Advertisement

Breast Cancer Research and Treatment

, Volume 172, Issue 1, pp 93–104 | Cite as

The clinical relevance of serum vascular endothelial growth factor (VEGF) in correlation to circulating tumor cells and other serum biomarkers in patients with metastatic breast cancer

  • Malgorzata Banys-Paluchowski
  • Isabell Witzel
  • Sabine Riethdorf
  • Klaus Pantel
  • Brigitte Rack
  • Wolfgang Janni
  • Peter A. Fasching
  • Bahriye Aktas
  • Sabine Kasimir-Bauer
  • Andreas Hartkopf
  • Erich-Franz Solomayer
  • Tanja Fehm
  • Volkmar Müller
Clinical trial

Abstract

Purpose

VEGF is one of the most important angiogenesis-stimulating cytokines and has been previously shown to be overexpressed in several solid cancers. The aim of the present study was to assess the clinical relevance of serum VEGF (sVEGF) in a large cohort of metastatic breast cancer patients and to explore the relationship between sVEGF and other blood-based biomarkers.

Methods

Two hundred fifty-three patients with metastatic breast cancer were enrolled in this prospective, multicentre study. Blood samples were collected before start of first-line or later-line treatment. sVEGF was quantified by a commercially available ELISA. Circulating tumor cells (CTCs) were detected using CellSearch and other biomarkers (EGFR, HER2, RAS p21, TIMP1, CAIX) by ELISA.

Results

Levels of sVEGF were determined in all patients, with a median concentration of 231 pg/ml. After a median follow-up of 19 months, median overall survival (OS) was 10.2 months in patients with sVEGF levels above the upper quartile (i.e. 367 pg/ml), while median OS has not been reached in patients with sVEGF < 367 pg/ml (p < 0.001). Median progression-free survival (PFS) was 4.8 months for patients with sVEGF ≥ 367 pg/ml versus 9.1 months with sVEGF levels < 367 pg/ml (p < 0.001). Patients with sVEGF levels ≥ 367 pg/ml and ≥ 5 CTCs had the shortest OS, while those with sVEGF < 367 pg/ml and non-elevated CTCs had the longest OS. CTCs, grading, line of therapy and RAS p21 were independent predictors of OS. sVEGF, line of therapy and CTCs were independent predictors of PFS in the multivariate analysis.

Conclusions

Metastatic breast cancer patients with elevated levels of sVEGF have significantly worse clinical outcome. This finding supports the biological role of VEGF in breast cancer. Trial registration: Current Controlled Trials ISRCTN59722891 (DETECT).

Keywords

Breast cancer VEGF Circulating tumor cell Survival Biomarker 

Notes

Author contributions

TF, WJ, BA, PAF, SKB, KP, BR, SR, EFS, AH and VM designed and conducted the study. MBP analyzed and interpreted the data, performed statistical analysis and prepared the manuscript. TF, IW, PAF and VM analyzed and interpreted the data and were major contributors in writing the manuscript. All authors read and approved the final manuscript.

Funding

The DETECT study was supported by a research grant from Roche Pharma AG, Germany and by Adnagen AG, Germany. ELISA kits were provided at no cost by Oncogene Science. The funding agencies had no role in study design or collection, analysis and interpretation of data or in the writing of the manuscript.

Compliance with Ethical Standards

Conflict of interest

Wolfgang Janni received a research grant from Roche. Bahriye Aktas has served as a consultant/advisor for Roche, Pfizer and Novartis. Klaus Pantel has served as a consultant/advisor for Agena Bioscience. Sabine Kasimir-Bauer has served as a consultant/advisor for Qiagen. Peter A. Fasching has served as a consultant/advisor for Amgen, Novartis, Roche, Pfizer, Teva and Puma Celgene and received a research grant from Novartis. Brigitte Rack has received honoraria or research grants from Novartis, Roche, Pfizer, Janssen Diagnostics, Astra Zeneca, Novartis, Lilly, Chugai and Sanofi. Malgorzata Banys-Paluchowski, Isabell Witzel, Sabine Riethdorf, Andreas Hartkopf, Erich-Franz Solomayer, Tanja Fehm and Volkmar Müller declare that they have no conflicts of interest.

Ethical approval

All procedures performed in this study were in accordance with the ethical standard of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the local ethical committees of participation institutions.

Informed consent

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

Supplementary material

10549_2018_4882_MOESM1_ESM.docx (16 kb)
Supplementary material 1 (DOCX 15 KB)

References

  1. 1.
    Roskoski R Jr (2007) Vascular endothelial growth factor (VEGF) signaling in tumor progression. Crit Rev Oncol Hematol 62:179–213.  https://doi.org/10.1016/j.critrevonc.2007.01.006 CrossRefPubMedGoogle Scholar
  2. 2.
    Goel HL, Mercurio AM (2013) VEGF targets the tumour cell. Nat Rev Cancer 13:871–882.  https://doi.org/10.1038/nrc3627 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Li S, Wang L, Meng Y, Chang Y, Xu J, Zhang Q (2017) Increased levels of LAPTM4B, VEGF and survivin are correlated with tumor progression and poor prognosis in breast cancer patients. Oncotarget 8:41282–41293.  https://doi.org/10.18632/oncotarget.17176 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Linderholm B, Lindh B, Tavelin B, Grankvist K, Henriksson R (2000) p53 and vascular-endothelial-growth-factor (VEGF) expression predicts outcome in 833 patients with primary breast carcinoma. Int J Cancer 89:51–62CrossRefGoogle Scholar
  5. 5.
    Gasparini G (2000) Prognostic value of vascular endothelial growth factor in breast cancer. Oncologist 5:37–44CrossRefGoogle Scholar
  6. 6.
    Eppenberger U, Kueng W, Schlaeppi JM, Roesel JL, Benz C, Mueller H, Matter A, Zuber M, Luescher K, Litschgi M, Schmitt M, Foekens JA, Eppenberger-Castori S (1998) Markers of tumor angiogenesis and proteolysis independently define high- and low-risk subsets of node-negative breast cancer patients. J Clin Oncol 16:3129–3136.  https://doi.org/10.1200/JCO.1998.16.9.3129 CrossRefPubMedGoogle Scholar
  7. 7.
    Linderholm B, Tavelin B, Grankvist K, Henriksson R (1998) Vascular endothelial growth factor is of high prognostic value in node-negative breast carcinoma. J Clin Oncol 16:3121–3128.  https://doi.org/10.1200/JCO.1998.16.9.3121 CrossRefPubMedGoogle Scholar
  8. 8.
    Manders P, Beex LV, Tjan-Heijnen VC, Geurts-Moespot J, Van Tienoven TH, Foekens JA, Sweep CG (2002) The prognostic value of vascular endothelial growth factor in 574 node-negative breast cancer patients who did not receive adjuvant systemic therapy. Br J Cancer 87:772–778.  https://doi.org/10.1038/sj.bjc.6600555 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Linardou H, Kalogeras KT, Kronenwett R, Kouvatseas G, Wirtz RM, Zagouri F, Gogas H, Christodoulou C, Koutras AK, Samantas E, Pectasides D, Bafaloukos D, Fountzilas G (2012) The prognostic and predictive value of mRNA expression of vascular endothelial growth factor family members in breast cancer: a study in primary tumors of high-risk early breast cancer patients participating in a randomized Hellenic Cooperative Oncology Group trial. Breast Cancer Res 14:R145.  https://doi.org/10.1186/bcr3354 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Banys-Paluchowski M, Fehm T, Müller V (2017) The value of antiangiogenics in breast cancer therapy. Tumor Angiogenesis.  https://doi.org/10.1007/978-3-319-31215-6_24-1 CrossRefGoogle Scholar
  11. 11.
    Cobleigh MA, Langmuir VK, Sledge GW, Miller KD, Haney L, Novotny WF, Reimann JD, Vassel A (2003) A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol 30:117–124CrossRefGoogle Scholar
  12. 12.
    Pivot X, Schneeweiss A, Verma S, Thomssen C, Passos-Coelho JL, Benedetti G, Ciruelos E, von Moos R, Chang HT, Duenne AA, Miles DW (2011) Efficacy and safety of bevacizumab in combination with docetaxel for the first-line treatment of elderly patients with locally recurrent or metastatic breast cancer: results from AVADO. Eur J Cancer 47:2387–2395.  https://doi.org/10.1016/j.ejca.2011.06.018 CrossRefPubMedGoogle Scholar
  13. 13.
    Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676CrossRefGoogle Scholar
  14. 14.
    Gligorov J, Doval D, Bines J, Alba E, Cortes P, Pierga JY, Gupta V, Costa R, Srock S, de Ducla S, Freudensprung U, Mustacchi G (2014) Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, open-label, phase 3 trial. Lancet Oncol 15:1351–1360.  https://doi.org/10.1016/S1470-2045(14)70444-9 CrossRefPubMedGoogle Scholar
  15. 15.
    Baselga J, Zamagni C, Gomez P, Bermejo B, Nagai S, Melichar B, Chan A, Mangel L, Bergh J, Costa FP, Gomez HL, Gradishar W, Hudis C, Rapoport B, Roche H, Maeda P, Huang L, Zhang J, Schwartzberg LS (2014) A phase III randomized, double-blind, trial comparing sorafenib plus capecitabine versus placebo plus capecitabine in the treatment of locally advanced breast cancer (ESMO 2014). Ann Oncol 25:1–41CrossRefGoogle Scholar
  16. 16.
    Schwartzberg LS, Tauer KW, Hermann RC, Makari-Judson G, Isaacs C, Beck JT, Kaklamani V, Stepanski EJ, Rugo HS, Wang W, Bell-McGuinn K, Kirshner JJ, Eisenberg P, Emanuelson R, Keaton M, Levine E, Medgyesy DC, Qamar R, Starr A, Ro SK, Lokker NA, Hudis CA (2013) Sorafenib or placebo with either gemcitabine or capecitabine in patients with HER-2-negative advanced breast cancer that progressed during or after bevacizumab. Clin Cancer Res 19:2745–2754.  https://doi.org/10.1158/1078-0432.CCR-12-3177 CrossRefPubMedGoogle Scholar
  17. 17.
    Bergh J, Bondarenko IM, Lichinitser MR, Liljegren A, Greil R, Voytko NL, Makhson AN, Cortes J, Lortholary A, Bischoff J, Chan A, Delaloge S, Huang X, Kern KA, Giorgetti C (2012) First-line treatment of advanced breast cancer with sunitinib in combination with docetaxel versus docetaxel alone: results of a prospective, randomized phase III study. J Clin Oncol 30:921–929.  https://doi.org/10.1200/JCO.2011.35.7376 CrossRefPubMedGoogle Scholar
  18. 18.
    Heer K, Kumar H, Read JR, Fox JN, Monson JR, Kerin MJ (2001) Serum vascular endothelial growth factor in breast cancer: its relation with cancer type and estrogen receptor status. Clin Cancer Res 7:3491–3494PubMedGoogle Scholar
  19. 19.
    Adams J, Carder PJ, Downey S, Forbes MA, MacLennan K, Allgar V, Kaufman S, Hallam S, Bicknell R, Walker JJ, Cairnduff F, Selby PJ, Perren TJ, Lansdown M, Banks RE (2000) Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen. Cancer Res 60:2898–2905PubMedGoogle Scholar
  20. 20.
    Santos LV, Cruz MR, Lopes Gde L, Lima JP (2015) VEGF-A levels in bevacizumab-treated breast cancer patients: a systematic review and meta-analysis. Breast Cancer Res Treat 151:481–489.  https://doi.org/10.1007/s10549-015-3410-7 CrossRefPubMedGoogle Scholar
  21. 21.
    Banys-Paluchowski M, Witzel I, Riethdorf S, Rack B, Janni W, Fasching PA, Solomayer EF, Aktas B, Kasimir-Bauer S, Pantel K, Fehm T, Muller V (2017) Clinical Relevance of Serum HER2 and Circulating Tumor Cell Detection in Metastatic Breast Cancer Patients. Anticancer Res 37:3117–3128.  https://doi.org/10.21873/anticanres.11669 CrossRefPubMedGoogle Scholar
  22. 22.
    Banys-Paluchowski M, Witzel I, Riethdorf S, Rack B, Janni W, Fasching PA, Solomayer EF, Aktas B, Kasimir-Bauer S, Pantel K, Fehm T, Muller V (2017) Evaluation of serum epidermal growth factor receptor (EGFR) in correlation to circulating tumor cells in patients with metastatic breast cancer. Sci Rep 7:17307.  https://doi.org/10.1038/s41598-017-17514-8 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Banys-Paluchowski M, Fehm T, Janni W, Aktas B, Fasching PA, Kasimir-Bauer S, Milde-Langosch K, Pantel K, Rack B, Riethdorf S, Solomayer EF, Witzel I, Müller V (2018) Elevated serum RAS p21 is an independent prognostic factor in metastatic breast cancer. BMC Cancer, 18:541CrossRefGoogle Scholar
  24. 24.
    Muller V, Riethdorf S, Rack B, Janni W, Fasching PA, Solomayer E, Aktas B, Kasimir-Bauer S, Zeitz J, Pantel K, Fehm T (2011) Prospective evaluation of serum tissue inhibitor of metalloproteinase 1 and carbonic anhydrase IX in correlation to circulating tumor cells in patients with metastatic breast cancer. Breast Cancer Res 13:R71.  https://doi.org/10.1186/bcr2916 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer 93:387–391.  https://doi.org/10.1038/sj.bjc.6602678 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Gianni L, Romieu GH, Lichinitser M, Serrano SV, Mansutti M, Pivot X, Mariani P, Andre F, Chan A, Lipatov O, Chan S, Wardley A, Greil R, Moore N, Prot S, Pallaud C, Semiglazov V (2013) AVEREL: a randomized phase III Trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol 31:1719–1725.  https://doi.org/10.1200/JCO.2012.44.7912 CrossRefPubMedGoogle Scholar
  27. 27.
    Miles DW, de Haas SL, Dirix LY, Romieu G, Chan A, Pivot X, Tomczak P, Provencher L, Cortes J, Delmar PR, Scherer SJ (2013) Biomarker results from the AVADO phase 3 trial of first-line bevacizumab plus docetaxel for HER2-negative metastatic breast cancer. Br J Cancer 108:1052–1060.  https://doi.org/10.1038/bjc.2013.69 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Miles D, Cameron D, Bondarenko I, Manzyuk L, Alcedo JC, Lopez RI, Im SA, Canon JL, Shparyk Y, Yardley DA, Masuda N, Ro J, Denduluri N, Hubeaux S, Quah C, Bais C, O’Shaughnessy J (2017) Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): A double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation. Eur J Cancer 70:146–155.  https://doi.org/10.1016/j.ejca.2016.09.024 CrossRefPubMedGoogle Scholar
  29. 29.
    Kwon KA, Kim SH, Oh SY, Lee S, Han JY, Kim KH, Goh RY, Choi HJ, Park KJ, Roh MS, Kim HJ, Kwon HC, Lee JH (2010) Clinical significance of preoperative serum vascular endothelial growth factor, interleukin-6, and C-reactive protein level in colorectal cancer. BMC Cancer 10:203.  https://doi.org/10.1186/1471-2407-10-203 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, Hayes DF (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781–791CrossRefGoogle Scholar
  31. 31.
    Zhang L, Riethdorf S, Wu G, Wang T, Yang K, Peng G, Liu J, Pantel K (2012) Meta-analysis of the prognostic value of circulating tumor cells in breast cancer. Clin Cancer Res 18:5701–5710.  https://doi.org/10.1158/1078-0432.CCR-12-1587 CrossRefPubMedGoogle Scholar
  32. 32.
    Kondo S, Asano M, Matsuo K, Ohmori I, Suzuki H (1994) Vascular endothelial growth factor/vascular permeability factor is detectable in the sera of tumor-bearing mice and cancer patients. Biochim Biophys Acta 1221:211–214CrossRefGoogle Scholar
  33. 33.
    Salven P, Manpaa H, Orpana A, Alitalo K, Joensuu H (1997) Serum vascular endothelial growth factor is often elevated in disseminated cancer. Clin Cancer Res 3:647–651PubMedGoogle Scholar
  34. 34.
    Salven P, Perhoniemi V, Tykka H, Maenpaa H, Joensuu H (1999) Serum VEGF levels in women with a benign breast tumor or breast cancer. Breast Cancer Res Treat 53:161–166CrossRefGoogle Scholar
  35. 35.
    Coskun U, Gunel N, Toruner FB, Sancak B, Onuk E, Bayram O, Cengiz O, Yilmaz E, Elbeg S, Ozkan S (2003) Serum leptin, prolactin and vascular endothelial growth factor (VEGF) levels in patients with breast cancer. Neoplasma 50:41–46PubMedGoogle Scholar
  36. 36.
    Iovino F, Ferraraccio F, Orditura M, Antoniol G, Morgillo F, Cascone T, Diadema MR, Aurilio G, Santabarbara G, Ruggiero R, Belli C, Irlandese E, Fasano M, Ciardiello F, Procaccini E, Lo Schiavo F, Catalano G, De Vita F (2008) Serum vascular endothelial growth factor (VEGF) levels correlate with tumor VEGF and p53 overexpression in endocrine positive primary breast cancer. Cancer Invest 26:250–255.  https://doi.org/10.1080/07357900701560612 CrossRefPubMedGoogle Scholar
  37. 37.
    Mueller MD, Vigne JL, Minchenko A, Lebovic DI, Leitman DC, Taylor RN (2000) Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors alpha and beta. Proc Natl Acad Sci U S A 97:10972–10977.  https://doi.org/10.1073/pnas.200377097 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Applanat MP, Buteau-Lozano H, Herve MA, Corpet A (2008) Vascular endothelial growth factor is a target gene for estrogen receptor and contributes to breast cancer progression. Adv Exp Med Biol 617:437–444.  https://doi.org/10.1007/978-0-387-69080-3_42 CrossRefPubMedGoogle Scholar
  39. 39.
    Sengupta K, Banerjee S, Saxena N, Banerjee SK (2003) Estradiol-induced vascular endothelial growth factor-A expression in breast tumor cells is biphasic and regulated by estrogen receptor-alpha dependent pathway. Int J Oncol 22:609–614PubMedGoogle Scholar
  40. 40.
    Addison CL, Pond GR, Cochrane B, Zhao H, Chia SK, Levine MN, Clemons M (2015) Correlation of baseline biomarkers with clinical outcomes and response to fulvestrant with vandetanib or placebo in patients with bone predominant metastatic breast cancer: An OCOG ZAMBONEY sub-study. J Bone Oncol 4:47–53.  https://doi.org/10.1016/j.jbo.2015.04.001 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Bachelot T, Ray-Coquard I, Menetrier-Caux C, Rastkha M, Duc A, Blay JY (2003) Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of vascular endothelial growth factor in hormone-refractory metastatic breast cancer patients. Br J Cancer 88:1721–1726.  https://doi.org/10.1038/sj.bjc.6600956 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Rocca A, Cancello G, Bagnardi V, Sandri MT, Torrisi R, Zorzino L, Viale G, Pietri E, Veronesi P, Dellapasqua S, Ferrucci F, Luini A, Johansson H, Ghisini R, Goldhirsch A, Colleoni M (2009) Perioperative serum VEGF and extracellular domains of EGFR and HER2 in early breast cancer. Anticancer Res 29:5111–5119PubMedGoogle Scholar
  43. 43.
    Lam SW, Nota NM, Jager A, Bos MM, van den Bosch J, van der Velden AM, Portielje JE, Honkoop AH, van Tinteren H, Boven E (2016) Angiogenesis- and hypoxia-associated proteins as early indicators of the outcome in patients with metastatic breast cancer given first-line bevacizumab-based therapy. Clin Cancer Res 22:1611–1620.  https://doi.org/10.1158/1078-0432.ccr-15-1005 CrossRefPubMedGoogle Scholar
  44. 44.
    Pectasides D, Papaxoinis G, Kotoula V, Fountzilas H, Korantzis I, Koutras A, Dimopoulos AM, Papakostas P, Aravantinos G, Varthalitis I, Kosmidis P, Skarlos D, Bournakis E, Bafaloukos D, Kalofonos HP, Kalogeras KT, Fountzilas G (2012) Expression of angiogenic markers in the peripheral blood of docetaxel-treated advanced breast cancer patients: a Hellenic Cooperative Oncology Group (HeCOG) study. Oncol Rep 27:216–224.  https://doi.org/10.3892/or.2011.1504 CrossRefPubMedGoogle Scholar
  45. 45.
    Burstein HJ, Chen YH, Parker LM, Savoie J, Younger J, Kuter I, Ryan PD, Garber JE, Chen H, Campos SM, Shulman LN, Harris LN, Gelman R, Winer EP (2008) VEGF as a marker for outcome among advanced breast cancer patients receiving anti-VEGF therapy with bevacizumab and vinorelbine chemotherapy. Clin Cancer Res 14:7871–7877.  https://doi.org/10.1158/1078-0432.CCR-08-0593 CrossRefPubMedGoogle Scholar
  46. 46.
    Arisato T, Hashiguchi T, Sarker KP, Arimura K, Asano M, Matsuo K, Osame M, Maruyama I (2003) Highly accumulated platelet vascular endothelial growth factor in coagulant thrombotic region. J Thromb Haemost 1:2589–2593CrossRefGoogle Scholar
  47. 47.
    Werther K, Christensen IJ, Nielsen HJ (2002) Determination of vascular endothelial growth factor (VEGF) in circulating blood: significance of VEGF in various leucocytes and platelets. Scand J Clin Lab Invest 62:343–350CrossRefGoogle Scholar
  48. 48.
    Kallergi G, Markomanolaki H, Giannoukaraki V, Papadaki MA, Strati A, Lianidou ES, Georgoulias V, Mavroudis D, Agelaki S (2009) Hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression in circulating tumor cells of breast cancer patients. Breast Cancer Res 11:R84.  https://doi.org/10.1186/bcr2452 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Skerenova M, Mikulova V, Capoun O, Zima T, Tesarova P (2017) Circulating tumor cells and serum levels of MMP-2, MMP-9 and VEGF as markers of the metastatic process in patients with high risk of metastatic progression. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 161:272–280.  https://doi.org/10.5507/bp.2017.022 CrossRefPubMedGoogle Scholar
  50. 50.
    Vilsmaier T, Rack B, Janni W, Jeschke U, Weissenbacher T, Group SS (2016) Angiogenic cytokines and their influence on circulating tumour cells in sera of patients with the primary diagnosis of breast cancer before treatment. BMC Cancer 16:547.  https://doi.org/10.1186/s12885-016-2612-7 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Pineda E, Salud A, Vila-Navarro E, Safont MJ, Llorente B, Aparicio J, Vera R, Escudero P, Casado E, Bosch C, Bohn U, Perez-Carrion R, Carmona A, Ayuso JR, Ripolles T, Bouzas R, Gironella M, Garcia-Albeniz X, Feliu J, Maurel J (2017) Dynamic soluble changes in sVEGFR1, HGF, and VEGF promote chemotherapy and bevacizumab resistance: A prospective translational study in the BECOX (GEMCAD 09 – 01) trial. Tumour Biol.  https://doi.org/10.1177/1010428317705509 CrossRefPubMedGoogle Scholar
  52. 52.
    Mahner S, Woelber L, Eulenburg C, Schwarz J, Carney W, Jaenicke F, Milde-Langosch K, Mueller V (2010) TIMP-1 and VEGF-165 serum concentration during first-line therapy of ovarian cancer patients. BMC Cancer 10:139.  https://doi.org/10.1186/1471-2407-10-139 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Rogers CA, Scott LJ, Reeves BC, Phil D, Downes S, Lotery AJ, Dick AD, Chakravarthy U (2018) Serum vascular endothelial growth factor levels in the IVAN trial; relationships with drug, dosing, and systemic serious adverse events. Ophthalmology Retina 2:118–127CrossRefGoogle Scholar
  54. 54.
    Wu WC, Lien R, Liao PJ, Wang NK, Chen YP, Chao AN, Chen KJ, Chen TL, Hwang YS, Lai CC (2015) Serum levels of vascular endothelial growth factor and related factors after intravitreous bevacizumab injection for retinopathy of prematurity. JAMA Ophthalmol 133:391–397.  https://doi.org/10.1001/jamaophthalmol.2014.5373 CrossRefPubMedGoogle Scholar
  55. 55.
    Davidovic SP, Nikolic SV, Curic NJ, Latinovic SL, Draskovic DO, Cabarkapa VS, Stosic ZZ (2012) Changes of serum VEGF concentration after intravitreal injection of Avastin in treatment of diabetic retinopathy. Eur J Ophthalmol 22:792–798.  https://doi.org/10.5301/ejo.5000118 CrossRefPubMedGoogle Scholar
  56. 56.
    Muller V, Witzel I, Pantel K, Krenkel S, Luck HJ, Neumann R, Keller T, Dittmer J, Janicke F, Thomssen C (2006) Prognostic and predictive impact of soluble epidermal growth factor receptor (sEGFR) protein in the serum of patients treated with chemotherapy for metastatic breast cancer. Anticancer Res 26:1479–1487PubMedGoogle Scholar
  57. 57.
    Souder C, Leitzel K, Ali SM, Demers L, Evans DB, Chaudri-Ross HA, Hackl W, Hamer P, Carney W, Lipton A (2006) Serum epidermal growth factor receptor/HER-2 predicts poor survival in patients with metastatic breast cancer. Cancer 107:2337–2345.  https://doi.org/10.1002/cncr.22255 CrossRefPubMedGoogle Scholar
  58. 58.
    Witzel I, Loibl S, von Minckwitz G, Eidtmann H, Fehm T, Khandan F, Schmatloch S, Hauschild M, Bischoff J, Fasching PA, Mau C, Schem C, Rack B, Meinhold-Heerlein I, Liedtke C, Karn T, Huober J, Zu Eulenburg C, Issa-Nummer Y, Untch M, Muller V (2012) Predictive value of HER2 serum levels in patients treated with lapatinib or trastuzumab: a translational project in the neoadjuvant GeparQuinto trial. Br J Cancer 107:956–960.  https://doi.org/10.1038/bjc.2012.353 CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Kozlowski M, Laudanski W, Mroczko B, Szmitkowski M, Milewski R, Lapuc G (2013) Serum tissue inhibitor of metalloproteinase 1 (TIMP-1) and vascular endothelial growth factor A (VEGF-A) are associated with prognosis in esophageal cancer patients. Adv Med Sci 58:227–234.  https://doi.org/10.2478/ams-2013-0017 CrossRefPubMedGoogle Scholar
  60. 60.
    Erman H, Gelisgen R, Cengiz M, Tabak O, Erdenen F, Uzun H (2016) The association of vascular endothelial growth factor, metalloproteinases and their tissue inhibitors with cardiovascular risk factors in the metabolic syndrome. Eur Rev Med Pharmacol Sci 20:1015–1022PubMedGoogle Scholar
  61. 61.
    Lawicki S, Zajkowska M, Glazewska EK, Bedkowska GE, Szmitkowski M (2016) Plasma levels and diagnostic utility of VEGF, MMP-9, and TIMP-1 in the diagnosis of patients with breast cancer. Onco Targets Ther 9:911–919.  https://doi.org/10.2147/OTT.S99959 CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Kim YB, Han JY, Kim TS, Kim PS, Chu YC (2000) Overexpression of c-H-ras p21 is correlated with vascular endothelial growth factor expression and neovascularization in advanced gastric carcinoma. J Gastroenterol Hepatol 15:1393–1399CrossRefGoogle Scholar
  63. 63.
    Meadows KN, Bryant P, Pumiglia K (2001) Vascular endothelial growth factor induction of the angiogenic phenotype requires Ras activation. J Biol Chem 276:49289–49298.  https://doi.org/10.1074/jbc.M108069200 CrossRefPubMedGoogle Scholar
  64. 64.
    Tabernero J (2007) The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents. Mol Cancer Res 5:203–220.  https://doi.org/10.1158/1541-7786.MCR-06-0404 CrossRefPubMedGoogle Scholar
  65. 65.
    Falchook GS, Naing A, Hong DS, Zinner R, Fu S, Piha-Paul SA, Tsimberidou AM, Morgan-Linnell SK, Jiang Y, Bastida C, Wheler JJ, Kurzrock R (2013) Dual EGFR inhibition in combination with anti-VEGF treatment: a phase I clinical trial in non-small cell lung cancer. Oncotarget 4:118–127.  https://doi.org/10.18632/oncotarget.763 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Malgorzata Banys-Paluchowski
    • 1
  • Isabell Witzel
    • 2
  • Sabine Riethdorf
    • 3
  • Klaus Pantel
    • 3
  • Brigitte Rack
    • 4
  • Wolfgang Janni
    • 4
  • Peter A. Fasching
    • 5
  • Bahriye Aktas
    • 6
  • Sabine Kasimir-Bauer
    • 7
  • Andreas Hartkopf
    • 8
  • Erich-Franz Solomayer
    • 9
  • Tanja Fehm
    • 10
  • Volkmar Müller
    • 2
  1. 1.Department of Gynecology and ObstetricsMarienkrankenhaus HamburgHamburgGermany
  2. 2.Department of GynecologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  3. 3.Department of Tumour BiologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  4. 4.Department of Gynecology and ObstetricsUniversity Hospital UlmUlmGermany
  5. 5.Department of Gynecology and ObstetricsUniversity Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-NurembergErlangenGermany
  6. 6.Department of GynecologyUniversity Hospital LeipzigLeipzigGermany
  7. 7.Department of Obstetrics and Gynecology, University Hospital EssenUniversity of Duisburg-EssenEssenGermany
  8. 8.Department of Obstetrics and Gynecology, University Hospital TübingenUniversity of TübingenTübingenGermany
  9. 9.Department of Gynecology and ObstetricsSaarland University HospitalHomburg/SaarGermany
  10. 10.Department of Obstetrics and GynecologyHeinrich-Heine-University DüsseldorfDüsseldorfGermany

Personalised recommendations