Cancer Res Treat.  2022 Oct;54(4):1053-1064. 10.4143/crt.2021.748.

Clinical Significance of Major Angiogenesis-Related Effectors in Patients with Metastatic Breast Cancer Treated with Trastuzumab-Based Regimens

• Kourea HP
• Dimitrakopoulos FI
• Koliou GA
• Batistatou A
• Papadopoulou K
• Bobos M
• Asimaki-Vlachopoulou A
• Chrisafi S
• Pavlakis K
• Chatzopoulos K
• Galani E
• Pentheroudakis G
• Pectasides D
• Bafaloukos D
• Res E
• Papakostas P
• Koutras A
• Kotoula V
• Fountzilas G

• KMID: 2534184
• DOI: http://doi.org/10.4143/crt.2021.748

Abstract

Purpose
Angiogenesis is a crucial phenomenon in the development and progression of breast cancer (BC), but the clinical significance of angiogenesis-related proteins in metastatic BC remains unknown. This study investigates the prognostic value of vascular endothelial growth factor receptors 1, 2, 3 (VEGFR1, VEGFR2, VEGFR3) as well as vascular endothelial growth factors A and C (VEGFA and VEGFC) in metastatic BC patients treated with trastuzumab-based regimens.
Materials and Methods
Two hundred female patients were included. Protein and mRNA expression of the studied angiogenesis-related factors were evaluated by immunohistochemistry and quantitative polymerase chain reaction, respectively.
Results
High expression of VEGFA, VEGFC, VEGFR1, VEGFR2, and VEGFR3 in the tumor cells was observed in 43.5%, 24.2%, 36%, 29.5%, and 43%, respectively. Stromal elements expressed high levels of VEGFA, VEGFC, VEGFR1, VEGFR2, and VEGFR3 in 78.9%, 93.3%, 90.7%, 90.2%, and 74.8% of tumors with available data. High tumor cell expression of VEGFR1 was a favorable prognosticator for survival among patients with human epidermal growth factor receptor 2 (HER2)–positive tumors (hazard ratio [HR], 0.55; p=0.013). A trend towards longer progression-free survival was detected univariately for patients with HER2-negative tumors and high expression of VEGFR2 (HR, 0.60; p=0.059).
Conclusion
VEGFR1 and VEGFR2 seem to have significant prognostic value in BC patients with metastatic disease treated with trastuzumab-based regimens.

Keyword

Breast neoplasms; HER2; Vascular endothelial growth factor A; VEGFR; Angiogenesis; Prognosis

Figure

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  Fig. 1 Kaplan-Meier curves with respect to survival based on tumor cell expression of VEGFR1 in patients with HER2-positive tumors (A) and PFS based on tumor cell VEGFR2 expression in patients with HER2-negative disease (B). CI, confidence interval; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; PFS, progression-free survival; VEGFR, vascular endothelial growth factor receptor.

Reference

References

1. Momenimovahed Z, Salehiniya H. Epidemiological characteristics of and risk factors for breast cancer in the world. Breast Cancer (Dove Med Press). 2019; 11:151–64.

2. Harbeck N, Penault-Llorca F, Cortes J, Gnant M, Houssami N, Poortmans P, et al. Breast cancer. Nat Rev Dis Primers. 2019; 5:66.

3. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987; 235:177–82.

4. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001; 344:783–92.

5. Madu CO, Wang S, Madu CO, Lu Y. Angiogenesis in breast cancer progression, diagnosis, and treatment. J Cancer. 2020; 11:4474–94.

6. Alameddine RS, Otrock ZK, Awada A, Shamseddine A. Crosstalk between HER2 signaling and angiogenesis in breast cancer: molecular basis, clinical applications and challenges. Curr Opin Oncol. 2013; 25:313–24.

7. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013; 310:2191–4.

8. Linardou H, Kalogeras KT, Kronenwett R, Alexopoulou Z, Wirtz RM, Zagouri F, et al. Prognostic significance of VEGFC and VEGFR1 mRNA expression according to HER2 status in breast cancer: a study of primary tumors from patients with high-risk early breast cancer participating in a randomized Hellenic Cooperative Oncology Group Trial. Anticancer Res. 2015; 35:4023–36.

9. Fountzilas G, Kourea HP, Bobos M, Televantou D, Kotoula V, Papadimitriou C, et al. Paclitaxel and bevacizumab as first line combined treatment in patients with metastatic breast cancer: the Hellenic Cooperative Oncology Group experience with biological marker evaluation. Anticancer Res. 2011; 31:3007–18.

10. Gogas H, Kotoula V, Alexopoulou Z, Christodoulou C, Kostopoulos I, Bobos M, et al. MYC copy gain, chromosomal instability and PI3K activation as potential markers of unfavourable outcome in trastuzumab-treated patients with metastatic breast cancer. J Transl Med. 2016; 14:136.

11. Hennig G, Gehrmann M, Stropp U, Brauch H, Fritz P, Eichelbaum M, et al. Automated extraction of DNA and RNA from a single formalin-fixed paraffin-embedded tissue section for analysis of both single-nucleotide polymorphisms and mRNA expression. Clin Chem. 2010; 56:1845–53.

12. Lebok P, Huber J, Burandt EC, Lebeau A, Marx AH, Terracciano L, et al. Loss of membranous VEGFR1 expression is associated with an adverse phenotype and shortened survival in breast cancer. Mol Med Rep. 2016; 14:1443–50.

13. Ghosh S, Sullivan CA, Zerkowski MP, Molinaro AM, Rimm DL, Camp RL, et al. 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. 2008; 39:1835–43.

14. Kosaka Y, Kataoka A, Yamaguchi H, Ueo H, Akiyoshi S, Sengoku N, et al. Vascular endothelial growth factor receptor-1 mRNA overexpression in peripheral blood as a useful prognostic marker in breast cancer. Breast Cancer Res. 2012; 14:R140.

15. Ning Q, Liu C, Hou L, Meng M, Zhang X, Luo M, et al. Vascular endothelial growth factor receptor-1 activation promotes migration and invasion of breast cancer cells through epithelial-mesenchymal transition. PLoS One. 2013; 8:e65217.

16. Aldridge SE, Lennard TW, Williams JR, Birch MA. Vascular endothelial growth factor acts as an osteolytic factor in breast cancer metastases to bone. Br J Cancer. 2005; 92:1531–7.

17. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005; 438:820–7.

18. Sadremomtaz A, Mansouri K, Alemzadeh G, Safa M, Rastaghi AE, Asghari SM. Dual blockade of VEGFR1 and VEGFR2 by a novel peptide abrogates VEGF-driven angiogenesis, tumor growth, and metastasis through PI3K/AKT and MAPK/ERK1/2 pathway. Biochim Biophys Acta Gen Subj. 2018; 1862:2688–700.

19. Goussia A, Simou N, Zagouri F, Manousou K, Lazaridis G, Gogas H, et al. Associations of angiogenesis-related proteins with specific prognostic factors, breast cancer subtypes and survival outcome in early-stage breast cancer patients: a Hellenic Cooperative Oncology Group (HeCOG) trial. PLoS One. 2018; 13:e0200302.

20. Esteva FJ, Hubbard-Lucey VM, Tang J, Pusztai L. Immunotherapy and targeted therapy combinations in metastatic breast cancer. Lancet Oncol. 2019; 20:e175–86.

21. Kodack DP, Chung E, Yamashita H, Incio J, Duyverman AM, Song Y, et al. Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases. Proc Natl Acad Sci U S A. 2012; 109:E3119–27.

22. Yan JD, Liu Y, Zhang ZY, Liu GY, Xu JH, Liu LY, et al. Expression and prognostic significance of VEGFR-2 in breast cancer. Pathol Res Pract. 2015; 211:539–43.

23. Koutras A, Lazaridis G, Koliou GA, Kouvatseas G, Christodoulou C, Pectasides D, et al. Evaluation of the prognostic value of all four HER family receptors in patients with metastatic breast cancer treated with trastuzumab: a Hellenic Cooperative Oncology Group (HeCOG) study. PLoS One. 2018; 13:e0207707.

24. Paik S, Bryant J, Tan-Chiu E, Romond E, Hiller W, Park K, et al. Real-world performance of HER2 testing: National Surgical Adjuvant Breast and Bowel Project experience. J Natl Cancer Inst. 2002; 94:852–4.

25. Roche PC, Suman VJ, Jenkins RB, Davidson NE, Martino S, Kaufman PA, et al. Concordance between local and central laboratory HER2 testing in the breast intergroup trial N9831. J Natl Cancer Inst. 2002; 94:855–7.

26. Griggs JJ, Hamilton AS, Schwartz KL, Zhao W, Abrahamse PH, Thomas DG, et al. Discordance between original and central laboratories in ER and HER2 results in a diverse, population-based sample. Breast Cancer Res Treat. 2017; 161:375–84.

27. Kaufman PA, Bloom KJ, Burris H, Gralow JR, Mayer M, Pegram M, et al. Assessing the discordance rate between local and central HER2 testing in women with locally determined HER2-negative breast cancer. Cancer. 2014; 120:2657–64.