Current Oncology Reports

, Volume 5, Issue 3, pp 171–176 | Cite as

Neoadjuvant chemoimmunotherapy in locally advanced breast cancer: A new avenue to be explored

  • Jan Buter
  • Herbert M. Pinedo
Editor’s Commentary


Prolonged neoadjuvant chemotherapy has shown favorable results in patients with LABC. Patients treated with six cycles showed more favorable results compared with patients receiving four or five cycles. The prolonged presence of the draining lymph nodes, in combination with the repeated tumor antigen release from the primary tumor, DC recruitment, and activation, which may be further stimulated by GM-CSF administration, may account for the observed increase in survival. Furthermore, factors inhibiting new vessel formation produced by the primary tumor may inhibit growth of micrometastases, thus enhancing the effects of chemotherapy. We hypothesized that these immunologic and biologic processes inherent to the primary tumor and its draining lymph nodes, and their prolonged presence during chemotherapy, may be responsible for the observed survival. To study these biologic and immunologic events in tissue samples and peripheral blood of patients with LABC, we initiated an international randomized clinical trial using LABC as a model for other locally advanced tumors.


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  1. 1.
    Brito RA, Valero V, Buzdar AU, et al.: Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metastases: the University of Texas M.D. Anderson Cancer Center Experience. J Clin Oncol 2001, 19:628–633.PubMedGoogle Scholar
  2. 2.
    Booser DJ, Hortobagyi GN: Treatment of locally advanced breast cancer. Semin Oncol 1992, 19:278–285.PubMedGoogle Scholar
  3. 3.
    Smith BM, Slade MJ, English J, et al.: Response of circulating tumor cells to systemic therapy in patients with metastatic breast cancer: comparison of quantitative polymerase chain reaction and immunocytochemical techniques. J Clin Oncol 2000, 18:1432–1439.PubMedGoogle Scholar
  4. 4.
    Braun S, Pantel K, Muller P, et al.: Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 2000, 342:525–533.PubMedCrossRefGoogle Scholar
  5. 5.
    Lankelma J, Dekker H, Luque FR, et al.: Doxorubicin gradients in human breast cancer. Clin Cancer Res 1999, 5:1703–1707.PubMedGoogle Scholar
  6. 6.
    Abolhoda A, Wilson AE, Ross H, et al.: Rapid activation of MDR1 gene expression in human metastatic sarcoma after in vivo exposure to doxorubicin. Clin Cancer Res 1999, 5:3352–3356.PubMedGoogle Scholar
  7. 7.
    Braun S, Kentenich C, Janni W, et al.: Lack of effect of adjuvant chemotherapy on the elimination of single dormant tumor cells in bone marrow of high-risk breast cancer patients. J Clin Oncol 2000, 18:80–86.PubMedGoogle Scholar
  8. 8.
    Kasimir-Bauer S, Mayer S, Bojko P, et al.: Survival of tumor cells in stem cell preparations and bone marrow of patients with high-risk or metastatic breast cancer after receiving dose-intensive or high-dose chemotherapy. Clin Cancer Res 2001, 7:1582–1589.PubMedGoogle Scholar
  9. 9.
    Perez EA, Foo ML, Fulmer JT: Management of locally advanced breast cancer. Oncology (Huntingt) 1997, 11:9–17.Google Scholar
  10. 10.
    Fisher B, Bryant J, Wolmark N, et al.: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 1998, 16:2672–2685.PubMedGoogle Scholar
  11. 11.
    Powles TJ, Hickish TF, Makris A, et al.: Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary breast cancer. J Clin Oncol 1995, 13:547–552.PubMedGoogle Scholar
  12. 12.
    van der Hage JA, van de Velde CJ, Julien JP, et al.: Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol 2001, 19:4224–4237.PubMedGoogle Scholar
  13. 13.
    Rubens RD, Bartelink H, Engelsman E, et al.: Locally advanced breast cancer: the contribution of cytotoxic and endocrine treatment to radiotherapy: an EORTC Breast Cancer Co-operative Group Trial (10792). Eur J Cancer Clin Oncol 1989, 25:667–678.PubMedCrossRefGoogle Scholar
  14. 14.
    Gazet JC, Ford HT, Coombes RC: Randomised trial of chemotherapy versus endocrine therapy in patients presenting with locally advanced breast cancer (a pilot study). Br J Cancer 1991, 63:279–282.PubMedGoogle Scholar
  15. 15.
    Attia-Sobol J, Ferriere JP, Cure H, et al.: Treatment results, survival and prognostic factors in 109 inflammatory breast cancers: univariate and multivariate analysis. Eur J Cancer 1993, 29A:1081–1088.PubMedCrossRefGoogle Scholar
  16. 16.
    Chevallier B, Bastit P, Graic Y, et al.: The Centre H. Becquerel studies in inflammatory non metastatic breast cancer. Combined modality approach in 178 patients. Br J Cancer 1993, 67:594–601.PubMedGoogle Scholar
  17. 17.
    Karlsson YA, Malmstrom PO, Hatschek T, et al.: Multimodality treatment of 128 patients with locally advanced breast carcinoma in the era of mammography screening using standard polychemotherapy with 5-fluorouracil, epirubicin, and cyclophosphamide: prognostic and therapeutic implications. Cancer 1998, 83:936–947.PubMedCrossRefGoogle Scholar
  18. 18.
    Rouesse J, Friedman S, Sarrazin D, et al.: Primary chemotherapy in the treatment of inflammatory breast carcinoma: a study of 230 cases from the Institut Gustave-Roussy. J Clin Oncol 1986, 4:1765–1771.PubMedGoogle Scholar
  19. 19.
    Honkoop AH, Luykx-de Bakker SA, Hoekman K, et al.: Prolonged neoadjuvant chemotherapy with GM-CSF in locally advanced breast cancer. Oncologist 1999, 4:106–111.PubMedGoogle Scholar
  20. 20.
    LeBedis C, Chen K, Fallavollita L, et al.: Peripheral lymph node stromal cells can promote growth and tumorigenicity of breast carcinoma cells through the release of IGF-I and EGF. Int J Cancer 2002, 100:2–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Disis ML, Calenoff E, McLaughlin G, et al.: Existent T-cell and antibody immunity to HER-2/neu protein in patients with breast cancer. Cancer Res 1994, 54:16–20.PubMedGoogle Scholar
  22. 22.
    Schlom J, Kantor J, Abrams S, et al.: Strategies for the development of recombinant vaccines for the immunotherapy of breast cancer. Breast Cancer Res Treat 1996, 38:27–39.PubMedCrossRefGoogle Scholar
  23. 23.
    Southall PJ, Boxer GM, Bagshawe KD, et al.: Immunohistological distribution of 5T4 antigen in normal and malignant tissues. Br J Cancer 1990, 61:89–95.PubMedGoogle Scholar
  24. 24.
    von Mensdorff-PouillyS, Verstraeten AA, Kenemans P, et al.: Survival in early breast cancer patients is favorably influenced by a natural humoral immune response to polymorphic epithelial mucin. J Clin Oncol 2000, 18:574–583.Google Scholar
  25. 25.
    Gabrilovich DI, Corak J, Ciernik IF, et al.: Decreased antigen presentation by dendritic cells in patients with breast cancer. Clin Cancer Res 1997, 3:483–490.PubMedGoogle Scholar
  26. 26.
    Banchereau J, Steinman RM: Dendritic cells and the control of immunity. Nature 1998, 392:245–252.PubMedCrossRefGoogle Scholar
  27. 27.
    Luykx-de Bakker SA, de GruijlTD, Scheper RJ, et al.: Dendritic cells: a novel therapeutic modality. Ann Oncol 1999, 10:21–27.PubMedCrossRefGoogle Scholar
  28. 28.
    Mayordomo JI, Zorina T, Storkus WJ, et al.: Bone marrowderived dendritic cells serve as potent adjuvants for peptidebased antitumor vaccines. Stem Cells 1997, 15:94–103.PubMedCrossRefGoogle Scholar
  29. 29.
    Coppola D, Fu L, Nicosia SV, et al.: Prognostic significance of p53, bcl-2, vimentin, and S100 protein-positive Langerhans cells in endometrial carcinoma. Hum Pathol 1998, 29:455–462.PubMedCrossRefGoogle Scholar
  30. 30.
    Gallo O, Bianchi S, Giannini A, et al.: Correlations between histopathological and biological findings in nasopharyngeal carcinoma and its prognostic significance. Laryngoscope 1991, 101:487–493.PubMedCrossRefGoogle Scholar
  31. 31.
    Ikeguchi M, Ikeda M, Tatebe S, et al.: Clinical significance of dendritic cell infiltration in esophageal squamous cell carcinoma. Oncol Rep 1998, 5:1185–1189.PubMedGoogle Scholar
  32. 32.
    Ishigami S, Aikou T, Natsugoe S, et al.: Prognostic value of HLA-DR expression and dendritic cell infiltration in gastric cancer. Oncology 1998, 55:65–69.PubMedCrossRefGoogle Scholar
  33. 33.
    Saito H, Tsujitani S, Ikeguchi M, et al.: Relationship between the expression of vascular endothelial growth factor and the density of dendritic cells in gastric adenocarcinoma tissue. Br J Cancer 1998, 78:1573–1577.PubMedGoogle Scholar
  34. 34.
    Zhang L, Conejo-Garcia JR, Katsaros D, et al.: Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 2003, 348:203–213.PubMedCrossRefGoogle Scholar
  35. 35.
    Bell D, Chomarat P, Broyles D, et al.: In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. J Exp Med 1999, 190:1417–1426.PubMedCrossRefGoogle Scholar
  36. 36.
    Ochsenbein AF, Klenerman P, Karrer U, et al.: Immune surveillance against a solid tumor fails because of immunological ignorance. Proc Natl Acad Sci U S A 1999, 96:2233–2238.PubMedCrossRefGoogle Scholar
  37. 37.
    Buelens C, Verhasselt V, De Groote D, et al.: Interleukin-10 prevents the generation of dendritic cells from human peripheral blood mononuclear cells cultured with interleukin-4 and granulocyte/macrophage-colony-stimulating factor. Eur J Immunol 1997, 27:756–762.PubMedCrossRefGoogle Scholar
  38. 38.
    Gabrilovich D, Ishida T, Oyama T, et al.: Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 1998, 92:4150–4166.PubMedGoogle Scholar
  39. 39.
    Gabrilovich DI, Chen HL, Girgis KR, et al.: Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 1996, 2:1096–1103.PubMedCrossRefGoogle Scholar
  40. 40.
    Morel AS, Quaratino S, Douek DC, Londei M: Split activity of interleukin-10 on antigen capture and antigen presentation by human dendritic cells: definition of a maturative step. Eur J Immunol 1997, 27:26–34.PubMedCrossRefGoogle Scholar
  41. 41.
    Sombroek CC, Stam AG, Masterson AJ, et al.: Prostanoids play a major role in the primary tumor-induced inhibition of dendritic cell differentiation. J Immunol 2002, 168:4333–4343.PubMedGoogle Scholar
  42. 42.
    Gastman BR, Johnson DE, Whiteside TL, Rabinowich H: Tumor-induced apoptosis of T lymphocytes: elucidation of intracellular apoptotic events. Blood 2000, 95:2015–2023.PubMedGoogle Scholar
  43. 43.
    Marrogi AJ, Munshi A, Merogi AJ, et al.: Study of tumor infiltrating lymphocytes and transforming growth factor-beta as prognostic factors in breast carcinoma. Int J Cancer 1997, 74:492–501.PubMedCrossRefGoogle Scholar
  44. 44.
    Lespagnard L, Gancberg D, Rouas G, et al.: Tumor-infiltrating dendritic cells in adenocarcinomas of the breast: a study of 143 neoplasms with a correlation to usual prognostic factors and to clinical outcome. Int J Cancer 1999, 84:309–314.PubMedCrossRefGoogle Scholar
  45. 45.
    Demicheli R, Terenziani M, Valagussa P, et al.: Local recurrences following mastectomy: support for the concept of tumor dormancy. J Natl Cancer Inst 1994, 86:45–48.PubMedCrossRefGoogle Scholar
  46. 46.
    Holmgren L, O’Reilly MS, Folkman J: Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1995, 1:149–153.PubMedCrossRefGoogle Scholar
  47. 47.
    O’Reilly MS, Holmgren L, Shing Y, et al.: Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994, 79:315–328.PubMedCrossRefGoogle Scholar
  48. 48.
    O’Reilly MS, Boehm T, Shing Y, et al.: Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997, 88:277–285.PubMedCrossRefGoogle Scholar
  49. 49.
    Hanahan D, Folkman J: Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996, 86:353–364.PubMedCrossRefGoogle Scholar
  50. 50.
    Fukumura D, Xavier R, Sugiura T, et al.: Tumor induction of VEGF promoter activity in stromal cells. Cell 1998, 94:715–725.PubMedCrossRefGoogle Scholar
  51. 51.
    Pinedo HM, Verheul HM, D’Amato RJ, Folkman J: Involvement of platelets in tumour angiogenesis? Lancet 1998, 352:1775–1777.PubMedCrossRefGoogle Scholar
  52. 52.
    Polverini PJ, Leibovich SJ: Induction of neovascularization in vivo and endothelial proliferation in vitro by tumor-associated macrophages. Lab Invest 1984, 51:635–642.PubMedGoogle Scholar
  53. 53.
    Good DJ, Polverini PJ, Rastinejad F, et al.: A tumor suppressordependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. Proc Natl Acad Sci U S A 1990, 87:6624–6628.PubMedCrossRefGoogle Scholar
  54. 54.
    Homandberg GA, Williams JE, Grant D, et al.: Heparin-binding fragments of fibronectin are potent inhibitors of endothelial cell growth. Am J Pathol 1985, 120:327–332.PubMedGoogle Scholar
  55. 55.
    Lee TH, Rhim T, Kim SS: Prothrombin kringle-2 domain has a growth inhibitory activity against basic fibroblast growth factor-stimulated capillary endothelial cells. J Biol Chem 1998, 273:28805–28812.PubMedCrossRefGoogle Scholar
  56. 56.
    O’Reilly MS, Boehm T, Shing Y, et al.: Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997, 88:277–285.PubMedCrossRefGoogle Scholar
  57. 57.
    Morelli D, Lazzerini D, Cazzaniga S, et al.: Evaluation of the balance between angiogenic and antiangiogenic circulating factors in patients with breast and gastrointestinal cancers. Clin Cancer Res 1998, 4:1221–1225.PubMedGoogle Scholar
  58. 58.
    Verheul HM, Hoekman K, Luykx-de Bakker S, et al.: Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res 1997, 3:2187–2190.PubMedGoogle Scholar
  59. 59.
    Verheul HM, Hoekman K, Lupu F, et al.: Platelet and coagulation activation with vascular endothelial growth factor generation in soft tissue sarcomas. Clin Cancer Res 2000, 6:166–71.PubMedGoogle Scholar
  60. 60.
    Verheul HM, Jorna AS, Hoekman K, et al.: Vascular endothelial growth factor-stimulated endothelial cells promote adhesion and activation of platelets. Blood 2000, 96:4216–4221.PubMedGoogle Scholar
  61. 61.
    Joseph IB, Isaacs JT: Macrophage role in the anti-prostate cancer response to one class of antiangiogenic agents. J Natl Cancer Inst 1998, 90:1648–1653.PubMedCrossRefGoogle Scholar
  62. 62.
    Dong Z, Kumar R, Yang X, Fidler IJ: Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma. Cell 1997, 88:801–810.PubMedCrossRefGoogle Scholar
  63. 63.
    Dong Z, Yoneda J, Kumar R, Fidler IJ: Angiostatin-mediated suppression of cancer metastases by primary neoplasms engineered to produce granulocyte/macrophage colony-stimulating factor. J Exp Med 1998, 188:755–763.PubMedCrossRefGoogle Scholar
  64. 64.
    Honkoop AH, Pinedo HM, de Jong JS, et al.: Effects of chemotherapy on pathologic and biologic characteristics of locally advanced breast cancer. Am J Clin Pathol 1997, 107:211–218.PubMedGoogle Scholar
  65. 65.
    Albert ML, Sauter B, Bhardwaj N: Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 1998, 392:86–89.PubMedCrossRefGoogle Scholar
  66. 66.
    Inaba K, Turley S, Yamaide F, et al.: Efficient presentation of phagocytosed cellular fragments on the major histocompatibility complex class II products of dendritic cells. J Exp Med 1998, 188:2163–2173.PubMedCrossRefGoogle Scholar
  67. 67.
    Steinman RM, Turley S, Mellman I, Inaba K: The induction of tolerance by dendritic cells that have captured apoptotic cells. J Exp Med 2000, 191:411–416.PubMedCrossRefGoogle Scholar
  68. 68.
    Gallucci S, Lolkema M, Matzinger P: Natural adjuvants: endogenous activators of dendritic cells. Nat Med 1999, 5:1249–1255.PubMedCrossRefGoogle Scholar
  69. 69.
    Sauter B, Albert ML, Francisco L, et al.: Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J Exp Med 2000, 191:423–434.PubMedCrossRefGoogle Scholar
  70. 70.
    Machiels JP, Reilly RT, Emens LA, et al.: Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res 2001, 61:3689–3697.PubMedGoogle Scholar
  71. 71.
    Carmo-Pereira J, Costa FO, Henriques E, et al.: A comparison of two doses of adriamycin in the primary chemotherapy of disseminated breast carcinoma. Br J Cancer 1987, 56:471–473.PubMedGoogle Scholar
  72. 72.
    Frei E III, Teicher BA, Holden SA, et al.: Preclinical studies and clinical correlation of the effect of alkylating dose. Cancer Res 1988, 48:6417–6423.PubMedGoogle Scholar
  73. 73.
    Honkoop AH, Hoekman K, Wagstaff J, et al.: Dose-intensive chemotherapy with doxorubicin, cyclophosphamide and GM-CSF fails to improve survival of metastatic breast cancer patients. Ann Oncol 1996, 7:35–39.PubMedGoogle Scholar
  74. 74.
    Hryniuk W, Bush H: The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol 1984, 2:1281–1288.PubMedGoogle Scholar
  75. 75.
    Jones RB, Holland JF, Bhardwaj S, et al.: A phase I–II study of intensive-dose adriamycin for advanced breast cancer. J Clin Oncol 1987, 5:172–177.PubMedGoogle Scholar
  76. 76.
    Hoekman K, Wagstaff J, van GroeningenCJ, et al.: Effects of recombinant human granulocyte-macrophage colony-stimulating factor on myelosuppression induced by multiple cycles of high-dose chemotherapy in patients with advanced breast cancer. J Natl Cancer Inst 1991, 83:1546–1553.PubMedCrossRefGoogle Scholar
  77. 77.
    Luykx-de Bakker SA, Verheul HM, de GruijlTD, Pinedo HM: Prolonged neoadjuvant treatment in locally advanced tumours: a novel concept based on biological considerations. Ann Oncol 1999, 10:155–160.PubMedCrossRefGoogle Scholar

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© Current Science Inc 2003

Authors and Affiliations

  • Jan Buter
  • Herbert M. Pinedo
    • 1
  1. 1.Department of Medical OncologyVU University Medical CenterMB AmsterdamThe Netherlands

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