SEARCH

SEARCH BY CITATION

Keywords:

  • inflammatory breast cancer;
  • vasculolymphatic processes;
  • epidermal growth factor receptor;
  • erlotinib;
  • extracellular signal-regulated protein kinase

Abstract

  1. Top of page
  2. Abstract
  3. RESULTS OF THE LITERATURE REVIEW
  4. CURRENT RESEARCH ON IBC
  5. CONFLICT OF INTEREST DISCLOSURES
  6. REFERENCES

Despite the introduction of multimodality treatment approaches, the prognosis of inflammatory breast cancer (IBC) is poor. Recent developments in molecular targeted therapy may be effective against IBC. The authors report the results of a literature review. Trastuzumab and lapatinib, which target human epidermal growth factor receptor 2 (HER-2), have demonstrated benefit in clinical trials for HER-2–positive breast cancers. WNT1-inducible signaling pathway protein 3, Ras homolog gene family member C guanosine triphosphatase, epidermal growth factor receptor (EGFR), and p27kip1 also have been studied as potential targets in IBC. Molecular targets in vasculolymphatic processes (angiogenesis, lymphangiogenesis, and vasculogenesis) have demonstrated greater potential in IBC than in non-IBC. Although loss of E-cadherin is a hallmark of epithelial-to-mesenchymal transition and may correlate with the promotion of metastasis, paradoxically, E-cadherin is overexpressed in IBC through an unknown mechanism. On the basis of dissecting the molecular mechanism of the aggressiveness of IBC, the authors currently are investigating whether EGFR may aid in developing innovative targeted therapies. Cancer 2010;116(11 suppl):2758–9. © 2010 American Cancer Society.

Inflammatory breast cancer (IBC) is 1 of most aggressive types of breast cancer. Despite multimodality approaches, the prognosis for patients with this disease remains poor. Although we are making efforts to improve treatment for IBC, IBC research is limited, because it is a very rare disease with undefined biology, and there are few defined targets for IBC. To improve this situation, we require insights from clinical trials and epidemiologic studies investigating IBC biology.

RESULTS OF THE LITERATURE REVIEW

  1. Top of page
  2. Abstract
  3. RESULTS OF THE LITERATURE REVIEW
  4. CURRENT RESEARCH ON IBC
  5. CONFLICT OF INTEREST DISCLOSURES
  6. REFERENCES

Molecular targets in vasculolymphatic processes (angiogenesis, lymphangiogenesis, and vasculogenesis) have exhibited greater potential in IBC than in non-IBC. High expression of angiogenic factors has been observed in IBC. Antiangiogenesis therapies (bevacizumab and SU5416 [semaxinib]) have demonstrated some clinical effect in clinical trials. Lymphangiogenesis may play an important role in early lymph node spread in patients with IBC. Vasculogenesis may be related to hematogenous metastasis and has been investigated extensively in a human IBC mouse xenograft model.1

Molecular targets in cell proliferation processes have been investigated the most and have yielded promising clinical results, leading to improved outcomes for patients with IBC. These cell proliferation targets include human epidermal growth factor receptor 2 (HER-2) and epidermal growth factor receptor (EGFR). Like what was observed in non-IBC, the HER-2 antibody trastuzumab dramatically changed the prognosis of patients with HER-2–overexpressing IBC. Lapatinib, which inhibits both HER-2 and EGFR, also produced a benefit in patients with HER-2–positive breast cancer, including IBC, in clinical trials. Additional cell proliferation targets (WNT1-inducible signaling pathway protein 3 [WISP3], Ras homolog gene family member C [RhoC], guanosine triphosphatase [GTPase], and p27kip1) also have been studied in IBC.

Molecules involved in metastasis processes may have a unique role in IBC because of the aggressiveness of this disease. E-cadherin overexpression has been reported IBC, and loss of E-cadherin is a hallmark of epithelial-mesenchymal transition. Although this E-cadherin overexpression may be a transient phenomenon, we may be able to target this unique feature.

CURRENT RESEARCH ON IBC

  1. Top of page
  2. Abstract
  3. RESULTS OF THE LITERATURE REVIEW
  4. CURRENT RESEARCH ON IBC
  5. CONFLICT OF INTEREST DISCLOSURES
  6. REFERENCES

Guided by the knowledge gained from our review, currently, we are investigating whether EGFR may represent a potential therapeutic target in IBC. EGFR is overexpressed in 30% of IBCs. Patients with EGFR-positive tumors have worse 5-year overall survival than patients with EGFR-negative tumors, and EGFR expression is associated with an increased risk of recurrence in patients with IBC.

By using the EGFR-overexpressing IBC cell lines SUM149 and KPL-4, we investigated the effectiveness of EGFR blocking against IBC. Erlotinib, an EGFR tyrosine kinase inhibitor, inhibited cell proliferation and anchorage-independent growth of these IBC cell lines but had little effect on EGFR-overexpressing non-IBC cell lines (MDA-MB-468 and BT-20). We also observed that erlotinib inhibited the activation of protein kinase B (Akt) and extracellular signal-regulated protein kinase (ERK). ERK activation is associated with increased resistance to erlotinib in IBC cells. ERK small-interfering RNA (siRNA) knockdown enhanced the antiproliferative activity of erlotinib. This suggested that erlotinib activity depends in part on ERK. The ERK pathway may be an important pathway in IBC tumorigenesis, and targeting EGFR through the ERK pathway may prevent metastasis in EGFR-expressing IBC.

In a 3-dimensional culture system, erlotinib reversed the mesenchymal phenotype of IBC cells at drug concentrations lower than the level at which a cytotoxic effect was observed. In an IBC xenograft model, erlotinib dramatically inhibited not only IBC tumor growth but also IBC lung metastasis. Higher expression of the epithelial marker E-cadherin and lower expression of the mesenchymal marker vimentin were observed in erlotinib-treated tumors compared with untreated tumors. Inhibition of epithelial-mesenchymal transition by erlotinib may lead the inhibition of metastasis in IBC.2

A molecular pathway that is unique to IBC needs to be discovered. One potential candidate is the EGFR pathway. We have been investigating the role of this pathway and the possibility of EGFR-targeted therapy for IBC. Further extensive preclinical and clinical work based on molecular findings is needed to improve outcomes in patients with IBC. Soon, we will be starting to test panitumumab, a human EGFR antibody, plus chemotherapy (nanoparticle-bound paclitaxel and carboplatin) as a preoperative regimen in patients with HER-2–negative IBC.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. RESULTS OF THE LITERATURE REVIEW
  4. CURRENT RESEARCH ON IBC
  5. CONFLICT OF INTEREST DISCLOSURES
  6. REFERENCES

This supplement was sponsored by the Houston Affiliate of 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. This article received the following grant support: NIH grant R01 CA123318-01A1, Morgan Welch Inflammatory Breast Cancer Research Program, State of Texas Rare and Aggressive Breast Cancer Research Program (N.T. Ueno), and Susan G. Komen Post-doctoral Fellowship grant KG091192 (D. Zhang).

REFERENCES

  1. Top of page
  2. Abstract
  3. RESULTS OF THE LITERATURE REVIEW
  4. CURRENT RESEARCH ON IBC
  5. CONFLICT OF INTEREST DISCLOSURES
  6. REFERENCES
  • 1
    Yamauchi H, Cristofanilli M, Nakamura S, et al. Molecular targets for treatment of inflammatory breast cancer. Nat Rev Clin Oncol. 2009; 6: 387-394.
  • 2
    Zhang D, LaFortune TA, Krishnamurthy S, et al. Epidermal growth factor receptor tyrosine kinase inhibitor reverses mesenchymal to epithelial phenotype and inhibits metastasis in inflammatory breast cancer. Clin Cancer Res. 2009; 15: 6639-6648.