The Quantitative Indices of ERCC1 Expression in Serous Ovarian Cancer Tissue and the Efficacy of First-Line Platinum-Based Chemotherapy

Platinum-based drugs are widely used in clinical practice. Their efficacy varies widely among patients, which may be due to a disruption of the expression of ERCC1 - excision repair protein. In the prospective study a strictly quantitative analysis of the ERCC1 protein expression was carried out in surgical biopsy specimens of serous ovarian cancer by flow cytometry. ERCC1 expression was revealed in 100% of cases, but the expression level of the marker (the percentage of cells expressing ERCC1) varied significantly between tumors: the minimum was 40%, the maximum - 77%, the median - 64.5%; the average - 64.3+9.0%. The analysis of the Kaplan-Mayer curves showed an inverse relationship between the expression of ERCC1 and the duration of the relapse-free period during a 40-month follow-up after the first-line platinum-taxane chemotherapy (p<0.0008). The median relapse-free period was not achieved in the group of patients with the low ERCC1 expression level (<64.5%), whereas it was 9 months in the group of high ERCC1 expression level (>64.5%). The number of relapses in the groups with high and low levels of ERCC1 was different, 26% and 79% cases, respectively. Similar correlations were revealed by comparison of the average intensity of ERCC1 expression with relapse-free survival. Thus, quantitative assessment of ERCC1 expression indices may predict the efficiency of first-line platinum-based chemotherapy of ovarian cancer.

ERCC1, serous ovarian cancer, ERCC1, platinum-based chemotherapy, flow cytometry

1. Steffensen K D., Waldstrom M., Jakobsen A. The relationship of platinum resistance and ERCC1 protein expression in epithelial ovarian cancer. Int J Gynecol Cancer 2009; 19: 5: 820-825.

2. Lee S. M., Falzon M., Blackhall F. et al. Randomized prospective bio-marker trial of ercc1 for comparing platinum and nonplatinum therapy in advanced non-small-cell lung cancer: ERCC1 trial (ET). J Clin Oncol 2017; 35: 4: 402-411.

3. Kang C. H., Jang B. G., Kim D. W. et al. The prognostic significance of ERCC1, BRCA1, XRCC1, and betaIII-tubulin expression in patients with non-small cell lung cancer treated by platinum- and taxane-based neoadjuvant chemotherapy and surgical resection. Lung Cancer 2010; 68: 3: 478-483.

4. Богуш Т. А., Попова A. C., Дудко E. А. и др. ERCC1 как маркер резистентности рака яичников к препаратам платины. Антибиотики и химиотер 2015; 60: 3-4: 42-50

5. Богуш T. A., Шатурова A. C., Дудко E. A. и др. Количественная иммунофлуоресцентная оценка с использованием проточной цитофлуориметрии экспрессии эстрогеновых рецепторов - в солидных опухолях человека. Вестн Моск ун-та Сер 2, Химия 2011; 52: 4: 305-312

6. Deloia J. A., Bhagwat N. R., Darcy K. M. et al. Comparison of ERCC1/XPF genetic variation, mRNA and protein levels in women with advanced stage ovarian cancer treated with intraperitoneal platinum. Gynecol Oncol 2012; 126: 3: 448-454.

7. Syrios J., Banerjee S., Kaye S. B. Advanced epithelial ovarian cancer: from standard chemotherapy to promising molecular pathway targets - where are we now? Anticancer Res 2014; 34: 5: 2069-2077.

8. Lee K. B, Parker R. J., Bohr V. et al. Cisplatin sensitivity/resistance in UV repair-deficient Chinese hamster ovary cells of complementation groups 1 and 3. Carcinogenesis 1993; 14: 10: 2177-2180.

9. Bösmüller H., Haitchi-Petnehazy S., Webersinke G. et al. Intratumoral lymphocyte density in serous ovarian carcinoma is superior to ERCC1 expression for predicting response to platinum-based therapy. Virchows Arch 2011; 459: 2: 183-191.

10. Xie C, Yin R. T, Li Y. L. et al. The protein expression of ERCC1 and survivin in epithelial ovarian carcinoma and their clinical significance. Sichuan Da Xue Xue Bao Yi Xue Ban 2011; 42: 1: 86-89.

11. Cepeda V., Fuertes M. A., Castilla J. et al. Biochemical mechanisms of cisplatin cytotoxicity. Anticancer Agents Med Chem 2007; 7: 1: 3-18.

12. Colombo P. E., Fabbro M., Theillet C. et al. Sensitivity and resistance to treatment in the primary management of epithelial ovarian cancer. Crit Rev Oncol Hematol 2014; 89: 2: 207-216.

13. Богуш Т. А., Попова A. C., Дудко E. А. и др. Дискордантность статуса эстрогеновых рецепторов между первичным и метастатическим раком молочной железы - возможные причины и прогностическая значимость. Антибиотики и химиотер 2013; 58: 7-8: 11-18.

14. Tolles J., Bai Y., Baquero M. et al. Optimal tumor sampling for immunostaining of biomarkers in breast carcinoma. Breast Cancer Res 2011; 13: 3: R51.

15. Богуш Т. A., Дудко E. A., Родионова М. В. и др. Анализ информативности методов иммуногистохимии и проточной цитофлуориметрии при оценке экспрессии эстрогеновых рецепторов альфа. ДАН 2015; 465: 2: 235-40.

16. Moxley K. M., Benbrook D. M., Queimado L. et al. The role of single nucleotide polymorphisms of the ERCC1 and MMS19 genes in predicting platinum-sensitivity, progression-free and overall survival in advanced epithelial ovarian cancer. Gynecol Oncol 2013; 130: 2: 377-382.

17. Marsh S., Paul J., King C. R., Gifford G et al. Pharmacogenetic assessment of toxicity and outcome after platinum plus taxane chemotherapy in ovarian cancer: the Scottish randomised trial in ovarian cancer. J Clin Oncol 2007; 25: 29: 4528-4535.

18. Tang X., Hu G., Xu C. et al. HZ08 reverse the aneuploidy-induced cisplatin-resistance in Gastric cancer by modulating the p53 pathway. Eur J Pharmacol 2013; 720: 1-3: 84-97.

19. Danielsen H. E., Pradhan M., Novelli M. Revisiting tumour aneuploidy - the place of ploidy assessment in the molecular era. Nat Rev Clin Oncol 2016; 13: 5: 291-304.

20. Klatte T., Seitz C., Rink M. et al. ERCC1 as a Prognostic and Predictive Biomarker for Urothelial Carcinoma of the Bladder following Radical Cystectomy. J Urol 2015; 194: 5: 1456-1462.

21. Wang J., Zhou X. Q., Li J. Y. et al. Prognostic significance of ERCC1 expression in postoperative patients with gastric cancer. Chin J Cancer Res 2014; 26: 3: 323-330.