Overall survival in colon cancer patients with different levels of circulating tumor cells and feasibility of enhancing its prognostic value
https://doi.org/10.21294/1814-4861-2022-21-4-32-39
Abstract
Development of personalized approaches to diagnosis, treatment and prognosis of colon cancer (CC) still remains challenging. Levels of circulating tumor (CTC) and cancer stem cells (CSC) are promising non-invasive prognostic factors. Our aim was to assess the overall survival (OS) of patients with stage II–IV CC with different levels of CTCs as well as to enhance their prognostic value by additionally determining the level of CD44+ CSCs. Material and methods. The study included 299 patients with stage II–IV CC. All patients underwent surgery followed by adjuvant chemotherapy (FOLFOX). patients with stage IV CC with resectable liver metastases underwent simultaneous resection of the primary tumor and liver metastases, followed by FOLFOX chemotherapy. the proportion of CTCs was evaluated before surgery using Veridex CellSearch™, and the level of CD44+ CSCs was determined in the tissue of the removed tumor by the IHC method. OS was studied in patients with different CTC levels, cumulative OS was calculated by Kaplan–Meier`s method. prognostic algorithm was designed by logistic regression analysis and cox proportional hazards model. Results. OS was found to be lower in patients with higher CTC levels divided into ranges: 0, 1–3, 4–9, ≥10 (χ2=11.59, p=0.009); thus enabling us to use it for prognosis. its prognostic value is enhanced by estimation of CD44+ CSC in tumor. Statistically significant conjugation between CTC and CD44+ ranges was found. an increase in CTC level by 1 range resulted in the increase in the risk of fatal outcome by 1.58 times (р=0.002); the additive increase in CD44+ expression ≥10 % resulted in the increase in the risk of fatal outcome by 7.2 times (p<0.001). For individual risk assessment, a model for calculating the prognostic coefficient K with high diagnostic sensitivity and specificity was developed, and its mathematical expression was proposed. the value of K≥0.411 indicates a high risk of adverse outcome. Conclusion. The prognostic algorithm for the risk of unfavorable outcome of patients with CC, based on the assessment of CTC and CD44+ CSC levels, was developed.
Keywords
About the Authors
O. I. KitRussian Federation
Oleg I. Kit - MD, Professor, Member of the Russian Academy of Sciences, General Director, National Medical Research Centre for Oncology of the Ministry of Health of Russia.
63, 14 Line St., 344037, Rostov-on-Don.
Researcher ID (WOS): U-2241-2017. Author ID (Scopus): 55994103100.
E. Y. Zlatnik
Russian Federation
Elena Yu. Zlatnik - MD, Professor, Chief Researcher, Laboratory for Immunophenotyping of Tumors, National Medical Research Centre for Oncology of the Ministry of Health of Russia.
63, 14 Line St., 344037, Rostov-on-Don.
Author ID (Scopus): 6603160432.
I. A. Novikova
Russian Federation
Inna A. Novikova - MD, PhD, Deputy General Director for Science, National Medical Research Centre for Oncology of the Ministry of Health of Russia.
63, 14 Line St., 344037, Rostov-on-Don.
Researcher ID (WOS): E-7710-2018. Author ID (Scopus): 7005153343.
E. P. Ulianova
Russian Federation
Elena P. Ulyanova - Researcher, Laboratory of Immunophenotyping of Tumors, National Medical Research Centre for Oncology of the Ministry of Health of Russia.
63, 14 Line St., 344037, Rostov-on-Don.
Author ID (Scopus): 57203357998.
A. A. Demidova
Russian Federation
Aleksandra A. Demidova - MD, PhD, National Medical Research Centre for Oncology of the Ministry of Health of Russia; Associate Professor, Head of the Department of Medical and Biological Physics, Rostov State Medical University of the Ministry of Health of Russia.
63, 14 Line St., 344037, Rostov-on-Don; 29, Nakhichevan Ln., 344022, Rostov-on-Don.
Researcher ID (WOS): O-9155-2016. Author ID (Scopus): 7006838349.
E. N. Kolesnikov
Russian Federation
Evgeny N. Kolesnikov - MD, DSc, Head of the Department of Abdominal Oncology № 1 with a group of X-ray endovascular methods of diagnosis and treatment, National Medical Research Centre for Oncology of the Ministry of Health of Russia.
63, 14 Line St., 344037, Rostov-on-Don.
Yu. A. Gevorkyan
Russian Federation
Yuri A. Gevorkyan - MD, Professor, Head of the Department of Abdominal Oncology № 2, National Medical Research Centre for Oncology of the Ministry of Health of Russia.
63, 14 Line St., 344037, Rostov-on-Don.
N. V. Soldatkina
Russian Federation
Natalya V. Soldatkina - MD, DSc, Oncologist, Department of Abdominal Oncology № 2, National Medical Research Centre for Oncology of the Ministry of Health of Russia.
63, 14 Line St., 344037, Rostov-on-Don.
A. V. Snezhko
Russian Federation
Alexander V. Snezhko - MD, DSc, Surgeon of the Department of Abdominal Oncology № 1 with a group of X-ray endovascular methods of diagnosis and treatment, National Medical Research Centre for Oncology of the Ministry of Health of Russia.
63, 14 Line St., 344037, Rostov-on-Don.
References
1. McGranahan N., Swanton C. Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. Cell. 2017; 168(4): 613–28. doi: 10.1016/j.cell.2017.01.018.
2. De Smedt L., Palmans S., Sagaert X. Tumour budding in colorectal cancer: what do we know and what can we do? Virchows Arch. 2016; 468(4): 397–408. doi: 10.1007/s00428-015-1886-5.
3. Sinyansky L.E., Vtorushin S.V., Patalyak S.V., Afanasyev S.G. Prognostic role of molecular subtypes of colon cancer. A current view on the problem. Siberian Journal of Oncology. 2021; 20(3): 107–114. (in Russian). doi: 10.21294/1814-4861-2021-20-3-107-114.
4. Sagakyanc A.B. United immunological forum: current trends in the development of fundamental and applied oncoimmunology (Novosibirsk, 2019). South Russian Journal of Cancer. 2020; 1(2): 36–45. (in Russian). doi:10.37748/2687-0533-2020-1-2-5.
5. Tan Y., Wu H. The significant prognostic value of circulating tumor cells in colorectal cancer: A systematic review and meta-analysis. Curr Probl Cancer. 2018; 42(1): 95–106. doi: 10.1016/j.currproblcancer.2017.11.002.
6. Nepomnyashchaya E.M., Kit O.I., Nistratova O.V., Novikova I.A., Nikipelova E.A., Bahtin A.V., Ul’yanova E.P., Vostrikova Zh.I., Selyutina O.N. Circulating tumor cells and some morpho-immunohistochemical parameters in colorectal cancer. Modern Problems of Science and Education. 2016; 2: 140. (in Russian).
7. Veyrune L., Naumann D.N., Christou N. Circulating Tumour Cells as Prognostic Biomarkers in Colorectal Cancer: A Systematic Review. Int J Mol Sci. 2021; 22(8): 3437. doi: 10.3390/ijms22083437.
8. Nanduri L.K., Hissa B., Weitz J., Schölch S., Bork U. The prognostic role of circulating tumor cells in colorectal cancer. Expert Rev Anticancer Ther. 2019; 19(12): 1077–88. doi: 10.1080/14737140.2019.1699065.
9. Hinz S., Hendricks A., Wittig A., Schafmayer C., Tepel J., Kalthoff H., Becker T., Röder C. Detection of circulating tumor cells with CK20 RT-PCR is an independent negative prognostic marker in colon cancer patients – a prospective study. BMC Cancer. 2017; 17(1): 53. doi: 10.1186/s12885-016-3035-1.
10. Tsai W.S., Chen J.S., Shao H.J., Wu J.C., Lai J.M., Lu S.H., Hung T.F., Chiu Y.C., You J.F., Hsieh P.S., Yeh C.Y., Hung H.Y., Chiang S.F., Lin G.P., Tang R., Chang Y.C. Circulating Tumor Cell Count Correlates with Colorectal Neoplasm Progression and Is a Prognostic Marker for Distant Metastasis in Non-Metastatic Patients. Sci Rep. 2016; 6: 24517. doi: 10.1038/srep24517.
11. Kit O.I., Gevorkyan YU.A., Soldatkina N.V., Novikova I.A., Vodolazhskij D.I., Shulikov P.B. Method for predicting metastasis in colon cancer. The patent of the Russian Federation № 2613142. 15.03.2017. (in Russian).
12. Rothé F., Maetens M., Rouas G., Paesmans M., Van den Eynde M., Van Laethem J.L., Vergauwe P., Deboever G., Bareche Y., Vandeputte C., Ignatiadis M., Hendlisz A. CTCs as a prognostic and predictive biomarker for stage II/III Colon Cancer: a companion study to the PePiTA trial. BMC Cancer. 2019; 19(1): 304. doi: 10.1186/s12885-019-5528-1.
13. Abdalla T.S.A., Meiners J., Riethdorf S., König A., Melling N., Gorges T., Karstens K.F., Izbicki J.R., Pantel K., Reeh M. Prognostic value of preoperative circulating tumor cells counts in patients with UICC stage I-IV colorectal cancer. PLoS One. 2021; 16(6). doi: 10.1371/journal.pone.0252897.
14. Yang C., Shi D., Wang S., Wei C., Zhang C., Xiong B. Prognostic value of pre- and post-operative circulating tumor cells detection in colorectal cancer patients treated with curative resection: a prospective cohort study based on ISET device. Cancer Manag Res. 2018; 10: 4135–44. doi: 10.2147/CMAR.S176575.
15. Pan R.J., Hong H.J., Sun J., Yu C.R., Liu H.S., Li P.Y., Zheng M.H. Detection and Clinical Value of Circulating Tumor Cells as an Assisted Prognostic Marker in Colorectal Cancer Patients. Cancer Manag Res. 2021; 13: 4567–78. doi: 10.2147/CMAR.S300554.
16. Baek D.H., Kim G.H., Song G.A., Han I.S., Park E.Y., Kim H.S., Jo H.J., Ko S.H., Park D.Y., Cho Y.K. Clinical Potential of Circulating Tumor Cells in Colorectal Cancer: A Prospective Study. Clin Transl Gastroenterol. 2019; 10(7): e00055. doi: 10.14309/ctg.0000000000000055.
17. Grillet F., Bayet E., Villeronce O., Zappia L., Lagerqvist E.L., Lunke S., Charafe-Jauffret E., Pham K., Molck C., Rolland N., Bourgaux J.F., Prudhomme M., Philippe C., Bravo S., Boyer J.C., Canterel-Thouennon L., Taylor G.R., Hsu A., Pascussi J.M., Hollande F., Pannequin J. Circulating tumour cells from patients with colorectal cancer have cancer stem cell hallmarks in ex vivo culture. Gut. 2017; 66(10): 1802–10. doi: 10.1136/gutjnl-2016-311447.
18. Agnoletto C., Corrà F., Minotti L., Baldassari F., Crudele F., Cook W.J.J., Di Leva G., d’Adamo A.P., Gasparini P., Volinia S. Heterogeneity in Circulating Tumor Cells: The Relevance of the Stem-Cell Subset. Cancers (Basel). 2019; 11(4): 483. doi: 10.3390/cancers11040483.
19. Katoh S., Goi T., Naruse T., Ueda Y., Kurebayashi H., Nakazawa T., Kimura Y., Hirono Y., Yamaguchi A. Cancer stem cell marker in circulating tumor cells: expression of CD44 variant exon 9 is strongly correlated to treatment refractoriness, recurrence and prognosis of human colorectal cancer. Anticancer Res. 2015; 35(1): 239–44.
20. Hensler M., Vančurová I., Becht E., Palata O., Strnad P., Tesařová P., Čabiňaková M., Švec D., Kubista M., Bartůňková J., Špíšek R., Sojka L. Gene expression profiling of circulating tumor cells and peripheral blood mononuclear cells from breast cancer patients. Oncoimmunology. 2015; 5(4): e1102827. doi: 10.1080/2162402X.2015.1102827.
Review
For citations:
Kit O.I., Zlatnik E.Y., Novikova I.A., Ulianova E.P., Demidova A.A., Kolesnikov E.N., Gevorkyan Yu.A., Soldatkina N.V., Snezhko A.V. Overall survival in colon cancer patients with different levels of circulating tumor cells and feasibility of enhancing its prognostic value. Siberian journal of oncology. 2022;21(4):32-39. (In Russ.) https://doi.org/10.21294/1814-4861-2022-21-4-32-39