Significance of the cytokeratin-19 fragment and CXCR1, CXCR2 receptors in the blood for prediction of the relapse-free survival of patients with stage III non-small cell lung cancer
https://doi.org/10.29235/1814-6023-2023-20-2-112-125
Abstract
Stage III non-small cell lung cancer (NSCLC) is a heterogeneous group of tumors. The prognosis for patients with stage III NSCLC remains poor, and the 5-year survival rate is not more than 20 %. Therefore, an actual problem is to develop prognostic indicators that would allow predicting the progression of the tumor process in patients in order to correctly build strategy and tactics for their treatment.
The objective of the study was to clarify and substantiate the possibility of using laboratory parameters characterizing the level of blood proteins – participants in carcinogenesis in predicting the NSCLC progression in patients with stage III disease.
In 1187 patients who were first diagnosed with stage III NSCLC, the duration of the relapse-free period after treatment was analyzed using the observation results for one year. The mean age of patients was 63 ± 23 years. In 89 patients (58 ± 23.5 years), the concentration of CYFRA 21-1, SCC, TPA were determined by electrochemiluminescent method; pyruvate kinase M2, CXCL5, CXCL8 chemokines – by enzyme immunoassay; CXCR1 and CXCR2 receptors– by flow cytometry.
A proportional hazards model was used to identify potentially informative indicators for predicting the duration of the relapse-free period in patients with stage III NSCLC: the levels of lymphocytes containing CXCR1 and CYFRA 21-1. Based on the one-year observation results and the graphical analysis of Kaplan-Meier, groups of low (T1N2M0, T3N1M0, T2N2M0, T4N0M0, T3N2M0) and high (T1N3M0, T2N3M0, T3N3M0, T4N1M0, T4N2M0, T4N3M0) risk of tumor progression were identified. High-risk patients had a higher level of CYFRA 21-1, a relative content of the receptor CXCR1 in lymphocytes, and a relative content of the receptor CXCR2 in monocytes compared to low-risk patients (p < 0.05). With their participation, based on the results of logistic regression analysis, an equation was constructed, the calculation of which makes it possible to predict the risk of tumor recurrence. The threshold value of the equation is 0.519. The sensitivity of the prediction model was 80.9 %, the specificity was 83.3 %, and the prediction value of a positive result was 84.4 % and that of a negative result – 79.6 %. The study results give grounds to recommend a set of laboratory parameters in the blood of stage III NSCLC patients, including the CYFRA 21-1 level and the receptors CXCR1 and CXCR2, in order to assess their tumor progression risk.>< 0.05). With their participation, based on the results of logistic regression analysis, an equation was constructed, the calculation of which makes it possible to predict the risk of tumor recurrence. The threshold value of the equation is 0.519. The sensitivity of the prediction model was 80.9 %, the specificity was 83.3 %, and the prediction value of a positive result was 84.4 % and that of a negative result – 79.6 %.
The study results give grounds to recommend a set of laboratory parameters in the blood of stage III NSCLC patients, including the CYFRA 21-1 level and the receptors CXCR1 and CXCR2, in order to assess their tumor progression risk.
About the Authors
A. D. TahanovichBelarus
Anatoli D. Tahanovich – D. Sc. (Med.), Professor, Head of the Department
83, Dzerzhinski Ave., 220116, Minsk
N. N Kauhanka
Belarus
Nikolai N. Kauhanka – Ph. D. (Chem.), Associate Professor
83, Dzerzhinski Ave., 220116, Minsk
V. I. Prokhorova
Belarus
Violetta I. Prokhorova – D. Sc. (Med.), Professor, Head of the Laboratory
223040, Lesnoy, Minsk region
A. V. Kolb
Belarus
Alexander V. Kolb – Ph. D. (Biol.), Associate Professor
83, Dzerzhinski Ave., 220116, Minsk
O. V. Got’ko
Belarus
Oksana V. Got’ko – Senior Researcher
223040, Lesnoy, Minsk region
References
1. Siegel R. L., Miller K. D., Jemal A. Cancer statistics, 2019. CA: a Cancer Journal for Clinicians, 2019, vol. 69, no. 1, pp. 7–34. https://doi.org/10.3322/caac.21551
2. Blackstock A. W., Govindan R. Definitive chemoradiation for the treatment of locally advanced non small-cell lung cancer. Journal of Clinical Oncology, 2007, vol. 25, no. 26, pp. 4146–4152. https://doi.org/10.1200/JCO.2007.12.6581
3. Govindan R., Bogart J., Vokes E. E. Locally advanced non-small cell lung cancer: the past, present, and future. Journal of Thoracic Oncology, 2008, vol. 3, no. 8, pp. 917–928. https://doi.org/10.1097/JTO.0b013e318180270b
4. Anufreenok I. V., Dubrovskii A. Ch., Evmenenko A. A., Ermakov N. B., Zhavrid E. A., Zharkov V. V. [et al.]. Algorithms for the diagnosis and treatment of malignant neoplasms: clinical protocol. Minsk, Professional’nye izdaniya Publ., 2019. 613 p. (in Russian).
5. Evison M. The current treatment landscape in the UK for stage III NSCLC. British Journal of Cancer, 2020, vol. 123, suppl. 1, pp. 3–9. https://doi.org/10.1038/s41416-020-01069-z
6. Tokito T., Azuma K., Yamada K., Naito Y., Matsuo N., Ishii H., Natori H., Kinoshita T., Hoshino T. Prognostic value of serum tumor markers in patients with stage III NSCLC treated with chemoradiotherapy. In Vivo, 2019, vol. 33, no. 3, pp. 889–895. https://doi.org/10.21873/invivo.11555
7. Ohri N., Duan F., Machtay M., Gorelick J. J., Snyder B. S., Alavi A., Siegel B. A., Johnson D. W., Bradley J. D., DeNittis A., Werner-Wasik M. Pretreatment FDG-PET metrics in stage III non-small cell lung cancer: ACRIN 6668/RTOG 0235. Journal of the National Cancer Institute, 2015, vol. 107, no. 4, art. djv004. https://doi.org/10.1093/jnci/djv004
8. Edelman M. J., Hodgson L., Rosenblatt P. Y., Christenson R. H., Vokes E. E., Wang X., Kratzke R. CYFRA 21-1 as a prognostic and predictive marker in advanced non-small-cell lung cancer in a prospective trial: CALGB 150304. Journal of Thoracic Oncology, 2012, vol. 7, no. 4, pp. 649–654. https://doi.org/10.1097/JTO.0b013e31824a8db0
9. McAleer M. F., Moughan J., Byhardt R. W., Cox J. D., Sause W. T., Komaki R. Does response to induction chemotherapy predict survival for locally advanced non-small-cell lung cancer? Secondary analysis of RTOG 8804/8808. International Journal of Radiation Oncology Biology Physics, 2010, vol. 76, no. 3, pp. 802–808. https://doi.org/10.1016/j.ijrobp.2009.02.053
10. Kozak M. M., Murphy J. D., Schipper M. L., Donington J. S., Zhou L., Whyte R. I. [et al.]. Tumor volume as a potential imaging-based risk-stratification factor in trimodality therapy for locally advanced non-small cell lung cancer. Journal of Thoracic Oncology, 2011, vol. 6, no. 5, pp. 920–926. https://doi.org/10.1097/jto.0b013e31821517db
11. Laird B. J., McMillan D. C., Fayers P., Fearon K., Kaasa S., Fallon M. T., Klepstad P. The systemic inflammatory response and its relationship to pain and other symptoms in advanced cancer. Oncologist, 2013, vol. 18, no. 9, pp. 1050–1055. https://doi.org/10.1634/theoncologist.2013-0120
12. Ha H., Debnath B., Neamati N. Role of the CXCL8-CXCR1/2 axis in cancer and inflammatory diseases. Theranostics, 2017, vol. 7, no. 6, pp. 1543–1588. https://doi.org/10.7150/thno.15625
13. Wu K., Yu S., Liu Q., Bai X., Zheng X., Wu K. The clinical significance of CXCL5 in non-small cell lung cancer. OncoTargets and Therapy, 2017, vol. 10, pp. 5561–5573. https://doi.org/10.2147/OTT.S148772
14. Taganovich A. D., Kovganko N. N., Prokhorova V. I., Murashko D. I., Got’ko O. V. Predicting the risk of tumor progression in patients with early stages of adenocarcinoma and squamous cell lung cancer based on laboratory parameters. Biomeditsinskaya khimiya [Biomedical chemistry], 2021, vol. 67, no. 6, pp. 507–517 (in Russian).
15. Kamyshnikov V. S. Differentiation of states “norm – pathology”. Methodology for establishing reference values, diagnostic and predictive information content of laboratory test indicators: assessment principles. Laboratornaya diagnostika. Vostochnaya Evropa = Laboratory diagnostics. Eastern Europe, 2018, vol. 7, no. 1, pp. 9–25 (in Russian).
16. Uramoto H., Tanaka F. Prediction of recurrence after complete resection in patients with NSCLC. Anticancer Research, 2012, vol. 32, no. 9, pp. 3953–3960.
17. Yasukawa M., Sawabata N., Kawaguchi T., Kawai N., Nakai T., Ohbayashi C., Taniguchi S. Histological grade: analysis of prognosis of non-small cell lung cancer after complete resection. In Vivo, 2018, vol. 32, no. 6, pp. 1505–1512. https://doi.org/10.21873/invivo.11407
18. Ettinger D. S., Wood D. E., Akerley W., Bazhenova L. A., Borghaei H., Camidge D. R. [et al.]. NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 4.2016. Journal of the National Comprehensive Cancer Network, 2016, vol. 14, no. 3, pp. 255–264. https://doi.org/10.6004/jnccn.2016.0031
19. Holdenrieder S., Wehnl B., Hettwer K., Simon K., Uhlig S., Dayyani F. Carcinoembryonic antigen and cytokeratin-19 fragments for assessment of therapy response in non-small cell lung cancer: a systematic review and meta-analysis. British Journal of Cancer, 2017, vol. 116, no. 8, pp. 1037–1045. https://doi.org/10.1038/bjc.2017.45
20. Ganti A. K., Mulshine J. L. Lung cancer screening. Oncologist, 2006, vol. 11, no. 5, pp. 481–487. https://doi. org/10.1634/theoncologist.11-5-481
21. Zhi X. Y., Yu J.-M., Shi Y.-K. Chinese guidelines on the diagnosis and treatment of primary lung cancer (2015 version). Cancer, 2015, vol. 121, suppl. 17, pp. 3165–3181. https://doi.org/10.1002/cncr.29550. Erratum in: Cancer, 2016, vol. 122, no. 1, p. 162.
22. Molina R., Marrades R. M., Augé J. M., Escudero J. M., Viñolas N., Reguart N., Ramirez J., Filella X., Molins L., Agustí A. Assessment of a combined panel of six serum tumor markers for lung cancer. American Journal of Respiratory and Critical Care Medicine, 2016, vol. 193, no. 4, pp. 427–437. https://doi.org/10.1164/rccm.201404-0603oc
23. Sone K., Oguri T., Ito K., Kitamura Y., Inoue Y., Takeuchi A. [et al.]. Predictive role of cyfra21-1 and cea for subsequent docetaxel in non-small cell lung cancer patients. Anticancer Research, 2017, vol. 37, no. 9, pp. 5125–5131. https://doi. org/10.21873/anticanres.11932
24. Pollán M., Varela G., Torres A., de la Torre M., Ludeña M. D., Ortega M. D. [et al.]. Clinical value of p53, c-erbB-2, CEA and CA125 regarding relapse, metastasis and death in resectable non-small cell lung cancer. International Journal of Cancer, 2003, vol. 107, no. 5, pp. 781–790. https://doi.org/10.1002/ijc.11472
25. Isaksson S., Jönsson P., Monsef N., Brunnström H., Bendahl P.-O., Jönsson M., Staaf J., Planck M. CA 19-9 and CA 125 as potential predictors of disease recurrence in resectable lung adenocarcinoma. PLoS ONE, 2017, vol. 12, no. 10, p. e0186284. https://doi.org/10.1371/journal.pone.0186284
26. Clevers M. R., Kastelijn E. A., Peters B. J. M., Kelder H., Schramel F. M. N. H. Evaluation of serum biomarker CEA and Ca-125 as immunotherapy response predictors in metastatic non-small cell lung cancer. Anticancer Research, 2021, vol. 41, no. 2, pp. 869–876. https://doi.org/10.21873/anticanres.14839
Review
For citations:
Tahanovich A.D., Kauhanka N.N., Prokhorova V.I., Kolb A.V., Got’ko O.V. Significance of the cytokeratin-19 fragment and CXCR1, CXCR2 receptors in the blood for prediction of the relapse-free survival of patients with stage III non-small cell lung cancer. Proceedings of the National Academy of Sciences of Belarus, Medical series. 2023;20(2):112-125. (In Russ.) https://doi.org/10.29235/1814-6023-2023-20-2-112-125