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Keywords:

  • inflammatory breast cancer;
  • chemotherapy;
  • HER2;
  • trastuzumab;
  • lapatinib

Abstract

  1. Top of page
  2. Abstract
  3. CONFLICT OF INTEREST DISCLOSURES
  4. REFERENCES

Inflammatory breast cancer (IBC) accounts for 1% to 5% of all breast cancer cases. Its aggressive biology is characterized by rapid disease progression and poor prognosis. To improve and standardize therapy for IBC, development of novel therapeutics to molecular targets of IBC is key. Trastuzumab treatment, an anti-HER2 humanized monoclonal antibody, has been demonstrated to improve the 3-year survival rate of patients with IBC (70.1% vs 53.3%; P = .0007). Another chemotherapeutic drug, lapatinib, a dual tyrosine inhibitor of epidermal growth factor (EGFR) and HER2 signaling, in combination with capecitabine demonstrated encouraging results, with a 51% decrease in disease progression. Further investigation is needed to confirm the efficacy of lapatinib. Cancer 2010;116(11 suppl):2837–9. © 2010 American Cancer Society.

Inflammatory breast cancer (IBC) is an aggressive subtype of locally advanced breast cancer (LABC), with an incidence that varies across different geographic locations but typically accounts for approximately 1% to 5% of all newly diagnosed breast cancers diagnosed in the United States.1 The multidisciplinary management approach to IBC, comprised of a sequential process of preoperative chemotherapy followed by surgery and radiotherapy, has only marginally improved overall prognosis, which remains dismal with a 40% survival at 5 years.2

Several molecular determinants of IBC have already been identified that may serve as prime targets for the future development of therapeutic agents and contribute to improvements in prognosis.3-5 Of particular interest in both respects is the overexpression and/or gene amplification of HER2. The introduction of trastuzumab, a humanized monoclonal antibody targeted against the HER2 protein, has been shown in combination with chemotherapy to significantly improve survival among women with both early6, 7 and advanced stage breast cancer.8 Furthermore, the incorporation of trastuzumab into preoperative regimens has also been associated with high pathologically complete response rates.9 With several studies documenting an increased frequency of HER2 overexpression and/or gene amplification in IBC, trastuzumab is an ideal agent for incorporation into the therapy for this disease. Several studies have evaluated the efficacy of preoperative trastuzumab with chemotherapy in patients with IBC,10-15 demonstrating pathologically complete response rates ranging from 17% to 40%. Gianni et al15 recently reported on a cohort of 327 patients enrolled on a phase 3 prospective randomized clinical trial, the objective of which was to evaluate the addition of trastuzumab to an anthracycline-based and taxane-based preoperative chemotherapy regimen for patients with HER2-positive LABC. The authors reported that 27% of the patients with HER2-positive disease had IBC and that the addition of trastuzumab to preoperative chemotherapy significantly increased the 3-year event-free survival rate compared with preoperative chemotherapy alone (70.1% vs 53.3%; P = .0007), and thus further concluded that trastuzumab-based preoperative chemotherapy should be considered a standard option for patients with HER2-positive LABC (including IBC).

Lapatinib (Tykerb, GlaxoSmithKline, Research Triangle Park, NC), a reversible inhibitor of the HER1 (ErbB1) and HER2 (ErbB2) tyrosine kinases,16 is another targeted agent whose efficacy currently is being evaluated among women with LABC, including those with IBC.17-20 In combination with capecitabine, lapatinib has been shown to reduce the risk of disease progression by 51% compared with capecitabine alone among patients with HER2-positive LABC or metastatic breast cancer who have developed disease progression while receiving trastuzumab-containing regimens.17 Cristofanilli et al20 reported on a cohort of 21 chemotherapy-naive patients who had HER2-positive IBC who received a combination of preoperative lapatinib and paclitaxel. According to study protocol, patients initially received 14 days of daily lapatinib (at a dose of 1500 mg) after which it was given in combination with weekly paclitaxel (at a dose of 80 mg/m2) for 12 weeks. The authors reported good tolerance to the regimen with an associated clinical response rate of approximately 80%. Combinations of lapatinib are currently being studied prospectively in larger cohorts of patients with IBC, including a phase 3, placebo- controlled trial assessing the combination with pazopanib (GW-786034; GlaxoSmithKline, London, UK) an orally administered second-generation tyrosine kinase that blocks tumor cell proliferation by its inhibitory action against vascular endothelial growth factor receptor-1 (VEGFR-1), VEGFR-2, and VEGFR-3; platelet-derived growth factor receptor-α (PDGFR-α) and PDGFR-β; and c-kit.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. CONFLICT OF INTEREST DISCLOSURES
  4. REFERENCES

This supplement was sponsored by the Houston Affiliate of the Susan G. Komen for the Cure, the National Cancer Institute, and the State of Texas Rare and Aggressive Breast Cancer Research Program. The First International Inflammatory Breast Cancer Conference was supported in part by GlaxoSmithKline, Pfizer, Eli Lilly and Company, and Cardinal Health. Supported by the First International Inflammatory Breast Cancer Conference (NIH-NCI 1R13 00451843), State of Texas Rare and Aggressive Breast Cancer Research Program, and American Airlines Susan G. Komen Promise Grant KGO81287.

REFERENCES

  1. Top of page
  2. Abstract
  3. CONFLICT OF INTEREST DISCLOSURES
  4. REFERENCES
  • 1
    Hance KW, Anderson WF, Devesa SS, Young HA, Levine PH. Trends in inflammatory breast carcinoma incidence and survival: the surveillance, epidemiology, and end results program at the National Cancer Institute. J Natl Cancer Inst. 2005; 97: 966-975.
  • 2
    Cristofanilli M, Valero V, Buzdar U, et al. Inflammatory breast cancer (IBC) and patterns of recurrence: understanding the biology of a unique disease. Cancer. 2007; 110: 1436-1444.
  • 3
    Kleer CG, van Golen KL, Merajver SD. Molecular biology of breast cancer metastasis. Inflammatory breast cancer: clinical syndrome and molecular determinants. Breast Cancer Res. 2000; 2: 423-429.
  • 4
    Guerin M, Gabillot M, Mathieu MC, et al. Structure and expression of c-erbB-2 and EGF receptor genes in inflammatory and non-inflammatory breast cancer: prognostic significance. Int J Cancer. 1989; 43: 201-208.
  • 5
    Parton M, Dowsett M, Ashley S, et al. High incidence of HER-2 positivity in inflammatory breast cancer. Breast. 2004; 13: 97-103.
  • 6
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005; 353: 1659-1684.
  • 7
    Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005; 353: 1673-1684.
  • 8
    Slamon DJ, Leyland-Jones B, Shak S, et al. Human breast cancer: use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpress HER2. N Engl J Med. 2001; 344: 783-792.
  • 9
    Buzdar AU, Ibrahim NK, Francis D et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth receptor 2- positive operable breast cancer. J Clin Oncol. 2005; 23: 3676-3685.
  • 10
    Hurley J, Doliny P, Reis I, et al. Docetaxel, cisplatin, and trastuzumab as primary systemic therapy for human epidermal growth factor receptor 2-postive locally advanced breast cancer. J Clin Oncol. 2006; 24: 1831-1838.
  • 11
    Van Pelt AE, Mohsin S, Elledge RM, et al. Neoadjuvant trastuzumab and docetaxel in breast cancer: preliminary results. Clin Breast Cancer. 2003; 4: 348-353.
  • 12
    Limentani SA, Brufsky AM, Erban JK,,et al. Phase II study of neoadjuvant docetaxel, vinorelbine, and trastuzumab followed by surgery and adjuvant doxorubicin plus cyclophosphamide in women with human epidermal growth factor receptor 2-overexpressing locally advanced breast cancer. J Clin Oncol. 2007; 25: 1232-1238.
  • 13
    Burstein HJ, Harris LN, Gelman R, et al. Preoperative therapy with trastuzumab and paclitaxel followed by sequential adjuvant doxorubicin/cyclophosphamide for HER2 overexpressing stage II or III breast cancer: a pilot study. J Clin Oncol. 2003; 21: 46-53.
  • 14
    Dawood S, Gonzalez-Angulo AM, Peintinger F, et al. Efficacy and safety of neoadjuvant trastuzumab combined with paclitaxel and epirubicin: a retrospective review of the M. D. Anderson experience. Cancer. 2007; 110: 1195-1200.
  • 15
    Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer: primary efficacy analysis of the NOAH trial [abstract]. Presented at San Antonio Breast Cancer Conference, San Antonio, Texas, December 10-14, 2008. Abstract 31.
  • 16
    Xia W, Mullin RJ, Keith BR, et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene. 2002; 21: 6255-6263.
  • 17
    Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006; 355: 2733-2743.
  • 18
    Burris HA III, Hurwitz HI, Dees EC et al. Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol. 2005; 23: 5305-5313.
  • 19
    Spector NL, Blackwell K, Hurley J, et al. EGF103009, a phase II trial of lapatinib monotherapy in patients with relapsed/refractory inflammatory breast cancer (IBC): clinical activity and biologic predictors of response. 2006 ASCO Annual Meeting Proceedings Part I. J Clin Oncol. 2006; 24( 18 suppl): 502.
  • 20
    Cristofanilli M, Boussen H, Baselga J, et al. A phase II combination study of lapatinib and paclitaxel as a neoadjuvant therapy in patients with newly diagnosed inflammatory breast cancer (IBC) [abstract]. Breast Cancer Res Treat. 2006; 100( 1 suppl):58(S3). Abstract 1.