MOLECULAR-GENETIC MARKERS OF RESPONSE TO NEOADJUVANT CHEMOTHERAPY WITH ANTHRACYCLINES IN BREAST CANCER PATIENTS

The purpose of the study: to evaluate the response to neoadjuvant anthracycline-based chemotherapy depending on the presence of deletions and amplifications of different chromosomal loci and the expression level of topoisomerase 2а in tumor tissue of breast cancer patients. Materials and methods. The study included 46 patients with stage T2–4N0–3M0 breast cancer, who received 2–6 cycles of neoadjuvant chemotherapy with FAC and CAX regimens. Results. The relationship between the expression level of Тор2а>5, deletions of ABCB1, ABCB3, 18р11.21, 11q22.1 loci and amplification of 1q24.1-43 and the response to preoperative treatment was found. Of the 34 patients having at least one of these markers in the tumor tissue, 85.3 % of them demonstrated partial response to neoadjuvant chemotherapy (> 50 % reduction of tumor) and 14.7 % had stable disease and disease progression. No above markers were found in the tumor tissue of 12 patients, who did not respond to preoperative treatment. Conclusion. High levels of Тор2а>5 expression, deletions of ABCB1; ABCB3; 18р11.21; 11q22.1 loci and 1q24.1-43 amplification were shown to be predictive markers of response to neoadjuvant anthracycline-based chemotherapy. The presence of at least one of these markers allowed us to predict response to preoperative treatment in 85 % of cases.

1. Eechoute K., Sparreboom A., Burger H., Franke R.M., Schiavon G., Verweij J., Loos W.J., Wiemer E.A., Mathijssen R.H. Drug transporters and imatinib treatment: implications for clinical practice // Clin. Cancer Res. 2011. Vol. 17 (3). P. 406–415. doi: 10.1158/1078-0432.CCR-10-2250.

2. Gillet J.P., Gottesman M.M. Overcoming multidrug resistance in cancer: 35 years after the discovery of ABCB1 // Drug Resist Updat. 2012. Vol. 15 (1–2). P. 2–4. doi: 10.1016/j.drup.2012.03.001.

3. Han S., Park K., Shin E., Kim H.J., Kim J.Y., Kim J.Y., Gwak G. Genomic change of chromosome 8 predicts the response to taxane-based neoadjuvant chemotherapy in node-positive breast cancer // Oncol. Reports. 2010. Vol. 24 (1). P. 121–128.

4. Han W., Woo J.H., Yu J.H., Lee M.J., Moon H.G., Kang D., Noh D.Y. Common genetic variants associated with breast cancer in Korean women and differential susceptibility accoding to intrisic subtype // Cancer Epidemiol. Biomarkers Prev. 2011. Vol. 20 (5). P. 793–798. doi: 10.1158/1055-9965.EPI-10-1282.

5. Kaufmann M., von Minckwitz G., Mamounas E.P., Cameron D., Carey L.A., Cristofanilli M., Denkert C., Eiermann W., Gnant M., Harris J.R., Karn T., Liedtke C., Mauri D., Rouzier R., Ruckhaeberle E., Semiglazov V., Symmans W.F., Tutt A., Pusztai L. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer // Ann. Surg. Oncol. 2012. Vol. 19 (5). P. 1508–1516. doi: 10.1245/s10434-011-2108-2.

6. Kawachi K., Sasaki T., Murakami A., Ishikawa T., Kito A., Ota I., Shimizu D., Nozawa A., Nagashima Y., Machinami R., Aoki I. The topoisomerase II alpha gene status in primary breast cancer is a predictive marker of the response to anthracycline-based neoadjuvant chemotherapy // Pathol. Res. Pract. 2010. Vol. 206 (3). P. 156–162. doi: 10.1016/j.prp.2009.10.009.

7. Konecny G.E., Pauletti C., Untch M., Wang H.-J., Modus V., Kulin W., Thomssen C., Harbeck N., Wang L., Apple S., Janicke F., Slamon D.J. Association between HER2, TOP2A, and response to antracycline-based preoperative chemotherapy in high-risk primary breast cancer // Breast Cancer Res. Treat. 2010. Vol. 120. P. 481–489. doi: 10.1007/s10549-010-0744-z.

8. Litviakov N., Cherdyntseva N., Tsyganov M., Denisov E., Garbukov E., Merzliakova M., Volkomorov V., Vtorushin S., Zavyalova M., Slonimskaya E. Changing the expression vector of multidrug resistance genes is related to neoadjuvant chemotherapy response // Cancer Chemother. Pharmacol. 2013. Vol. 71 (1). P. 153–163. doi: 10.1007/s00280-012-1992-x.

9. Litviakov N.V., Cherdyntseva N.V., Tsyganov N.V., Slonimskaya E.M., Ibragimova M.K., Kazantseva P.V., Kzhyshkowska J., Choinzonov E.L. Deletions of multidrug resistance gene loci in breast cancer leads to the down-regulation of its expression and predict tumor response to neoadjuvant chemotherapy // Oncotarget. 2016. Vol. 7 (7). P. 7829–7841. doi: 10.18632/oncotarget.6953.

10. Miller M., Ottesen R.A., Niland J.C., Kruper L., Chen S.L., Vito C. Tumor response ratio predicts overall survival in breast cancer patients treated with neoadjuvant chemotherapy // Ann. Surg. Oncol. 2014. Vol. 21. P. 3317–3323. doi: 10.1245/s10434-014-3922-0.

11. Miyoshi Y., Kurosumi M., Kurebayashi J., Matsuura N., Takahashi M., Tokunaga E., Egawa C., Masuda N., Kono S., Morimoto K., Kim S.J., Okishiro M., Yanagisawa T., Ueda S., Taguchi T., Tamaki Y., Noguchi S. Predictive factors for anthracycline-based chemotherapy for human breast cancer // Breast Cancer. 2010. Vol. 17 (2). P. 103–109. doi: 10.1007/s12282-009-0152-6.

12. O'Driscoll L., Clynes M. Molecular markers of multiple drug resistance in breast cancer // Chemotherapy. 2006. Vol. 52 (3). P. 125–129.

13. Schinkel A.H., Jonker J.W. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview // Adv. Drug Deliv. Rev. 2012. Vol. 64. P. 138–153.

14. Symmans W.F., Peintinger F., Hatzis C., Rajan R., Kuerer H., Valero V., Assad L., Poniecka A., Hennessy B., Green M., Buzdar A.U., Singletary S.E., Hortobagyi G.N., Pusztai L. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy // J. Clin. Oncol. 2007. Vol. 25 (28). P. 4414–4422.

15. Szakacs G., Paterson J.K., Ludwig J.A., Booth-Genthe C., Gottesman M.M. Targeting multidrug resistance in cancer // Nat. Rev. Drug Discov. 2006. Vol. 5 (3). P. 219–234.

16. Von Minckwitz D., Untch M., Blohmer J.U., Costa S.D., Eidtmann H., Fasching P.A., Gerber B., Eiermann W., Hilfrich J., Huober J., Jackisch C., Kaufmann M., Konecny C., Denkert C., Nekljudova V., Mehta K., Loibl S. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes // J. Clin. Oncol. 2012. Vol. 30 (15). P. 1796–1804. doi: 10.1200/JCO.2011.38.8595.

17. Wikman H., Sielaff-Frimpong B., Kropidlowski J., Witzel I., Milde-Langosch K., Sauter G., Westphal M., Lamszus K., Pantel K. Clinical Relevance of Loss of 11p15 in Primary and Metastatic Breast Cancer: Association with Loss of PRKCDBP Expression in Brain Metastases // PLoS ONE. 2012. Vol. 7 (10): e47537. doi: 10.1371/journal.pone.0047537.