus contributing to an increase of the overall survival among patients with lung cancer. Of the entire panel of markers, only glycoprotein CA-62 showed a strong correlation with histology (kappa 0.91) in identifying the malignant process with inconclusive results of low-dose CT (LDCT). In the future, introducing the CA-62 marker to the current system for assessing the LC risk as a pre-screening for LDCT can improve the detection of early LC by reducing false-positive results. Once introduced into existing screening programs, it can help significantly reduce the number of patients who need LDCT, decreasing the workload of LDCT and reducing radiation exposure.</p>CA-62 glycoproteinnon-small cell lung cancerearly diagnosislung cancer risk assessmentclinical studyCLIA-СА-62 chemiluminescence immunoassay kitгликопротеин СА-62немелкоклеточный рак легкогоранняя диагностикаоценки риска наличия рака легкогоклиническое исследованиеиммунохемилюминесцентный набор реагентов ИХА-СА-62[Cancer today. Available at: https://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf. Accessed: 15.01.2023.][Состояние онкологической помощи населению России в 2020 году. Под ред. А.Д. Каприна, В.В. Старинского, А.О. Шахзадовой. М.: МНИОИ им. П.А. Герцена − филиал ФГБУ «НМИЦ радиологии» Минздрава России, 2021 [Sostoianiie onkologicheskoi pomoshchi naseleniiu Rossii v 2020 godu. Pod red. AD Kaprina, VV Starinskogo, AO Shakhzadovoi. Moscow: MNIOI im. PA Gertsena − filial FGBU “NMITS radiologii” Minzdrava Rossii, 2021 (in Russian)].][Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33. DOI:10.3322/caac.21708][Verma M. Cancer Epidemiology. USA, 2009 Humana Totowa, NJ. DOI:10.1007/978-1-60327-492-0][Chaput G, Del Giudice ME, Kucharski E. Cancer screening in Canada: What's in, what's out, what's coming. Can Fam Physician. 2021;67(1):27-9. DOI:10.46747/cfp.670127][Screening for Lung Cancer US Preventive Services Task Force Recommendation Statement. JAMA. 2021;325(10):962-70. DOI:10.1001/jama.2021.1117][AJCC Cancer Staging Manual. 8th Edition. Eds MB Amin, SB Edge, FL Greene. 2017.][Fleiss JL, Levin B, Paik MC. Statistical Methods for Rates and Proportions, 3rd ed. New York: Wiley. 2003.][Единое цифровое пространство лучевой диагностики. Режим доступа: https://static-0.minzdrav.gov.ru/system/attachments/attaches/000/047/964/original/%D0%95%D0%B4%D0%B8%D0%BD%D0%BE%D0%B5_%D1%86%D0%B8%D1%84%D1%80%D0%BE%D0%B2%D0%BE%D0%B5_%D0%BF%D1%80%D0%BE%D1%81%D1%82%D1%80%D0%B0%D0%BD%D1%81%D1%82%D0%B2%D0%BE_%D0%BB%D1%83%D1%87%D0%B5%D0%B2%D0%BE%D0%B9_%D0%B4%D0%B8%D0%B0%D0%B3%D0%BD%D0%BE%D1%81%D1%82%D0%B8%D0%BA%D0%B8_%28%D0%B3._%D0%9C%D0%BE%D1%81%D0%BA%D0%B2%D0%B0%29.pdf?1571848385. Ссылка активна на 15.01.2023 [Unified digital space of radiation diagnostics. Available at: https://static-0.minzdrav.gov.ru/system/attachments/attaches/000/047/964/original/%D0%95%D0%B4%D0%B8%D0%BD%D0%BE%D0%B5_%D1%86%D0%B8%D1%84%D1%80%D0%BE%D0%B2%D0%BE%D0%B5_%D0%BF%D1%80%D0%BE%D1%81%D1%82%D1%80%D0%B0%D0%BD%D1%81%D1%82%D0%B2%D0%BE_%D0%BB%D1%83%D1%87%D0%B5%D0%B2%D0%BE%D0%B9_%D0%B4%D0%B8%D0%B0%D0%B3%D0%BD%D0%BE%D1%81%D1%82%D0%B8%D0%BA%D0%B8_%28%D0%B3._%D0%9C%D0%BE%D1%81%D0%BA%D0%B2%D0%B0%29.pdf?1571848385. Accessed: 15.01.2023 (in Russian)].][Okamura K, Takayama K, Izumi M, et al. Diagnostic value of CEA and CYFRA 21-1 tumor markers in primary lung cancer. Lung Cancer. 2013;80(1):45-9. DOI:10.1016/j.lungcan.2013.01.002][Fielda JK, Vulkanb D, Daviesa MPA, et al. Lung cancer mortality reduction by LDCT screening: UKLS randomized trial results and international meta-analysis. Lancet Reg Health Eur. 2021;10:100179. DOI:10.1016/j.lanepe.2021.100184][Krilaviciute A, Brenner H. Low positive predictive value of computed tomography screening for lung cancer irrespective of commonly employed definitions of target population. Int J Cancer. 2021;149(1):58-65. DOI:10.1002/ijc.33522][Sun J, Chen X, Wang Y. Comparison of the diagnostic value of CEA combined with OPN or DKK1 in non-small cell lung cancer. Oncol Lett. 2020;20(3):3046-52. DOI:10.3892/ol.2020.11846][Jett JR, Peek LJ, Fredericks L, et al Audit of the autoantibody test, EarlyCDT®-Lung, in 1600 patients: An evaluation of its performance in routine clinical practice. Lung Cancer. 2014;83(1):51-5. DOI:10.1016/j.lungcan.2013.10.008][Dama E, Melocchi V, Mazzarelli F, et al. Non-Coding RNAs as Prognostic Biomarkers: A miRNA Signature Specific for Aggressive Early-Stage Lung Adenocarcinomas. Noncoding RNA. 2020;6(48):1-13. DOI:10.3390/ncrna6040048][Molina R, Augé JM, Bosch X, et al. Usefulness of serum tumor markers, including progastrin-releasing peptide, in patients with lung cancer: correlation with histology. Tumour Biol. 2009;30(3):121-9. DOI:10.1159/000224628][Molina R, Auge JM, Escudero JM, et al. Mucins CA 125, CA 19.9, CA 15.3 and TAG-72.3 as tumor markers in patients with lung cancer: comparison with CYFRA 21-1, CEA, SCC and NSE. Tumour Biol. 2008;29(6):371-80. DOI:10.1159/000181180][Gilchrist JM. Weighted 2 x 2 kappa coefficients: recommended indices of diagnostic accuracy for evidence-based practice. J Clin Epidemiol. 2009;62(10):1045-53. DOI:10.1016/j.jclinepi.2008.11.012]