Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

Angiogenesis-related protein expression in bevacizumab-treated metastatic colorectal cancer: NOTCH1 detrimental to overall survival

Authors: Tadeu Ferreira Paiva Jr., Victor Hugo Fonseca de Jesus, Raul Amorim Marques, Alexandre André Balieiro Anastácio da Costa, Mariana Petaccia de Macedo, Patricia Maria Peresi, Aline Damascena, Benedito Mauro Rossi, Maria Dirlei Begnami, Vladmir Cláudio Cordeiro de Lima

Published in: BMC Cancer | Issue 1/2015

Login to get access

Abstract

Background

The development of targeted therapies has undoubtedly broadened therapeutic options for patients with colorectal cancer (CRC). The use of bevacizumab to reduce angiogenesis has been associated with improved clinical outcomes. However, an urgent need for prognostic/predictive biomarkers for anti-angiogenic therapies still exists.

Methods

Clinical data of 105 CRC patients treated with bevacizumab in conjunction with chemotherapy were analyzed. The expression of vascular endothelial growth factor (VEGF) receptors, NOTCH1 receptor and its ligand DLL4 were determined by immunohistochemistry. Tumor samples were arranged on a tissue microarray. The association between protein expression and clinicopathological characteristics and outcomes was determined.

Results

Bevacizumab was administered as a first-line of treatment in 70.5 % of our cases. The median progression-free survival (PFS) was 10.2 months. The median overall survival (OS) of the total cohort was 24.4 months. Bevacizumab, as the first-line of treatment, and the presence of liver metastasis were independently associated with objective response rate. Membrane VEGFR1 and VEGFR3 expressions were associated with the presence of lung metastasis; interestingly, VEGFR3 was associated with less liver metastasis. NOTCH1 expression was associated with lymph node metastasis. There was a trend toward association between improved PFS and lower NOTCH1 expression (p = 0.06). Improved OS was significantly associated with lower NOTCH1 expression (p = 0.01). In a multivariate analysis, ECOG (Eastern Cooperative Oncology Group) performance status, liver metastasis, histological grade, and NOTCH1 expression were independently associated with OS.

Conclusion

Our findings illustrated the expression profile of angiogenesis-related proteins and their association with clinicopathological characteristics and outcomes. NOTCH1 expression is a detrimental prognostic factor in metastatic CRC patients treated with chemotherapy plus bevacizumab.
Appendix
Available only for authorised users
Literature
1.
Ferlay JSI, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://​globocan.​iarc.​fr, accessed on 08/04/2014.
2.
Van Cutsem E, Oliveira J, Group EGW. Advanced colorectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Annals of oncology : official journal of the European Society for Medical Oncology/ESMO. 2009;20 Suppl 4:61–3.
3.
4.
5.
Ranganathan P, Weaver KL, Capobianco AJ. Notch signalling in solid tumours: a little bit of everything but not all the time. Nat Rev Cancer. 2011;11:338–51.CrossRefPubMed
6.
7.
Li JL, Sainson RC, Oon CE, Turley H, Leek R, Sheldon H, et al. DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo. Cancer Res. 2011;71(18):6073–83.CrossRefPubMed
8.
Temraz S, Mukherji D, Shamseddine A. Sequencing of treatment in metastatic colorectal cancer: Where to fit the target. World journal of gastroenterology: WJG. 2014;20(8):1993–2004.CrossRefPubMedPubMedCentral
9.
Gerber HP, Ferrara N. Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res. 2005;65(3):671–80.PubMed
10.
Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008;26(12):2013–9.CrossRef
11.
Hurwitz HI, Fehrenbacher L, Hainsworth JD, Heim W, Berlin J, Holmgren E, et al. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2005;23(15):3502–8.CrossRef
12.
Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007;25(12):1539–44.CrossRef
13.
Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2003;21(1):60–5.CrossRef
14.
Politano S, Overman M, Pathak P, Chadha R, Glover K, Chang DZ, et al. Second-line chemotherapy use in metastatic colon cancer varies by disease responsiveness. Clin Colorectal Cancer. 2008;7(1):55–9.CrossRefPubMed
15.
Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van Cutsem E, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14(1):29–37.CrossRefPubMed
16.
Ellis LM, Hicklin DJ. Pathways mediating resistance to vascular endothelial growth factor-targeted therapy. Clinical cancer research: an official journal of the American Association for Cancer Research. 2008;14(20):6371–5.CrossRef
17.
Zhang Y, Li B, Ji ZZ, Zheng PS. Notch1 regulates the growth of human colon cancers. Cancer. 2010;116(22):5207–18.CrossRefPubMed
18.
Jubb AM, Harris AL. Biomarkers to predict the clinical efficacy of bevacizumab in cancer. Lancet Oncol. 2010;11(12):1172–83.CrossRefPubMed
19.
Edge S, Byrd, D.R., Compton, C.C., Fritz, A.G., Greene, F.L., Trotti, A. AJCC (American Joint Committee on Cancer) Cancer Staging Manual. 7th ed. ed2010.
20.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.CrossRefPubMed
21.
22.
Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007;25(30):4779–86.CrossRef
23.
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42.CrossRefPubMed
24.
Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2008;26(21):3523–9.CrossRef
25.
Fourrier-Reglat A, Smith D, Rouyer M, Benichou J, Guimbaud R, Becouarn Y, et al. Survival outcomes of bevacizumab in first-line metastatic colorectal cancer in a real-life setting: results of the ETNA cohort. Target Oncol. 2013;9(4):311–9.CrossRefPubMed
26.
Gampenrieder SP, Romeder F, Muss C, Pircher M, Ressler S, Rinnerthaler G, et al. Hypertension as a predictive marker for bevacizumab in metastatic breast cancer: results from a retrospective matched-pair analysis. Anticancer Res. 2014;34(1):227–33.PubMed
27.
Cai J, Ma H, Huang F, Zhu D, Bi J, Ke Y, et al. Correlation of bevacizumab-induced hypertension and outcomes of metastatic colorectal cancer patients treated with bevacizumab: a systematic review and meta-analysis. World J Surg Oncol. 2013;11:306.CrossRefPubMedPubMedCentral
28.
Escalante CP, Zalpour A. Vascular endothelial growth factor inhibitor-induced hypertension: basics for primary care providers. Cardiol Res Pract. 2011;2011:816897.PubMedPubMedCentral
29.
Meyerhardt JA, Li L, Sanoff HK, Carpenter W, Schrag D. Effectiveness of bevacizumab with first-line combination chemotherapy for Medicare patients with stage IV colorectal cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2012;30(6):608–15.CrossRef
30.
Selcukbiricik F, Erdamar S, Ozkurt CU, Molinas Mandel N, Demirelli F, Ozguroglu M, et al. The role of K-RAS and B-RAF mutations as biomarkers in metastatic colorectal cancer. Journal of BUON : official journal of the Balkan Union of Oncology. 2013;18(1):116–23.
31.
Jubb AM, Hurwitz HI, Bai W, Holmgren EB, Tobin P, Guerrero AS, et al. Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006;24(2):217–27.CrossRef
32.
Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med. 2001;7(5):575–83.CrossRefPubMed
33.
Outtz HH, Wu JK, Wang X, Kitajewski J. Notch1 deficiency results in decreased inflammation during wound healing and regulates vascular endothelial growth factor receptor-1 and inflammatory cytokine expression in macrophages. J Immunol. 2010;185(7):4363–73.CrossRefPubMed
34.
Funahashi Y, Shawber CJ, Vorontchikhina M, Sharma A, Outtz HH, Kitajewski J. Notch regulates the angiogenic response via induction of VEGFR-1. J Angiogenes Res. 2010;2(1):3.CrossRefPubMedPubMedCentral
35.
Taylor KL, Henderson AM, Hughes CC. Notch activation during endothelial cell network formation in vitro targets the basic HLH transcription factor HESR-1 and downregulates VEGFR-2/KDR expression. Microvasc Res. 2002;64(3):372–83.CrossRefPubMed
36.
Willett CG, Duda DG, di Tomaso E, Boucher Y, Ancukiewicz M, Sahani DV, et al. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009;27(18):3020–6.CrossRef
37.
Bagley RG, Ren Y, Weber W, Yao M, Kurtzberg L, Pinckney J, et al. Placental growth factor upregulation is a host response to antiangiogenic therapy. Clinical cancer research : an official journal of the American Association for Cancer Research. 2011;17(5):976–88.CrossRef
38.
Batchelor TT, Duda DG, di Tomaso E, Ancukiewicz M, Plotkin SR, Gerstner E, et al. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28(17):2817–23.CrossRef
39.
Lambrechts D, Lenz HJ, de Haas S, Carmeliet P, Scherer SJ. Markers of response for the antiangiogenic agent bevacizumab. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013;31(9):1219–30.CrossRef
40.
Jayasinghe C, Simiantonaki N, Michel-Schmidt R, Kirkpatrick CJ. Endothelial VEGFR-3 expression in colorectal carcinomas is associated with hematogenous metastasis. Oncol Rep. 2009;22(5):1093–100.CrossRefPubMed
41.
Martins SF, Garcia EA, Luz MA, Pardal F, Rodrigues M, Filho AL. Clinicopathological correlation and prognostic significance of VEGF-A, VEGF-C, VEGFR-2 and VEGFR-3 expression in colorectal cancer. Cancer Genomics Proteomics. 2013;10(2):55–67.PubMed
42.
Chu D, Li Y, Wang W, Zhao Q, Li J, Lu Y, et al. High level of Notch1 protein is associated with poor overall survival in colorectal cancer. Ann Surg Oncol. 2010;17(5):1337–42.CrossRefPubMed
43.
Park HS, Jung CK, Lee SH, Chae BJ, Lim DJ, Park WC, et al. Notch1 receptor as a marker of lymph node metastases in papillary thyroid cancer. Cancer Sci. 2012;103(2):305–9.CrossRefPubMed
44.
Yildiz R, Coskun U, Baglan T, Buyukberber S, Uner A, Erdem O, et al. The relation between endoglin (CD105), thrombospondin-1 and VEGFR-3 and treatment results in metastatic colorectal cancer patients treated with Bevacizumab combination therapy. Ann Oncol. 2010;21 Suppl 8:A685. Presented at Colorectal Cancer Symposium of the 35th ESMO Congress Milan, Italy 8–12 October 2010.
45.
Shawber CJ, Funahashi Y, Francisco E, Vorontchikhina M, Kitamura Y, Stowell SA, et al. Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression. J Clin Invest. 2007;117(11):3369–82.CrossRefPubMedPubMedCentral
46.
Chu D, Zhang Z, Zhou Y, Wang W, Li Y, Zhang H, et al. Notch1 and Notch2 have opposite prognostic effects on patients with colorectal cancer. Ann Oncol. 2011;22:2440–7.CrossRefPubMed
47.
Chu D, Zhou Y, Zhang Z, Li Y, Zheng J, Zhang H, et al. Notch1 expression, which is related to p65 Status, is an independent predictor of prognosis in colorectal cancer. Clin Cancer Res. 2011;17(17):5686–94.CrossRefPubMed
Metadata
Title
Angiogenesis-related protein expression in bevacizumab-treated metastatic colorectal cancer: NOTCH1 detrimental to overall survival
Authors
Tadeu Ferreira Paiva Jr.
Victor Hugo Fonseca de Jesus
Raul Amorim Marques
Alexandre André Balieiro Anastácio da Costa
Mariana Petaccia de Macedo
Patricia Maria Peresi
Aline Damascena
Benedito Mauro Rossi
Maria Dirlei Begnami
Vladmir Cláudio Cordeiro de Lima
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1648-4

Other articles of this Issue 1/2015

BMC Cancer 1/2015 Go to the issue

Research article

BRCA1 Alternative splicing landscape in breast tissue samples

Research article

Cancers of unknown primary origin (CUP) are characterized by chromosomal instability (CIN) compared to metastasis of know origin

Research article

Epithelial ovarian cancer stem-like cells expressing α-gal epitopes increase the immunogenicity of tumor associated antigens

Research article

The leukemia inhibitory factor (LIF) and p21 mediate the TGFβ tumor suppressive effects in human cutaneous melanoma

Research article

Polymorphisms and plasma levels of IL-27: impact on genetic susceptibility and clinical outcome of bladder cancer

Research article

Outcome of vulvar reconstruction in patients with advanced and recurrent vulvar malignancies
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits