Skip to main content

Advertisement

SpringerLink
Log in

Predictive value of vascular endothelial growth factor receptor type 2 in triple-negative breast cancer patients treated with neoadjuvant chemotherapy

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

The identification of informative biomarkers that could predict the treatment response is particularly important in the triple-negative (TN) breast cancer, which is characterized by biological diversity. The aim of this study was to investigate the impact of vascular endothelial growth factor receptor (VEGFR2) expression and its gene polymorphisms on pathologic complete response (pCR) to neoadjuvant chemotherapy (NCT) in Russian patients with TN breast cancer. We performed a retrospective analysis of 70 women with operable TN breast cancer, who underwent NCT with 5-fluorouracil, adriamycin, and cyclophosphamide (FAC) or cyclophosphamide, adriamycin, and capecitabine (CAX) between 2007 and 2013. VEGFR2 expression was evaluated before NCT by immunohistochemistry. TaqMan SNP assays were used for genotyping KDR − 604T>C (rs2071559) and KDR 1192G>A (rs2305948) polymorphisms. The pCR was used as an end-point in the treatment efficacy analysis. In the univariate analysis, the pCR rate was strongly associated with young age (P = 0.004), high Ki67 expression (P = 0.012), lymph node negativity (P = 0.023) as well as with positive VEGFR2 expression (P = 0.019) and the CAX regimen (P = 0.005). In the multivariate analysis, only patient’s age (P = 0.005) and pre-NCT VEGFR2 expression (P = 0.048) remained significant predictors of pCR. The pCR rate was higher in the CAX-treated patients than that in the FAC-treated patients (P = 0.005). Our results revealed that − 604TT genotype of rs2071559 and age < 50 years were correlated with a pCR in the CAX-treated patients. VEGFR2 expression in pre-NCT tumors and KDR gene polymorphism can be considered as additional predictive molecular markers of pCR in Russian TN breast cancer patients treated with NCT.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Tomao F, Papa A, Zaccarelli E, Rossi L, Caruso D, Minozzi M, Vici P, Frati L, Tomao S (2015) Triple-negative breast cancer: new perspectives for targeted therapies. Onco Targets Ther 8:177–193. https://doi.org/10.2147/OTT.S67673

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Bosch A, Eroles P, Zaragoza R, Viña JR, Lluch A (2010) Triple-negative breast cancer: molecular features, pathogenesis, treatment and current lines of research. Cancer Treat Rev 36(3):206–215. https://doi.org/10.1016/j.ctrv.2009.12.002

    Article  PubMed  CAS  Google Scholar 

  3. Kuligina ES (2010) Epidemiological and molecular aspects of breast cancer. Pract Oncol 11(4):203–216

    Google Scholar 

  4. Choinzonov EL, Pisareva LF, Odintsova IN, Ananina OA, Boyarkina AP (2014) The state of oncological service in Siberia and Far East. Health Care Russ Fed 58(3):10–14

    Google Scholar 

  5. Gnant M, Thomssen C, Harbeck N (2015) St. Gallen/Vienna 2015: a brief summary of the consensus discussion. Breast Care (Basel) 10(2):124–130. https://doi.org/10.1159/000430488

    Article  Google Scholar 

  6. Prat A, Adamo B, Cheang MC, Anders CK, Carey LA, Perou CM (2013) Molecular characterization of basal-like and non-basal-like triple-negative breast cancer. Oncologist 18(2):123–133. https://doi.org/10.1634/theoncologist.2012-0397

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Dales JP, Garcia S, Carpentier S, Andrac L, Ramuz O, Lavaut MN, Allasia C, Bonnier P, Taranger-Charpin C (2004) Prediction of metastasis risk (11 year follow-up) using VEGF-R1, VEGF-R2, Tie-2/Tek and CD105 expression in breast cancer (n = 905). Br J Cancer 90(6):1216–1221

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Ghosh S, Sullivan CA, Zerkowski MP, Molinaro AM, Rimm DL, Camp RL, Chung GG (2008) High levels of vascular endothelial growth factor and its receptors (VEGFR-1, VEGFR-2, neuropilin-1) are associated with worse outcome in breast cancer. Hum Pathol 39(12):1835–1843. https://doi.org/10.1016/j.humpath.2008.06.004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Dhakal HP, Naume B, Synnestvedt M, Borgen E, Kaaresen R, Schlichting E, Wiedswang G, Bassarova A, Holm R, Giercksky KE, Nesland JM (2012) Expression of vascular endothelial growth factor and vascular endothelial growth factor receptors 1 and 2 in invasive breast carcinoma: prognostic significance and relationship with markers for aggressiveness. Histopathology 61(3):350–364. https://doi.org/10.1111/j.1365-2559.2012.04223.x

    Article  PubMed  Google Scholar 

  10. Jansson S, Bendahl PO, Grabau DA, Falck AK, Fernö M, Aaltonen K, Rydén L (2014) The three receptor tyrosine kinases c-KIT, VEGFR2 and PDGFRα, closely spaced at 4q12, show increased protein expression in triple-negative breast cancer. PLoS ONE 9(7):e102176. https://doi.org/10.1371/journal.pone.0102176

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Yan JD, Liu Y, Zhang ZY, Liu GY, Xu JH, Liu LY, Hu YM (2015) Expression and prognostic significance of VEGFR-2 in breast cancer. Pathol Res Pract 211(7):539–543. https://doi.org/10.1016/j.prp.2015.04.003

    Article  PubMed  CAS  Google Scholar 

  12. Wang Y, Zheng Y, Zhang W, Yu H, Lou K, Zhang Y, Qin Q, Zhao B, Yang Y, Hui R (2007) Polymorphisms of KDR gene are associated with coronary heart disease. J Am Coll Cardiol 50(8):760–767

    Article  PubMed  CAS  Google Scholar 

  13. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. https://doi.org/10.1016/j.ejca.2008.10.026

    Article  PubMed  CAS  Google Scholar 

  14. Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, Bonnefoi H, Cameron D, Gianni L, Valagussa P, Swain SM, Prowell T, Loibl S, Wickerham DL, Bogaerts J, Baselga J, Perou C, Blumenthal G, Blohmer J, Mamounas EP, Bergh J, Semiglazov V, Justice R, Eidtmann H, Paik S, Piccart M, Sridhara R, Fasching PA, Slaets L, Tang S, Gerber B, Geyer CE Jr, Pazdur R, Ditsch N, Rastogi P, Eiermann W, von Minckwitz G (2014) Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384(9938):164–172. https://doi.org/10.1016/S0140-6736(13)62422-8

    Article  PubMed  Google Scholar 

  15. Babyshkina N, Vtorushin S, Zavyalova M, Patalyak S, Dronova T, Litviakov N, Slonimskaya E, Kzhyshkowska J, Cherdyntseva N, Choynzonov E (2017) The distribution pattern of ERα expression, ESR1 genetic variation and expression of growth factor receptors: association with breast cancer prognosis in Russian patients treated with adjuvant tamoxifen. Clin Exp Med 17(3):383–393. https://doi.org/10.1007/s10238-016-0428-z

    Article  PubMed  CAS  Google Scholar 

  16. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff AC (2010) American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28(16):2784–2795. https://doi.org/10.1200/JCO.2009.25.6529

    Article  PubMed  PubMed Central  Google Scholar 

  17. Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, Thürlimann B, Senn HJ, Panel Members (2015) Tailoring therapies—improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol 26(8):1533–1546. https://doi.org/10.1093/annonc/mdv221

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10(16):5367–5374. https://doi.org/10.1158/1078-0432.CCR-04-0220

    Article  PubMed  CAS  Google Scholar 

  19. von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, Gerber B, Eiermann W, Hilfrich J, Huober J, Jackisch C, Kaufmann M, Konecny GE, Denkert C, Nekljudova V, Mehta K, Loibl S (2012) Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 30(15):1796–1804. https://doi.org/10.1200/JCO.2011.38.8595

    Article  Google Scholar 

  20. Guarneri V, Piacentini F, Ficarra G, Frassoldati A, D’Amico R, Giovannelli S, Maiorana A, Jovic G, Conte P (2009) A prognostic model based on nodal status and Ki-67 predicts the risk of recurrence and death in breast cancer patients with residual disease after preoperative chemotherapy. Ann Oncol 20(7):1193–1198. https://doi.org/10.1093/annonc/mdn761

    Article  PubMed  CAS  Google Scholar 

  21. Makhoul I, Griffin RJ, Siegel E, Lee J, Dhakal I, Raj V, Jamshidi-Parsian A, Klimberg S, Hutchins LF, Kadlubar S (2016) High- circulating Tie2 is associated with pathologic complete response to chemotherapy and antiangiogenic therapy in breast cancer. Am J Clin Oncol 39(3):248–254. https://doi.org/10.1097/COC.0000000000000046

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  23. Allegrini G, Coltelli L, Orlandi P, Fontana A, Camerini A, Ferro A, Cazzaniga M, Casadei V, Lucchesi S, Bona E, Di Lieto M, Pazzagli I, Villa F, Amoroso D, Scalese M, Arrighi G, Molinaro S, Fioravanti A, Finale C, Triolo R, Di Desidero T, Donati S, Marcucci L, Goletti O, Del Re M, Salvadori B, Ferrarini I, Danesi R, Falcone A, Bocci G (2014) Pharmacogenetic interaction analysis of VEGFR-2 and IL-8 polymorphisms in advanced breast cancer patients treated with paclitaxel and bevacizumab. Pharmacogenomics 15(16):1985–1999. https://doi.org/10.2217/pgs.14.140

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The study was supported by the ERA Net RUS Plus S&T CHIT-ALPHA-THER grant, the Russian Foundation for Basic Research (Project No. 16-54-76015). We acknowledge support of this work by the Tomsk State University Competitiveness Improvement Program. We are grateful to Dr. Viktoriya Stalbovskaya and Dr. Matvey Tsyganov for assistance with statistical analysis.

Author information

Authors and Affiliations

  1. Department of Molecular Oncology and Immunology, Federal State Budgetary Scientific Institution “Саncеr Research Institute”, Tomsk National Research Medical Center, Russian Academy of Sciences, 5 Kooperativny Street, Tomsk, 634050, Russian Federation

    Nataliya Babyshkina, Tatyana Dronova & Nadejda Cherdyntseva

  2. Department of General Oncology, Federal State Budgetary Scientific Institution “Cаncеr Research Institute”, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, 634050, Russian Federation

    Natalia Tarabanovskaya & Elena Slonimskaya

  3. Department of Pathological Anatomy and Cytology, Federal State Budgetary Scientific Institution “Саncеr Research Institute”, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, 634050, Russian Federation

    Marina Zavyalova & Nadejda Krakhmal

  4. Department of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk, 634050, Russian Federation

    Nataliya Babyshkina, Marina Zavyalova, Tatyana Dronova, Julia Kzhyshkowska & Nadejda Cherdyntseva

  5. Department of General Oncology, Siberian State Medical University, Tomsk, 634050, Russian Federation

    Marina Zavyalova, Nadejda Krakhmal, Elena Slonimskaya & Nadejda Cherdyntseva

  6. Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim University of Heidelberg, 68167, Mannheim, Germany

    Julia Kzhyshkowska

  7. Federal State Budgetary Scientific Institution “Саncеr Research Institute”, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, 634050, Russian Federation

    Evgeny Choynzonov

Authors
  1. Nataliya Babyshkina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marina Zavyalova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Natalia Tarabanovskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tatyana Dronova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nadejda Krakhmal
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elena Slonimskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Julia Kzhyshkowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Evgeny Choynzonov
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Nadejda Cherdyntseva
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nataliya Babyshkina.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Babyshkina, N., Zavyalova, M., Tarabanovskaya, N. et al. Predictive value of vascular endothelial growth factor receptor type 2 in triple-negative breast cancer patients treated with neoadjuvant chemotherapy. Mol Cell Biochem 444, 197–206 (2018). https://doi.org/10.1007/s11010-017-3244-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-017-3244-1

Keywords

Search

Navigation