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The Role of VEGF in Breast Cancer

Slide kit provided by ResearchVEGF.com, an online resource sponsored by Genentech BioOncology

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Angiogenesis and the VEGF ligand in cancer

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Overview

Angiogenesis (the formation of new blood vessels from existing ones) is an important process in the growth of malignant tumors1,2

An association between VEGF and angiogenesis, malignancy, and metastasis has been established1,2

Many pro- and anti-angiogenic cellular factors regulate angiogenesis1,2

Research thus far suggests that VEGF is a potent and predominant factor in this process1,2

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References: 1. Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027. 2. Ferrara N. Endocr Rev. 2004;25:581-611.

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Several critical mechanisms are involved in tumor growth

Reference: 1. Hanahan D, Weinberg RA. Cell. 2000;100:57-70.

Reprinted from Hanahan D, Weinberg RA, “The Hallmarks of Cancer,” in Cell, 2000;100:57-70, with permission from Elsevier.

Angiogenesis is 1 of the 6 acquired cellular capabilities leading to malignant growth1

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VEGF is a potent and predominant factor in the angiogenic process

Many pro- and anti-angiogenic cellular factors regulate angiogenesis

Growth factors involved in tumor angiogenesis include

— Vascular endothelial growth factor (VEGF)

— Basic fibroblast growth factor (bFGF)

— Endostatin

— Platelet-derived growth factor (PDGF)

Endothelial cell survival in newly formed vessels is VEGF-dependent

The VEGF ligand is the most potent direct-acting angiogenic protein known

— VEGF is relatively unique among growth factors due to its specificity for the vascular endothelium

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The VEGF ligand: at the center of the angiogenic pathway

The VEGF ligand:

• Stimulates vascular endothelial cell growth, survival, and proliferation1,2

• A genetically stable protein2-5

• Continuously expressed throughout the entire tumor life cycle6

• Direct and continuous VEGF inhibition is an important antitumor strategy

References: 1. Ferrara N. Endocr Rev. 2004;25:581-611. 2. Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027. 3. Bergers G, Benjamin LE. Nat Rev Cancer. 2003;3:401-410. 4. O’Dwyer PJ. Oncologist. 2006;11:992-998. 5. Mukhopadhyay D, Datta K. Semin Cancer Biol. 2004;14:123-130. 6. Folkman J. In: Devita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. Vol 2. 7th ed. Philadelphia, PA: Lippincott Williams & Wiklins; 2005:2865-2882.

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The VEGF ligand in breast cancer

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VEGF ligand expression is an important factor in breast cancer

“Angiogenesis, the process of new blood vessel formation, plays a central role in both local tumor growth and distant metastasis in breast cancer.”

— Schneider and Miller. J Clin Oncol, 2005.1

“[VEGF], a potent angiogenic factor, has been reported to be associated with a poor prognosis in primary breast cancer.…”

— Foekens et al. Cancer Res, 2001.2

References: 1. Schneider BP, Miller KD. J Clin Oncol. 2005;23:1782-1790. 2. Foekens JA, Peters HA, Grebenchtchikov N, et al. Cancer Res. 2001;61:5407-5414.

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The VEGF ligand is a key mediator of breast tumor angiogenesis

Relf et al: VEGF is one of the most important mediators of tumor angiogenesis in breast cancer1

— Of known pro-angiogenic factors measured, only VEGF was correlated with poor relapse-free survival

Reference: 1. Relf M, LeJeune S, Scott PA, et al. Cancer Res. 1997;57:963-969.

Reprinted with permission from the American Association for Cancer Research. Relf M, LeJeune S, Scott PA, et al. Cancer Res. 1997;57:963-969.

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The VEGF ligand is overexpressed in breast tumor tissue

Yoshiji et al: VEGF overexpressed in breast tumor tissue compared with surrounding normal tissue1

Reference: 1. Yoshiji H, Gomez DE, Shibuya M, Thorgeirsson UP. Cancer Res. 1996;56:2013-2016.

Reprinted with permission from the American Association for Cancer Research. Yoshiji H, Gomez DE, Shibuya M, Thorgeirsson UP. Cancer Res. 1996;56:2013-2016.

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The VEGF ligand is significant throughout breast tumor development

Reference: 1. Folkman J. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. Vol 2. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:2865-2882.

VEGF appears to be the only pro-angiogenic factor expressed throughout the breast tumor life cycle1

— The clinical significance of this finding is unknown

Adapted from Folkman 2005.

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VEGF ligand expression is ubiquitous in multiple forms of breast cancer

VEGF overexpression is observed across multiple forms of breast cancer1-5

Additional studies support a correlation between VEGF and breast cancer6,7

Inflammatory breast cancer is highly angiogenic8

— VEGF-C and VEGF-D are overexpressed in inflammatory breast cancer

References: 1. Foekens JA, Peters HA, Grebenchtchikov N, et al. Cancer Res. 2001;61:5407-5414. 2. Gasparini G, Toi M, Gion M, et al. J Natl Cancer Inst. 1997;89:139-147. 3. Konecny GE, Meng YG, Untch M, et al. Clin Cancer Res. 2004;10:1706-1716. 4. Linderholm B, Grankvist K, Wilking N, et al. J Clin Oncol. 2000;18:1423-1431. 5. Gasparini G, Toi M, Miceli R, et al. Cancer J Sci Am. 1999;5:101-111. 6. Brown LF, Berse B, Jackman RW, et al. Hum Pathol. 1995;26:86-91. 7. Jacobs EJ, Feigelson HS, Bain EB, et al. Breast Cancer Res. 2006;8:R22. 8. Van der Auwera I, Van Laere SJ, Van Den Eynden GG, et al. Clin Cancer Res. 2004;10:7965-7971.

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Effects of VEGF in breast cancerbeyond angiogenesis

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VEGF ligand may be involved in autocrine signaling pathways

The role of VEGF in breast cancer may extend beyond angiogenesis1,2

Breast cancer cells have been shown to express both VEGF and VEGF receptors1

Several possible mechanisms may be responsible for autocrine VEGF signaling in breast cancer1

References: 1. Mercurio AM, Lipscomb EA, Bachelder RE. J Mammary Gland Biol Neoplasia. 2005;10:283-290. 2. Weigand M, Hantel P, Kreienberg R, Waltenberger J. Angiogenesis. 2005;8:197-204.

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Prevalence of VEGFin breast cancer

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The VEGF ligand is overexpressed in the majority of breast tumors

Variable Positive for VEGF165-206 Positive for VEGF121-206

Overall 74% (453/611) 59% (359/611)

HER-2/neuNegativePositive

71% (353/497)88% (100/114)

55% (271/497)77% (88/114)

Lymph nodesNegativePositive

72% (210/290)75% (233/310)

53% (155/290)63% (196/310)

Hormone-receptor statusNegativePositive

80% (109/137)72% (343/474)

73% (100/137)55% (259/474)

HistologyInvasive ductalInvasive lobular

78% (432/554)22% (8/37)

61% (340/554)19% (7/37)

Reprinted from Clin Cancer Res, Vol. 10, Konecny GE, Meng YG, Untch M, et al, 1706-1716, 2004, with permission from the American Association for Cancer Research.

In a study of 611 patients, the majority of breast tumors expressed VEGF1

Reference: 1. Konecny GE, Meng YG, Untch M, et al. Clin Cancer Res. 2004;10:1706-1716.

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VEGF and metastasisin breast cancer

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VEGF ligand and microvessel density are associated with increased metastasis in breast cancer

Angiogenesis has been directly assessed by measuring microvessel density (new blood vessels per microscopic field)1

Microvessel count and density have been associated with breast cancer metastases1,2

References: 1. Weidner N, Semple JP, Welch WR, Folkman J. N Engl J Med. 1991;324:1-8. 2. Toi M, Inada K, Suzuki H, Tominaga T. Breast Cancer Res Treat. 1995;36:193-204.

Weidner N, Semple JP, Welch WR, Folkman J. N Engl J Med. 1991;324:1-8, Copyright © 1991 Massachusetts Medical Society.

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VEGF may be involved in breast cancer bone metastasis

VEGF may be involved in breast cancer metastasis to bone1

— Aldridge et al showed that VEGF stimulated monocyte differentiation into bone-resorbing osteoclast-like cells

Reference: 1. Aldridge SE, Lennard TW, Williams JR, Birch MA. Br J Cancer. 2005;92:1531-1537.

Adapted by permission from Macmillan Publishers Ltd: Br J Cancer. 2005;92:1531-1537. © 2005.

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VEGF as a prognostic and predictive factor in breast cancer

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The VEGF ligand is correlated with poor survival in breast cancer

Gasparini G, Toi M, Gion M, et al. Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer Inst. 1997;89(2):139-147. Adapted by permission of Oxford University Press.

Reference: 1. Gasparini G, Toi M, Gion M, et al. J Natl Cancer Inst. 1997;89:139-147.

VEGF expression negatively correlates with relapse-free and overall survival1

Large prospective clinical studies are needed to better clarify the prognostic role of VEGF in breast cancer

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The VEGF ligand and microvessel density are associated with poor prognosis in breast cancer

VEGF expression correlates with microvessel density in breast cancer1,2

Adapted from Toi 1995. Reproduced with permission from Breast Cancer Research and Treatment.

Guidi AJ, Berry DA, Broadwater G, et al. Association of angiogenesis in lymph node metastases with outcome of breast cancer. J Natl Cancer Inst. 2000;92(6):486-492. Adapted by permission of Oxford University Press.

References: 1. Toi M, Inada K, Suzuki H, Tominaga T. Breast Cancer Res Treat. 1995;36:193-204. 2. Guidi AJ, Schnitt SJ, Fischer L, et al. Cancer. 1997;80:1945-1953. 3. Guidi AJ, Berry DA, Broadwater G, et al. J Natl Cancer Inst. 2000;92:486-492.

Presence of microvascular “hot spots” is associated with poor disease-free and overall survival3

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The VEGF ligand may predict response to systemic therapy

A large clinical study has demonstrated that VEGF expression is correlated with poor response to systemic therapy1

— Tamoxifen (top image) or chemotherapy (lower image)

Preclinical data indicate that VEGF may contribute to hormone therapy resistance and tumor progression2

In tumor cell lines, antihormones have been shown to induce VEGF expression3

References: 1. Foekens JA, Peters HA, Grebenchtchikov N, et al. Cancer Res. 2001;61:5407-5414. 2. Liang Y, Brekken RA, Hyder SM. Endocr Rel Cancer. 2006;13:905-919. 3. Hyder SM. Endocr Rel Cancer. 2006;13:667-687.

Reprinted with permission from the American Association for Cancer Research. Foekens JA, Peters HA, Grebenchtchikov N, et al. Cancer Res. 2001;61:5407-5414.

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The VEGF ligand and other common breast cancer tumor markers

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VEGF, estrogen, and estrogen receptor interactions in breast cancer

VEGF may be regulated by hormones through autocrine and paracrine mechanisms1

Buteau-Lozano et al demonstrated that estrogen modulates VEGF expression at the gene transcriptional level1

VEGF levels have been associated with response to adjuvant anti-estrogen therapy2

Although VEGF may be regulated by estrogen, VEGF expression has been correlated with estrogen receptor (ER)–negative status3

— ER-negative status is associated with poor prognosis

References: 1. Buteau-Lozano H, Ancelin M, Lardeux B, et al. Cancer Res. 2002;62:4977-4984. 2. Linderholm B, Grankvist K, Wilking N, et al. J Clin Oncol. 2000;18:1423-1431. 3. Fučkar D, Dekanić A, Štifter S, et al. Int J Surg Pathol. 2006;14:49-55.

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VEGF ligand and HER-2 in breast cancer: a positive association

Preclinical research shows that overexpression of HER-2/neu results in induction of the basal level of VEGF1

In a study of 611 patients, the poorest outcomes were seen in patients whose tumors overexpressed both HER-2/neu and VEGF2

References: 1. Yen L, You XL, Al Moustafa AE, et al. Oncogene. 2000;19:3460-3469. 2. Konecny GE, Meng YG, Untch M, et al. Clin Cancer Res. 2004;10:1706-1716.

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VEGF ligand secretion: linked to BRCA-1

BRCA-1 is a gene that increases risk of breast cancer1

— Normal BRCA-1 is involved in reparation of DNA breaks

— In mutated BRCA-1, DNA repair function is disabled

Preclinical research has shown that VEGF expression is mediated by a direct interaction of BRCA-1 protein and ER1

— Normal BRCA-1 protein regulates VEGF expression and secretion

— Mutated BRCA-1 protein is unable to suppress VEGF expression

Reference: 1. Kawai H, Li H, Chun P, et al. Oncogene. 2002;21:7730-7739.

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The VEGF ligand in breast cancer: summary

VEGF appears to play a complex and critical role across many different forms of breast cancer and throughout the course of a breast tumor life cycle1-5

VEGF overexpression and/or angiogenesis have been observed to be associated with increased metastasis and poor outcome1-4,6

VEGF and VEGF expression play a role in a complex relationship with other breast cancer markers such as ER, BRCA-1 and, HER-2/neu2,3,7-9

New research continues to provide insight into the role of VEGF in breast cancer

Large prospective studies are needed to better define the relationship of prognosis with angiogenesis and VEGF

References: 1. Foekens JA, Peters HA, Grebenchtchikov N, et al. Cancer Res. 2001;61:5407-5414. 2. Gasparini G, Toi M, Gion M, et al. J Natl Cancer Inst. 1997;89:139-147. 3. Konecny GE, Meng YG, Untch M, et al. Clin Cancer Res. 2004;10:1706-1716. 4. Linderholm B, Grankvist K, Wilking N, et al. J Clin Oncol. 2000;18:1423-1431. 5. Folkman J. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. Vol 2. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:2865-2882. 6. Weidner N, Semple JP, Welch WR, Folkman J. N Engl J Med. 1991;324:1-8. 7. Buteau-Lozano H, Ancelin M, Lardeux B, et al. Cancer Res. 2002;62:4977-4984. 8. Fučkar D, Dekanić A, Štifter S, et al. Int J Surg Pathol. 2006;14:49-55. 9. Kawai H, Li H, Chun P, et al. Oncogene. 2002;21:7730-7739.