Prognostic value of Bax expression in the primary colon tumor of patients with metastatic colorectal cancer receiving first-line treatment with a triple combination of irinotecan + oxaliplatin + long-term infusion of 5-fluorouracil

Objective: to evaluate the prognostic value of Bax expression in the primary colon tumor of patients with metastatic colorectal cancer (mCRC) receiving first-line treatment with a triple combination of irinotecan + oxaliplatin + long-term infusion of 5-fluorouracil.

Materials and methods. The study included patients with mCRC (morphologically (histologically) verified diagnosis of colonic adenocarcinoma) that have never received treatment for disseminated disease. Study participants received a new first-line treatment regimen with a triple combination of irinotecan + oxaliplatin + long-term infusion of 5-fluorouracil. We evaluated both short-term and long-term treatment outcomes. We also assessed the level of Bax expression in primary tumor samples (biopsy/surgery specimens) collected prior to initiation of first-line treatment using immunohistochemical methods. We analyzed the correlation between the levels of Bax expression and short-term/long-term treatment outcomes.

Results. Seventeen out of 20 mCRC patients included in the study were tested for Bax expression in the primary tumor using immunohistochemical staining. The analysis of correlation between Bax expression in tumor tissue and time-to-progression in patients with mCRC receiving first-line treatment with a triple combination of drugs demonstrated that high Bax expression was a favorable prognostic factor associated with longer time-to-progression. Median time-to-progression was significantly longer in patients with Bax overexpression than in those with low levels of Bax expression or no expression: 15.7 15,7 ± 3.38 months vs 8.6 15,7 ± 0.6 months, р = 0.012. When analyzing the impact of Bax expression on the overall survival (OS) in patients with mCRC, we found that patients with Bax overexpression demonstrated better OS (median follow-up time 17.3 15,7 ± 2.54; OS was not reached; mean value 31.26 15,7 ± 2.85 months) than patients with low Bax expression or no expression (median OS 13.60 15,7 ± 3.03 months), p = 0.021.

1. Baldus S.E. Clinical, pathological and molecular prognostic factors in colorectal carcinomas. Pathologe 2003;24(1):49-60. PMID: 12601478. DOI: 10.1007/s00292-002-0592-7.

2. Bianco A.R., Carlomagno C., de Lauren-tiis M. et al. Prognostic factors in human colorectal cancer. Tumori 1997;83(1 Suppl):S15-8.

3. McLeod H.L., Murray G.I. Tumour markers of prognosis in colorectal cancer. Br J Cancer 1999;79(2):191-203. PMID: 9888457. DOI: 10.1038/sj.bjc.6690033.

4. Piard F., Martin L., Chapusot C. et al. New histologic prognostic factors in colorectal cancer. Gastroenterol Clin Biol 2002;26(Suppl 5):B62-73. PMID: 12068272.

5. Yamada H., Kondo S., Okushiba S. et al. Analysis of predictive factors for recurrence after hepatectomy for colorectal liver metastases. World J Surg 2001;25(9):1129—33.

6. Oncology: educational guidance with a CD. Ed. by V.I. Chissov, S.L. Daryalova. Moscow: GEOTAR-Media, 2007. 560 p. (In Russ.).

7. Darenskaya A.D., Dobrova N.V., Khochenkov D.A., Stepanova E.V Prognostic value of E-cadherin expression in the primary colon tumor in patients with metastatic colorectal cancer who received first-line chemotherapy with irinotecan + oxaliplatin + long-term infusion of 5-fluorouracil. Farmateka = Pharmateca 2018;7(360):89—96. (In Russ.).

8. Darenskaya A.D., Dobrova N.V., Stepanova E.V. Impact of topoisomerase IIa overexpression in the primary colon tumor on the prognosis of metastatic colorectal cancer. Onkologicheskaya ko-loproktologiya = Colorectal oncology 2018;8(3);26—35. (In Russ.).

9. Darenskaya A.D., Dobrova N.V., Stepanova E.V. Topoisomerase IIa (TopoIIa) as a prognostic factor in patients with metastatic colorectal cancer receiving first-line treatment with oxaliplatin + capecitabine. Zlokachestvennye opukholi = Malignant Tumors 2018;8(3 Suppl 1):155. (In Russ.).

10. Darenskaya A.D., Dobrova N.V., Stepanova E.V Intercellular adhesion molecules (E-cad-herin, p-catenin) in colorectal cancer: characteristics; their role in tumor invasion, metastasis, and regulation of tumor progression; effect on prognosis (literature review). Farmateka = Pharmateca 2018;7(360):33—9. (In Russ.).

11. Adachi Y., Inomata M., Kakisako K. et al. Histopathologic characteristics of colorectal cancer with liver metastasis. Dis Colon Rectum 1999;42(8):1053-6. PMID: 10458130.

12. Adachi Y., Yasuda K., Kakisako K. et al. Histopathologic criteria for local excision of colorectal cancer: multivariate analysis. Ann Surg Oncol 1999;6(4):385-8.

13. Ahmed F.E., Vos P.W., Holbert D. Modeling survival in colon cancer: a methodological review. Mol Cancer 2007;6(1):15.

14. Bendardaf R., Lamlum H., Pyrhonen S. Prognostic and predictive molecular markers in colorectal carcinoma. Anticancer Res 2004;24(4):2519-30.

15. Compton C.C. Colorectal carcinoma: diagnostic, prognostic, and molecular features. Mod Pathol 2003;16(4):376—88.

16. Davies R.J., Miller R., Coleman N. Colorectal cancer screening: prospects for molecular stool analysis. Nat Rev Cancer 2005;5(3):199—209. PMID: 15738983. DOI: 10.1038/nrc1545.

17. Forte A., D’Urso A., Gallinaro L.S. et al. Prognostic markers of the epithelial tumors of the large intestine. Ann Ital Chir 2002;73(6):587-96. PMID: 12820582.

18. Houlston R.S. What we could do now: molecular pathology of colorectal cancer. Mol Pathol 2001;54(4):206—14. PMID: 11477132.

19. Zlobec I., Lugli A. Prognostic and predictive factors in colorectal cancer. J Clin Pathol 2008;61(5):561 —9. PMID: 18326017. DOI: 10.1136/jcp.2007.054858.

20. Delektorskaya V.V. Molecular biomarkers of colon cancer metastasis and prognosis. Summary of thesis ... of doctor of medical sciences. Moscow, 2007. 23 p. (In Russ.).

21. Knysh V.I. Colon and rectal cancer. Moscow: Meditsina, 1997. 301 p. (In Russ.).

22. Darenskaya A.D., Dobrova N.V. Triple combination of irino-tecan + oxaliplatin + 5-fluorouracil as first-line chemotherapy for metastatic colorectal cancer: first experience with a new treatment regimen. Onkologiches-kaya koloproktologiya = Colorectal oncology 2018;1:50-66. (In Russ.).

23. Darenskaya A.D., Dobrova N.V. New regimen of first-line chemotherapy for metastatic colorectal cancer. Farmateka = Pharmate-ca 2014;8:57-61. (In Russ.).

24. Darenskaya A., Dobrova N.V., Lichinitser M.R. Oxaliplatin, irinotecan, and fluoro-uracil in the prolonged regimen for the first-line therapy of metastatic colorectal cancer: New therapy regimen. J Clin Oncol 2015;33(Suppl):e14617.

25. Darenskaya A.D. First-line chemotherapy for metastatic colorectal cancer. New treatment regimen. Prognostic value of molecular biomarkers. Summary of thesis ... of candidate of medical sciences. Moscow, 2017. 34 p. (In Russ.).

26. Darenskaya A.D., Dobrova N.V., Zhukova L.G. et al. Successful treatment of metastatic colorectal cancer with achieving complete pathological response (first-line chemotherapy): a case report. Farmateka = Pharmateca 2016;8:93-9. (In Russ.).

27. Stepanova E.V. Clinical and experimental aspects of investigating molecular biomarkers in malignant neoplasms. Summary of thesis ... of doctor of medical sciences. Moscow, 2008. 24 p. (In Russ.).

28. Therasse P., Arbuck S.G., Eisenhauer E.A. et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92(3):205-16. PMID: 10655437.

29. Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, 2007.