MOLECULAR-GENETIC CHARACTERISTICS OF PRIMARY TUMOR AND METASTATIC LYMPHATIC NODES IN BREAST CANCER

The purpose of systemic treatment in patients with breast cancer is based largely on the molecular characteristics of the primary tumor, but many clinical recommendations suggest also the study of metastatic nodes with an assessment of their receptor status (estrogen receptor ER, progesterone receptor RP, human epidermal growth factor receptor 2 Her2/neu). This is due to the fact that according to numerous studies, the discrepancy between the status of the primary tumor and the secondary nodes can reach high rates: 3–54 % for ER, 5–78 % for RP, and 0–34 % for Her2/neu. At the same time, more and more data actively demonstrate the imperfection of immunohistochemical analysis and the need to study additional parameters to improve the quality of diagnosis of patients with breast cancer. Material and methods. A morphological and immunohistochemical study of the tumor tissue of the primary node and axillary lymph nodes was performed in 199 patients with breast cancer (T1-3N0-3M0) using standard methods, and RT-PCR was also studied with the expression of 24 genes. Results. The incidence of differences between the molecular phenotypes of the main tumor and metastatic axillary lymph nodes was 26 (26 %) of 99 cases. Most often, differences were noted in cases of breast cancer with luminal A type – 13 cases (50 %). According to the results of a comparative PCR analysis of tissue samples from the primary tumor and metastatic regional lymph nodes, only the expression of the CD68, ERSR1, GRB7 and MMD11 receptors was statistically significant. Conclusion. The results indicate the need for an integrated approach and additional methods for the diagnosis of breast cancer, which will undoubtedly improve the quality of planning and the effectiveness of systemic treatment in patients with breast cancer.

1. Dergunova Yu.A., Kometova V.V., Bozhenko V.K., Vardanyan S.G., Kulinich T.M., Rodionov V.V., Kudinova E.A. Comparison of immunohistochemical and PCRmethod for determination of Ki-67 expression level in breast cancer tissue. Vestnik Rossiyskogo nauchnogo tsentra rentgenoradiologii Ministerstva zdravookhraneniya Rossiyskoy Federatsii = Bulletin of the Russian Scientific Center of Roentgenology. 2018; 18 (3): 52–6. [In Russian].

2. Bozhenko V.K., Kharchenko N.V., Zapirov G.M., Kudinova Ye.A., Trotsenko I.D., Solodkiy V.A. Analysis of the expression of proliferation and apoptosis genes depending on the status of steroid hormone receptors in breast cancer. Vestnik Rossiyskogo nauchnogo tsentra rentgenoradiologii Ministerstva zdravookhraneniya Rossiyskoy Federatsii = Bulletin of the Russian Scientific Center of Roentgenology. 2012; 12 (4): 24. [In Russian].

3. Bragina O.D., Slonimskaya E.M., Zavyalova M.V., Telegina N.S., Perelmuter V.M., Tarabanovskaya N.A., Doroshenko A.V. The predictive value of a number of molecular parameters in patients with basal-like triplenegative breast cancer. Sibirskiy onkologicheskiy zhurnal = Siberian Journal of Oncology. 2014; (3): 5–10. [In Russian].

4. Dergunova Yu.A., Kometova V.V., Bozhenko V.K., Vardanyan S.G., Kulinich T.M., Rodionov V.V., Kudinova E.A. Comparison of immunohistochemical and PCRmethod for determination of Ki-67 expression level in breast cancer tissue. Vestnik Rossiyskogo nauchnogo tsentra rentgenoradiologii Ministerstva zdravookhraneniya Rossiyskoy Federatsii = Bulletin of the Russian Scientific Center of Roentgenology. 2018; 18 (3): 52–6. [In Russian].

5. Stenina M.B., Frolova M.A., Kupchan D.Z., Tyulyandin S.A. Changes in neo- and adjuvant treatment of breast cancer in last 5 years. Prakticheskaya onkologiya = Practical Oncology. 2017; 18 (3): 256–264. [In Russian]. doi: 10.31917/1803256.

6. Bragina O.D., Slonimskaya E.M., Zavyalova M.V., Telegina N.S., Perelmuter V.M., Tarabanovskaya N.A., Doroshenko A.V. The predictive value of a number of molecular parameters in patients with basal-like triplenegative breast cancer. Sibirskiy onkologicheskiy zhurnal = Siberian Journal of Oncology. 2014; (3): 5–10. [In Russian].

7. Chernov V.I., Bragina O.D., Sinilkin I.G., Titskaya A.A., Zelchan R.V. Radioimmunotherapy in the treatment of malignancies. Sibirskiy onkologicheskiy zhurnal = Siberian Journal of Oncology. 2016; 15 (2): 101–106. [In Russian].

8. Stenina M.B., Frolova M.A., Kupchan D.Z., Tyulyandin S.A. Changes in neo- and adjuvant treatment of breast cancer in last 5 years. Prakticheskaya onkologiya = Practical Oncology. 2017; 18 (3): 256–264. [In Russian]. doi: 10.31917/1803256.

9. Babyshkina N., Malinovskaya E., Patalyak S., Bragina O., Tarabanovskaya N., Doroshenko A., Slonimskaya E., Perelmuter V., Cherdyntseva N. Neoadjuvant chemotherapy for different molecular breast cancer subtypes: a retrospective study in Russian population. Med. Oncol. 2014; 31 (9): 165. doi: 10.1007/s12032-014-0165-7.

10. Chernov V.I., Bragina O.D., Sinilkin I.G., Titskaya A.A., Zelchan R.V. Radioimmunotherapy in the treatment of malignancies. Sibirskiy onkologicheskiy zhurnal = Siberian Journal of Oncology. 2016; 15 (2): 101–106. [In Russian].

11. Cianfrocca M., Gradishar W. New molecular classifications of breast cancer. CA Cancer J. Clin. 2009; 59 (5): 303–313. doi: 10.3322/caac.20029.

12. Babyshkina N., Malinovskaya E., Patalyak S., Bragina O., Tarabanovskaya N., Doroshenko A., Slonimskaya E., Perelmuter V., Cherdyntseva N. Neoadjuvant chemotherapy for different molecular breast cancer subtypes: a retrospective study in Russian population. Med. Oncol. 2014; 31 (9): 165. doi: 10.1007/s12032-014-0165-7.

13. Goldhirsch A., Winer E.P., Coates A.S., Gelber R.D., Piccart-Gebhart M., Thürlimann B., Senn H.J. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer. Ann. Oncol. 2013; 24 (9): 2206–2223. doi: 10.1093/annonc/mdt303.

14. Cianfrocca M., Gradishar W. New molecular classifications of breast cancer. CA Cancer J. Clin. 2009; 59 (5): 303–313. doi: 10.3322/caac.20029.

15. Raica M., Cîmpean A.M., Ceausu R.A., Fulga V., Nica C., Rudico L., Saptefrati L. Hormone receptors and HER2 expression in primary breast carcinoma and corresponding lymph node metastasis: do we need both? Anticancer Res. 2014; 34 (3): 1435–40.

16. Goldhirsch A., Winer E.P., Coates A.S., Gelber R.D., Piccart-Gebhart M., Thürlimann B., Senn H.J. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer. Ann. Oncol. 2013; 24 (9): 2206–2223. doi: 10.1093/annonc/mdt303.

17. Schrijver W.A.M.E., Suijkerbuijk K.P.M., van Gils C.H., van der Wall E., Moelans C.B., van Diest P.J. Receptor conversion in distant breast cancer metastases: A systematic review and meta-analysis. JNCI J. Natl. Cancer Inst. 2018; 110 (6): 568–580. doi: 10.1093/jnci/djx273.

18. Raica M., Cîmpean A.M., Ceausu R.A., Fulga V., Nica C., Rudico L., Saptefrati L. Hormone receptors and HER2 expression in primary breast carcinoma and corresponding lymph node metastasis: do we need both? Anticancer Res. 2014; 34 (3): 1435–40.

19. Timmer M., Werner J.M., Röhn G., Ortmann M., Blau T., Cramer C., Stavrinou P., Krischek B., Mallman P., Goldbrunner R. Discordance and conversion rates of progesterone-, estrogen-, and HER2/neu-receptor status in primary breast cancer and brain metastasis mainly triggered by hormone therapy. Anticancer Res. 2017; 37 (9): 4859–4865. doi: 10.21873/anticanres.11894.

20. Schrijver W.A.M.E., Suijkerbuijk K.P.M., van Gils C.H., van der Wall E., Moelans C.B., van Diest P.J. Receptor conversion in distant breast cancer metastases: A systematic review and meta-analysis. JNCI J. Natl. Cancer Inst. 2018; 110 (6): 568–580. doi: 10.1093/jnci/djx273.

21. Untch M., Huober J., Jackisch C., Schneeweiss A., Brucker S.Y., Dall P., Denkert C., Fasching P.A., Fehm T., Gerber B., Janni W., Kühn T., Lüftner D., Möbus V., Müller V., Rody A., Sinn P., Thill M., Thomssen C., Harbeck N., Liedtke C. Initial treatment of patients with primary breast cancer: Evidence, controversies, consensus: spectrum of opinion of German specialists at the 15th international St. Gallen breast cancer conference (Vienna 2017). Geburtshilfe Frauenheilkd. 2017; 77 (6): 633–644. doi: 10.1055/s-0043-111601.

22. Timmer M., Werner J.M., Röhn G., Ortmann M., Blau T., Cramer C., Stavrinou P., Krischek B., Mallman P., Goldbrunner R. Discordance and conversion rates of progesterone-, estrogen-, and HER2/neu-receptor status in primary breast cancer and brain metastasis mainly triggered by hormone therapy. Anticancer Res. 2017; 37 (9): 4859–4865. doi: 10.21873/anticanres.11894.

23. Van Hellemond I.E.G., Geurts S.M.E., Tjan-Heijnen V.C.G. Current status of extended adjuvant endocrine therapy in early stage breast cancer. Curr. Treat. Options Oncol. 2018; 19 (5): 26. doi: 10.1007/s11864-018-0541-1.

24. Untch M., Huober J., Jackisch C., Schneeweiss A., Brucker S.Y., Dall P., Denkert C., Fasching P.A., Fehm T., Gerber B., Janni W., Kühn T., Lüftner D., Möbus V., Müller V., Rody A., Sinn P., Thill M., Thomssen C., Harbeck N., Liedtke C. Initial treatment of patients with primary breast cancer: Evidence, controversies, consensus: spectrum of opinion of German specialists at the 15th international St. Gallen breast cancer conference (Vienna 2017). Geburtshilfe Frauenheilkd. 2017; 77 (6): 633–644. doi: 10.1055/s-0043-111601.

25. Van Poznak C., Somerfield M.R., Bast R.C., Cristofanilli M., Goetz M.P., Gonzalez-Angulo A.M., Hicks D.G., Hill E.G., Liu M.C., Lucas W., Mayer I.A., Mennel R.G., Symmans W.F., Hayes D.F., Harris L.N. Use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: American Society of Clinical Oncology clinical practice guideline. J. Clin. Oncol. 2015; 33 (24): 2695–2704. doi: 10.1200/JCO.2015.61.1459.

26. Van Hellemond I.E.G., Geurts S.M.E., Tjan-Heijnen V.C.G. Current status of extended adjuvant endocrine therapy in early stage breast cancer. Curr. Treat. Options Oncol. 2018; 19 (5): 26. doi: 10.1007/s11864-018-0541-1.

27. Vorobyeva A., Bragina O., Altai M., Mitran B., Orlova A., Shulga A., Proshkina G., Chernov V., Tolmachev V., Deyev S. Comparative evaluation of radioiodine and technetium-labeled DARPin 9_29 for radionuclide molecular imaging of HER2 expression in malignant tumors. Contrast Media Mol. Imaging. 2018; 2018: 6930425. doi: 10.1155/2018/6930425.

28. Van Poznak C., Somerfield M.R., Bast R.C., Cristofanilli M., Goetz M.P., Gonzalez-Angulo A.M., Hicks D.G., Hill E.G., Liu M.C., Lucas W., Mayer I.A., Mennel R.G., Symmans W.F., Hayes D.F., Harris L.N. Use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: American Society of Clinical Oncology clinical practice guideline. J. Clin. Oncol. 2015; 33 (24): 2695–2704. doi: 10.1200/JCO.2015.61.1459.

29. Wolff A.C., Hammond M.E., Hicks D.G., Dowsett M., McShane L.M., Allison K.H., Allred D.C., Bartlett J.M., Bilous M., Fitzgibbons P., Hanna W., Jenkins R.B., Mangu P.B., Paik S., Perez E.A., Press M.F., Spears P.A., Vance G.H., Viale G., Hayes D.F. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Arch. Pathol. Lab. Med. 2014; 138 (2): 241–256. doi: 10.5858/arpa.2013-0953-SA.

30. Vorobyeva A., Bragina O., Altai M., Mitran B., Orlova A., Shulga A., Proshkina G., Chernov V., Tolmachev V., Deyev S. Comparative evaluation of radioiodine and technetium-labeled DARPin 9_29 for radionuclide molecular imaging of HER2 expression in malignant tumors. Contrast Media Mol. Imaging. 2018; 2018: 6930425. doi: 10.1155/2018/6930425.

31. Yeung C., Hilton J., Clemons M., Mazzarello S., Hutton B., Haggar F., Addison C.L., Kuchuk I., Zhu X., Gelmon K., Arnaout A. Estrogen, progesterone, and HER2/neu receptor discordance between primary and metastatic breast tumours – a review. Cancer Metastasis Rev. 2016; 35 (3): 427–437. doi: 10.1007/s10555-016-9631-3.

32. Wolff A.C., Hammond M.E., Hicks D.G., Dowsett M., McShane L.M., Allison K.H., Allred D.C., Bartlett J.M., Bilous M., Fitzgibbons P., Hanna W., Jenkins R.B., Mangu P.B., Paik S., Perez E.A., Press M.F., Spears P.A., Vance G.H., Viale G., Hayes D.F. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Arch. Pathol. Lab. Med. 2014; 138 (2): 241–256. doi: 10.5858/arpa.2013-0953-SA.

33. Zavyalova M., Vtorushin S., Krakhmal N., Savelieva O., Tashireva L., Kaigorodova E., Perelmuter V., Telegina N., Denisov E., Bragina O., Slonimskaya E., Choynzonov E. Clinicopathological features of nonspecific invasive breast cancer according to its molecular subtypes. Experim. Oncol. 2016; 38 (2): 122–127. doi: 10.31768/2312-8852.

34. Yeung C., Hilton J., Clemons M., Mazzarello S., Hutton B., Haggar F., Addison C.L., Kuchuk I., Zhu X., Gelmon K., Arnaout A. Estrogen, progesterone, and HER2/neu receptor discordance between primary and metastatic breast tumours – a review. Cancer Metastasis Rev. 2016; 35 (3): 427–437. doi: 10.1007/s10555-016-9631-3.

35. Zavyalova M., Vtorushin S., Krakhmal N., Savelieva O., Tashireva L., Kaigorodova E., Perelmuter V., Telegina N., Denisov E., Bragina O., Slonimskaya E., Choynzonov E. Clinicopathological features of nonspecific invasive breast cancer according to its molecular subtypes. Experim. Oncol. 2016; 38 (2): 122–127. doi: 10.31768/2312-8852.