Novel targeted therapies in inflammatory breast cancer

Authors

  • Massimo Cristofanilli MD

    Corresponding author
    1. Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
    Current affiliation:
    1. Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
    • Department of Breast Medical Oncology, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1354, Houston, TX 77030
    Search for more papers by this author
    • Fax: (713) 794-4385


  • The articles in this supplement were presented at the First International Inflammatory Breast Cancer Conference, Houston, Texas, December 5-7, 2008.

Abstract

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

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.

Ancillary