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The Role of Trastuzumab in Early Stage Breast Cancer: Current Data and Treatment Recommendations

  • Breast Carcinoma
  • Published:
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Opinion statement

Treatment of early stage breast cancer requires a multimodality approach in order to eradicate residual cancer and prevent recurrent disease. Targeting the pathways that promote or sustain cancer cell growth and invasion is critical to the effective treatment of breast and other cancers. Overexpression of the family of HER receptors have been associated with a variety of malignancies; the first and best studied is the association of overexpression of the HER2/neu receptor with a more aggressive breast cancer phenotype and poorer survival. A humanized antibody to HER2/neu, trastuzumab, is now FDA approved for the treatment of early stage, HER2/neu overexpressing breast cancer sequenced with chemotherapy including doxorubicin, cyclophosphamide, and paclitaxel. Additional international and national studies support the significant impact of trastuzumab on both disease free and overall survival in women with this aggressive form of breast cancer. Toxicity includes a low but clear risk of congestive heart failure, and the large phase III trials have helped to determine which patients are at higher risk for this complication. Non-anthracycline containing regimens are an alternative therapy associated with reduced cardiac toxicity. Trastuzumab therapy is now the standard of care for the treatment of early stage, HER2/neu positive breast cancer given in combination with one of several chemotherapy regimens. Ongoing questions include the appropriate duration of trastuzumab treatment as well as the optimal chemotherapy regimen and sequence. The next large phase III adjuvant trial for this subset of breast cancer is an international collaboration designed to evaluate the added or alternative benefit of an oral tyrosine kinase inhibitor targeting HER2/neu as well as the epidermal growth factor receptor (EGFR), lapatinib. Other trials are investigating differences in duration. Studies in the neoadjuvant setting should help to define markers of trastuzumab and lapatinib sensitivity and resistance. Preliminary data combining trastuzumab with the antiangiogenic antibody bevacizumab is encouraging; this combination will be tested in both early stage and late stage disease.

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References and Recommended Heading

  1. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005, 365:1687–1717.

  2. Levine MN, Pritchard KI, Bramwell VH, et al (2005) Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol 23:5166–5170

    Article  PubMed  CAS  Google Scholar 

  3. Berry DA, Inoue L, Shen Y, et al.: Modeling the impact of treatment and screening on U.S. breast cancer mortality: a Bayesian approach. J Natl Cancer Inst Monogr 2006, 30–36.

  4. Mamounas EP, Bryant J, Lembersky B, et al (2005) Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol 23:3686–3696

    Article  PubMed  CAS  Google Scholar 

  5. Henderson IC, Berry DA, Demetri GD, et al (2003) Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976–983

    Article  PubMed  CAS  Google Scholar 

  6. Slamon DJ, Clark GM, Wong SG, et al (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182

    Article  PubMed  CAS  Google Scholar 

  7. Paik S, Liu ET (2000) HER2 as a predictor of therapeutic response in breast cancer. Breast Dis 11:91–102

    PubMed  CAS  Google Scholar 

  8. Press MF, Jones LA, Godolphin W, et al (1990) HER-2/neu oncogene amplification and expression in breast and ovarian cancers. Prog Clin Biol Res 354A:209–221

    PubMed  CAS  Google Scholar 

  9. Carlson RW, Moench SJ, Hammond ME, et al.: HER2 testing in breast cancer: NCCN Task Force report and recommendations. J Natl Compr Canc Netw 2006, 4(Suppl 3):S1–S22; quiz S23–S4.16, 17.

    Google Scholar 

  10. Wang S, Saboorian MH, Frenkel E, et al (2000) Laboratory assessment of the status of Her-2/neu protein and oncogene in breast cancer specimens: comparison of immunohistochemistry assay with fluorescence in situ hybridisation assays. J Clin Pathol 53:374–381

    Article  PubMed  CAS  Google Scholar 

  11. Pauletti G, Dandekar S, Rong H, et al (2000) Assessment of methods for tissue-based detection of the HER-2/neu alteration in human breast cancer: a direct comparison of fluorescence in situ hybridization and immunohistochemistry. J Clin Oncol 18:3651–3664

    PubMed  CAS  Google Scholar 

  12. Vogel CL, Cobleigh MA, Tripathy D, et al (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719–726

    Article  PubMed  CAS  Google Scholar 

  13. Slamon DJ, Leyland-Jones B, Shak S, et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792

    Article  PubMed  CAS  Google Scholar 

  14. Dybdal N, Leiberman G, Anderson S, et al (2005) Determination of HER2 gene amplification by fluorescence in situ hybridization and concordance with the clinical trials immunohistochemical assay in women with metastatic breast cancer evaluated for treatment with trastuzumab. Breast Cancer Res Treat 93:3–11

    Article  PubMed  CAS  Google Scholar 

  15. Tokunaga E, Oki E, Nishida K, et al (2006) Trastuzumab and breast cancer: developments and current status. Int J Clin Oncol 11:199–208

    Article  PubMed  CAS  Google Scholar 

  16. Cobleigh MA, Vogel CL, Tripathy D, et al (1999) Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639–2648

    PubMed  CAS  Google Scholar 

  17. Baselga J, Albanell J, Molina MA, et al (2001) Mechanism of action of trastuzumab and scientific update. Semin Oncol 28:4–11

    Article  PubMed  CAS  Google Scholar 

  18. Sliwkowski MX, Lofgren JA, Lewis GD, et al (1999) Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin Oncol 26:60–70

    PubMed  CAS  Google Scholar 

  19. Albanell J, Codony J, Rovira A, et al (2003) Mechanism of action of anti-HER2 monoclonal antibodies: scientific update on trastuzumab and 2C4. Adv Exp Med Biol 532:253–268

    PubMed  CAS  Google Scholar 

  20. Clynes RA, Towers TL, Presta LG, et al (2000) Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 6:443–446

    Article  PubMed  CAS  Google Scholar 

  21. Izumi Y, Xu L, di Tomaso E, et al (2002) Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature 416:279–280

    Article  PubMed  CAS  Google Scholar 

  22. Baselga J, Carbonell X, Castaneda-Soto NJ, et al (2005) Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule. J Clin Oncol 23:2162–2171

    Article  PubMed  CAS  Google Scholar 

  23. Pegram MD, Konecny GE, O’Callaghan C, et al (2004) Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst 96:739–749

    Article  PubMed  CAS  Google Scholar 

  24. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al (2006) Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354:809–820

    Article  PubMed  CAS  Google Scholar 

  25. Nahta R, Yuan LX, Zhang B, et al (2005) Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res 65:11118–11128

    Article  PubMed  CAS  Google Scholar 

  26. Zabrecky JR, Lam T, McKenzie SJ, et al (1991) The extracellular domain of p185/neu is released from the surface of human breast carcinoma cells, SK-BR-3. J Biol Chem 266:1716–1720

    PubMed  CAS  Google Scholar 

  27. Nagata Y, Lan KH, Zhou X, et al (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6:117–127

    Article  PubMed  CAS  Google Scholar 

  28. Pegram MD, Reese DM (2002) Combined biological therapy of breast cancer using monoclonal antibodies directed against HER2/neu protein and vascular endothelial growth factor. Semin Oncol 29:29–37

    PubMed  CAS  Google Scholar 

  29. Nahta R, Esteva FJ (2006) HER2 therapy: Molecular mechanisms of trastuzumab resistance. Breast Cancer Res 8:215

    Article  PubMed  CAS  Google Scholar 

  30. Geyer C, Cameron D, Lindquist D, et al.: A phase III randomized, open-label, international study comparing lapatinib and capecitabine vs capecitabine in women with refractory advanced or metastatic breast cancer (EGF100151). Presentation at Scientific Special Session, "Lapatinib in Trastuzumab-Resistant Breast Cancer". J Clin Oncol 2006, 24(18S).

Papers of particular interest, published recently, have been highlighted as: •Of importance ••Of major importance

  1. Society AC (2006) Cancer Facts and Figures 2006. American Cancer Society, Atlanta, GA

    Google Scholar 

  2. Ravdin PM, Chamness GC (1995) The c-erbB-2 proto-oncogene as a prognostic and predictive marker in breast cancer: a paradigm for the development of other macromolecular markers–a review. Gene 159:19–27

    Article  PubMed  CAS  Google Scholar 

  3. Slamon DJ, Clark G, Wong S, et al (1987) Human Breast Cancer: Correlation of Relapse and Survival with Amplification of the HER-2/neu Oncogene. Science 235:177–182

    Article  PubMed  CAS  Google Scholar 

  4. Romond EH, Perez EA, Bryant J, et al (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684

    Article  PubMed  CAS  Google Scholar 

Data from two large cooperative group trials, N9831 and B31 were analyzed together showing that trastuzumab in combination with paclitaxel and for one total year following doxorubicin and cyclophosphamide improved disease-free and overall survival.

  1. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672

    Article  PubMed  CAS  Google Scholar 

HERA trial demonstrated that treatment with trastuzumab for one year following completion of anthracycline based chemotherapy improved disease-free and overall survival in patients with HER2 positive early breast cancer.

  1. Slamon D, Eiermann W, Robert N, et al (2006) BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients. Breast Cancer Res Treat 100(S1):52

    Google Scholar 

BCIRG 006 trial showing benefit in trastuzumab treatment in conjunction with two chemotherapy regimens, including a nonanthracycline combination.

  1. Multi-agent chemotherapy for early breast cancer. Cochrane Database Syst Rev:CD000487, 2002.

National recommendations for HER2 testing.

  1. Wolff AC, Hammond ME, Schwartz JN, et al (2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118–45

    Article  PubMed  CAS  Google Scholar 

National recommendations for HER2 testing.

  1. Perez EA, Suman VJ, Davidson NE, et al (2006) HER2 testing by local, central, and reference laboratories in specimens from the North Central Cancer Treatment Group N9831 intergroup adjuvant trial. J Clin Oncol 24:3032–3038

    Article  PubMed  Google Scholar 

FinHER trial showing that short term use of trastuzumab in combination with chemotherapy resulted in better three-year recurrence-free survival compared to no trastuzumab.

  1. Perez EA, Rodeheffer R (2004) Clinical cardiac tolerability of trastuzumab. J Clin Oncol 22:322–329

    Article  PubMed  CAS  Google Scholar 

Cardiac toxicity of trastuzumab and risk factors from NSABP B31.

  1. Tan-Chiu E, Yothers G, Romond E, et al (2005) Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 23:7811–7819

    Article  PubMed  CAS  Google Scholar 

Cardiac toxicity of trastuzumab and risk factors from NSABP B31.

  1. Crone SA, Zhao YY, Fan L, et al (2002) ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 8:459–465

    Article  PubMed  CAS  Google Scholar 

Phase III trial demonstrating improved PFS with the combination of lapatinib and capecitabine compared to capecitabine alone in patients with trastuzumab resistant advanced breast cancer.

  1. Pegram M, Chan D, Dichmann RA, et al (2006) Phase II combined biological therapy targeting the HER2 proto-oncogene and the vascular endothelial growth factor using trastuzumab (T) and bevacizumab (B) as first line treatment of HER2-amplified breast cancer. Breast Cancer Res Treat 100(S1):301

    Google Scholar 

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Correspondence to Hope S. Rugo MD.

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Lin, A., Rugo, H.S. The Role of Trastuzumab in Early Stage Breast Cancer: Current Data and Treatment Recommendations. Curr. Treat. Options in Oncol. 8, 47–60 (2007). https://doi.org/10.1007/s11864-007-0008-2

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