Breast Cancer
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Breast Cancer

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Breast Cancer Breast Cancer Presentation Transcript

  • The Role of VEGF in Breast Cancer Slide kit provided by ResearchVEGF.com, an online resource sponsored by Genentech BioOncology
  • Angiogenesis and VEGF in cancer
  • Angiogenesis and VEGF play an important role in tumor biology
    • Angiogenesis (the formation of new blood vessels from existing ones) is an important process in the growth of malignant tumors 1,2
    • An association between VEGF and angiogenesis, malignancy, and metastasis has been established 1,2
    • Many pro- and anti-angiogenic cellular factors regulate angiogenesis 1,2
    • Research thus far suggests that VEGF is a potent and predominant factor in this process 1,2
    • .
    References: 1. Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027. 2. Ferrara N. Endocr Rev. 2004;25:581-611.
  • Several critical mechanisms are involved in tumor growth
    • Angiogenesis is 1 of the 6 acquired cellular capabilities leading to malignant growth 1
    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.
  • VEGF in breast cancer
  • VEGF 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.
  • VEGF is a key mediator of breast tumor angiogenesis
    • Relf et al: VEGF is one of the most important mediators of tumor angiogenesis in breast cancer 1
      • 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.
  • VEGF is overexpressed in breast tumor tissue
    • Yoshiji et al: VEGF overexpressed in breast tumor tissue compared with surrounding normal tissue 1
    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.
  • VEGF 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 cycle 1
      • The clinical significance of this finding is unknown
    Adapted from Folkman 2005.
  • VEGF expression is ubiquitous in multiple forms of breast cancer
    • VEGF overexpression is observed across multiple forms of breast cancer 1-5
    • Additional studies support a correlation between VEGF and breast cancer 6,7
    • Inflammatory breast cancer is highly angiogenic 8
      • 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.
  • Effects of VEGF in breast cancer beyond angiogenesis
  • VEGF may be involved in autocrine signaling pathways
    • The role of VEGF in breast cancer may extend beyond angiogenesis 1,2
    • Breast cancer cells have been shown to express both VEGF and VEGF receptors 1
    • Several possible mechanisms may be responsible for autocrine VEGF signaling in breast cancer 1
    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.
  • Prevalence of VEGF in breast cancer
  • VEGF is overexpressed in the majority of breast tumors 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 VEGF 1
    Reference: 1. Konecny GE, Meng YG, Untch M, et al. Clin Cancer Res. 2004;10:1706-1716. 61% (340/554) 19% (7/37) 78% (432/554) 22% (8/37) Histology Invasive ductal Invasive lobular 73% (100/137) 55% (259/474) 80% (109/137) 72% (343/474) Hormone-receptor status Negative Positive 53% (155/290) 63% (196/310) 72% (210/290) 75% (233/310) Lymph nodes Negative Positive 55% (271/497) 77% (88/114) 71% (353/497) 88% (100/114) HER-2/ neu Negative Positive 59% (359/611) 74% (453/611) Overall Positive for VEGF 121-206 Positive for VEGF 165-206 Variable
  • VEGF and metastasis in breast cancer
  • VEGF 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 metastases 1,2
    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, et al. 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.
  • VEGF may be involved in breast cancer bone metastasis
    • VEGF may be involved in breast cancer metastasis to bone 1
      • 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.
  • VEGF as a prognostic and predictive factor in breast cancer
  • VEGF 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 survival 1
    • Large prospective clinical studies are needed to better clarify the prognostic role of VEGF in breast cancer
  • VEGF and microvessel density are associated with poor prognosis in breast cancer
    • VEGF expression correlates with microvessel density in breast cancer 1,2
    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 survival 3
  • VEGF may predict response to systemic therapy
    • A large clinical study has demonstrated that VEGF expression is correlated with poor response to systemic therapy 1
      • Tamoxifen (top image) or chemotherapy (lower image)
    • Preclinical data indicate that VEGF may contribute to hormone therapy resistance and tumor progression 2
    • In tumor cell lines, antihormones have been shown to induce VEGF expression 3
    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.
  • VEGF and other common breast cancer tumor markers
  • VEGF, estrogen, and estrogen receptor interactions in breast cancer
    • VEGF may be regulated by hormones through autocrine and paracrine mechanisms 1
    • Buteau-Lozano et al demonstrated that estrogen modulates VEGF expression at the gene transcriptional level 1
    • VEGF levels have been associated with response to adjuvant anti-estrogen therapy 2
    • Although VEGF may be regulated by estrogen, VEGF expression has been correlated with estrogen receptor (ER)–negative status 3
      • 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. Fu č kar D, Dekani ć A, Š tifter S, et al. Int J Surg Pathol. 2006;14:49-55.
  • VEGF 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 VEGF 1
    • In a study of 611 patients, the poorest outcomes were seen in patients whose tumors overexpressed both HER-2/ neu and VEGF 2
    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.
  • VEGF secretion: linked to BRCA-1
    • BRCA-1 is a gene that increases risk of breast cancer 1
      • 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 ER 1
      • 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.
  • VEGF 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 cycle” 1-5
    • VEGF overexpression and/or angiogenesis have been observed to be associated with increased metastasis and poor outcome 1-4,6
    • VEGF and VEGF expression play a role in a complex relationship with other breast cancer markers such as ER, BRCA-1 and, HER-2/ neu 2,3,7-9
    • 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. Fu č kar D, Dekani ć A, Š tifter 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.