Skip to main content

Advertisement

SpringerLink
Log in

Plasma levels of angiopoietin-2, VEGF-A, and VCAM-1 as markers of bevacizumab-induced hypertension: CALGB 80303 and 90401 (Alliance)

  • Original Paper
  • Published:
Angiogenesis Aims and scope Submit manuscript

Abstract

Hypertension is a common toxicity induced by bevacizumab and other antiangiogenic drugs. There are no biomarkers to predict the risk of bevacizumab-induced hypertension. This study aimed to identify plasma proteins related to the function of the vasculature to predict the risk of severe bevacizumab-induced hypertension. Using pretreated plasma samples from 398 bevacizumab-treated patients in two clinical trials (CALGB 80303 and 90401), the levels of 17 proteins were measured via ELISA. The association between proteins and grade 3 bevacizumab-induced hypertension was performed by calculating the odds ratio (OR) from logistic regression adjusting for age, sex, and clinical trial. Using the optimal cut-point of each protein, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for hypertension were estimated. Five proteins showed no difference in levels between clinical trials and were used for analyses. Lower levels of angiopoietin-2 (p = 0.0013, OR 3.41, 95% CI 1.67–7.55), VEGF-A (p = 0.0008, OR 4.25, 95% CI 1.93–10.72), and VCAM-1 (p = 0.0067, OR 2.68, 95% CI 1.34–5.63) were associated with an increased risk of grade 3 hypertension. The multivariable model suggests independent effects of angiopoietin-2 (p = 0.0111, OR 2.71, 95% CI 1.29–6.10), VEGF-A (p = 0.0051, OR 3.66, 95% CI 1.54–9.73), and VCAM-1 (p = 0.0308, OR 2.27, 95% CI 1.10–4.92). The presence of low levels of 2–3 proteins had an OR of 10.06 (95% CI 3.92–34.18, p = 1.80 × 10–5) for the risk of hypertension, with sensitivity of 89.7%, specificity of 53.5%, PPV of 17.3%, and NPV of 97.9%. This is the first study providing evidence of plasma proteins with potential value to predict patients at risk of developing bevacizumab-induced hypertension.

Clinical trial registration: ClinicalTrials.gov Identifier: NCT00088894 (CALGB 80303); and NCT00110214 (CALGB 90401).

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
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

Data will be made available on reasonable request.

Code availability

Code will be made available on reasonable request.

References

  1. Garcia J, Hurwitz HI, Sandler AB et al (2020) Bevacizumab (Avastin®) in cancer treatment: a review of 15 years of clinical experience and future outlook. Cancer Treat Rev 86:102017

    Article  CAS  PubMed  Google Scholar 

  2. EMA summary of product characteristics (2017). https://www.ema.europa.eu/en/documents/product-information/avastin-epar-product-information_en.pdf. Accessed 05 Oct 2020

  3. FDA AVASTIN®prescribing information (2020). https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125085s332lbl.pdf. Accessed 05 Oct 2020

  4. Quintanilha JCF, Wang J, Sibley AB et al (2020) Bevacizumab-induced hypertension and proteinuria: a genome-wide analysis of more than 1,000 patients. Eur J Cancer 138:S9–S10

    Article  Google Scholar 

  5. Moslehi JJ (2016) Cardiovascular toxic effects of targeted cancer therapies. N Engl J Med 375:1457–1467

    Article  CAS  PubMed  Google Scholar 

  6. Li M, Kroetz DL (2018) Bevacizumab-induced hypertension: clinical presentation and molecular understanding. Pharmacol Ther 182:152–160

    Article  CAS  PubMed  Google Scholar 

  7. Lazarus A, Keshet E (2011) Vascular endothelial growth factor and vascular homeostasis. Proc Am Thorac Soc 8:508–511

    Article  CAS  PubMed  Google Scholar 

  8. Ferroni P, Della-Morte D, Palmirotta R et al (2012) Angiogenesis and hypertension: the dual role of anti-hypertensive and anti-angiogenic therapies. Curr Vasc Pharmacol 10:479–493

    Article  CAS  PubMed  Google Scholar 

  9. Ky B, Putt M, Sawaya H et al (2014) Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab. J Am Coll Cardiol 63:809–816

    Article  CAS  PubMed  Google Scholar 

  10. Putt M, Hahn VS, Januzzi JL et al (2015) Longitudinal changes in multiple biomarkers are associated with cardiotoxicity in breast cancer patients treated with doxorubicin, taxanes, and trastuzumab. Clin Chem 61:1164–1172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Van Boxtel W, Bulten BF, Mavinkurve-Groothuis AMC et al (2015) New biomarkers for early detection of cardiotoxicity after treatment with docetaxel, doxorubicin and cyclophosphamide. Biomarkers 20:143–148

    Article  PubMed  Google Scholar 

  12. Kindler HL, Niedzwiecki D, Hollis D et al (2010) Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: Phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol 28:3617–3622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kelly WK, Halabi S, Carducci M et al (2012) Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol 30:1534–1540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Innocenti F, Owzar K, Cox NL et al (2012) A genome-wide association study of overall survival in pancreatic cancer patients treated with gemcitabine in CALGB 80303. Clin Cancer Res 18:577–584

    Article  CAS  PubMed  Google Scholar 

  15. Hertz DL, Owzar K, Lessans S et al (2016) Pharmacogenetic discovery in CALGB (alliance) 90401 and mechanistic validation of a VAC14 polymorphism that increases risk of docetaxel-induced neuropathy. Clin Cancer Res 22:4890–4900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nixon AB, Pang H, Starr MD et al (2013) Prognostic and predictive blood-based biomarkers in patients with advanced pancreatic cancer: results from CALGB80303 (alliance). Clin Cancer Res 19:6957–6966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Innocenti F, Jiang C, Sibley AB et al (2018) Genetic variation determines VEGF-A plasma levels in cancer patients. Sci Rep 8:16332

    Article  PubMed  PubMed Central  Google Scholar 

  18. Liu Y, Starr MD, Brady JC et al (2014) Modulation of circulating protein biomarkers following TRC105 (anti-endoglin antibody) treatment in patients with advanced cancer. Cancer Med 3:580–591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hatch AJ, Sibley AB, Starr MD et al (2016) Blood-based markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance). Cancer Med 5:2249–2260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Liu Y, Starr MD, Bulusu A et al (2013) Correlation of angiogenic biomarker signatures with clinical outcomes in metastatic colorectal cancer patients receiving capecitabine, oxaliplatin, and bevacizumab. Cancer Med 2:234–342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Barber MJ, Mangravite LM, Hyde CL et al (2010) Genome-wide association of lipid-lowering response to statins in combined study populations. PLoS ONE 5:e9763

    Article  PubMed  PubMed Central  Google Scholar 

  22. Chu AY, Guilianini F, Barrat BJ, Nyberg F, Chasman DI, Ridker PM (2012) Pharmacogenetic determinants of statin-induced reductions in C-reactive protein. Circ Genom Precis Med 5:58–65

    CAS  Google Scholar 

  23. Kwiterovich PO, Virgil DG, Chu AY, Khouzami VA, Alaupovic P, Otvos JD (2013) Interrelationships between the concentration and size of the largest high-density lipoprotein subfraction and apolipoprotein C-I in infants at birth and follow-up at 2–3 months of age and their parents. J Clin Lipidol 7:29–37

    Article  PubMed  Google Scholar 

  24. Etheridge AS, Gallins PJ, Jima D et al (2020) A new liver expression quantitative trait locus map from 1,183 individuals provides evidence for novel expression quantitative trait loci of drug response, metabolic, and sex-biased phenotypes. Clin Pharmacol Ther 107:1383–1393

    Article  CAS  PubMed  Google Scholar 

  25. Innocenti F, Jiang C, Sibley AB et al (2019) An initial genetic analysis of gemcitabine-induced high-grade neutropenia in pancreatic cancer patients in CALGB 80303 (Alliance). Pharmacogenet Genom 29:123–131

    Article  CAS  Google Scholar 

  26. R Core Team (2020) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria

  27. Ferrara N (2005) The role of VEGF in the regulation of physiological and pathological angiogenesis. EXS 64:209–231

    Google Scholar 

  28. Akwii RG, Sajib MS, Zahra FT, Mikelis CM (2019) Role of angiopoietin-2 in vascular physiology and pathophysiology. Cells 8:471

    Article  CAS  PubMed Central  Google Scholar 

  29. Kong DH, Kim YK, Kim MR, Jang JH, Lee S (2018) Emerging roles of vascular cell adhesion molecule-1 (VCAM-1) in immunological disorders and cancer. Int J Mol Sci 19:1057

    Article  PubMed Central  Google Scholar 

  30. Schlingemann RO, Van Hinsbergh VWM (1997) Role of vascular permeability factor/vascular endothelial growth factor in eye disease. Br J Ophthalmol 81:501–512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Möhle R, Green D, Moore MAS, Nachman RL, Rafii S (1997) Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc Natl Acad Sci USA 94:663–668

    Article  PubMed  PubMed Central  Google Scholar 

  32. Verheul HMW, Hoekman K, Luykx-De Bakker S et al (1997) Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res 3:2187–2190

    CAS  PubMed  Google Scholar 

  33. Banks RE, Forbes MA, Kinsey SE et al (1998) Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology. Br J Cancer 77:956–964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gunsilius E, Petzer A, Stockhammer G et al (2000) Thrombocytes are the major source for soluble vascular endothelial growth factor in peripheral blood. Oncology 58:169–174

    Article  CAS  PubMed  Google Scholar 

  35. Webb NJA, Myers CR, Watson CJ, Bottomley MJ, Brenchley PEC (1998) Activated human neutrophils express vascular endothelial growth factor (VEGF). Cytokine 10:254–257

    Article  CAS  PubMed  Google Scholar 

  36. Bocci G, Man S, Green SK et al (2004) Increased plasma vascular endothelial growth factor (VEGF) as a surrogate marker for optimal therapeutic dosing of VEGF receptor-2 monoclonal antibodies. Cancer Res 64:6616–6625

    Article  CAS  PubMed  Google Scholar 

  37. Schmitz V, Vilanueva H, Raskopf E et al (2006) Increased VEGF levels induced by anti-VEGF treatment are independent of tumor burden in colorectal carcinomas in mice. Gene Ther 13:1198–1205

    Article  CAS  PubMed  Google Scholar 

  38. Eun SL, Oh MJ, Jae WJ et al (2007) The levels of circulating vascular endothelial growth factor and soluble Flt-1 in pregnancies complicated by preeclampsia. J Korean Med Sci 22:94–98

    Article  Google Scholar 

  39. Blann AD (2003) How a damaged blood vessel wall contibutes to thrombosis and hypertension. Pathophysiol Haemost Thromb 33:445–448

    Article  PubMed  Google Scholar 

  40. Henry TD, Rocha-Singh K, Isner JM et al (2001) Intracoronary administration of recombinant human vascular endothelial growth factor to patients with coronary artery disease. Am Heart J 142:878–880

    Article  Google Scholar 

  41. Lobov IB, Brooks PC, Lang RA (2002) Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci USA 99:11205–11210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kim I, Moon SO, Kim SH, Kim HJ, Koh YS, Koh GY (2001) Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear Factor-κB activation in endothelial cells. J Biol Chem 276:7614–7660

    Article  CAS  PubMed  Google Scholar 

  43. Belgore FM, Blann AD, Li-Saw-Hee FL, Beevers DG, Lip GYH (2001) Plasma levels of vascular endothelial growth factor and its soluble receptor (SFlt-1) in essential hypertension. Am J Cardiol 87:805–807

    Article  CAS  PubMed  Google Scholar 

  44. David S, Kümpers P, Lukasz A, Kielstein JT, Haller H, Fliser D (2009) Circulating angiopoietin-2 in essential hypertension: relation to atherosclerosis, vascular inflammation, and treatment with olmesartan/ pravastatin. J Hypertens 27:1641–1647

    Article  CAS  PubMed  Google Scholar 

  45. Palomo I, Marín P, Alarcón M et al (2003) Patients with essential hypertension present higher levels of sE-selectin and sVCAM-1 than normotensive volunteers. Clin Exp Hypertens 25:517–523

    Article  CAS  PubMed  Google Scholar 

  46. Desouza CA, Dengel DR, Macko RF, Cox K, Seals DR (1997) Elevated levels of circulating cell adhesion molecules in uncomplicated essential hypertension. Am J Hypertens 10:1335–1341

    Article  CAS  PubMed  Google Scholar 

  47. Nadar SK, Blann A, Beevers DG, Lip GYH (2005) Abnormal angiopoietins 1&2, angiopoietin receptor Tie-2 and vascular endothelial growth factor levels in hypertension: relationship to target organ damage [a sub-study of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)]. J Intern Med 258:336–343

    Article  CAS  PubMed  Google Scholar 

  48. Tsai WC, Li YH, Huang YY et al (2005) Plasma vascular endothelial growth factor as a marker for early vascular damage in hypertension. Clin Sci 109:39–43

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821, and U24CA196171 (to the Alliance for Clinical Trials in Oncology), UG1CA233253, UG1CA233327, UG1CA233337, and UG1CA233373 (https://acknowledgments.alliancefound.org). Also supported in part by funds from Abraxis BioScience, Bristol Meyers Squibb, Celgene, and Genentech. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations

  1. UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Genetic Medicine Bldg. 120 Mason Farm Rd, Campus Box 7361, Chapel Hill, NC, 27599-7361, USA

    Julia C. F. Quintanilha, Amy S. Etheridge, Akram Yazdani & Federico Innocenti

  2. Duke University School of Medicine, Duke University, Durham, NC, USA

    Yingmiao Liu & Andrew B. Nixon

  3. Department of Medicine, University of Chicago, Chicago, IL, USA

    Hedy L. Kindler

  4. Department of Medical Oncology, Yale School of Medicine, New Haven, CT, USA

    William Kevin Kelly

Authors
  1. Julia C. F. Quintanilha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yingmiao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amy S. Etheridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akram Yazdani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hedy L. Kindler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. William Kevin Kelly
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Andrew B. Nixon
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Federico Innocenti
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: FI; methodology: JCFQ, AY, and FI; formal analysis and investigation: JCFQ, YL, ASE, AY, HLK, WKK, ABN, and FI; writing—original draft preparation: JCFQ; writing—review and editing: JCFQ, YL, ASE, AY, HLK, WKK, ABN, and FI; funding acquisition: FI; resources: ABN and FI; supervision: FI.

Corresponding author

Correspondence to Federico Innocenti.

Ethics declarations

Conflict of interest

JCFQ and FI are coinventors of a patent application, serial number 16/932,002. FI is an advisor for Emerald Lake Safety. These relationships have been disclosed to and are under management by UNC-Chapel Hill.

Ethical approval

All trials were conducted in accordance with recognized ethical guidelines. The study was performed in accordance with the Declaration of Helsinki and was approved by the local IRB.

Consent to participate

All participants provided written informed consent for sample collection and analysis.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 166 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Quintanilha, J.C.F., Liu, Y., Etheridge, A.S. et al. Plasma levels of angiopoietin-2, VEGF-A, and VCAM-1 as markers of bevacizumab-induced hypertension: CALGB 80303 and 90401 (Alliance). Angiogenesis 25, 47–55 (2022). https://doi.org/10.1007/s10456-021-09799-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10456-021-09799-1

Keywords

Search

Navigation