Encyclopedia of Cancer

2017 Edition
| Editors: Manfred Schwab

Metastatic Breast Cancer Experimental Therapeutics

  • Alexandra Silveira
Reference work entry
DOI: https://doi.org/10.1007/978-3-662-46875-3_6794

Synonyms

Definition

Experimental therapies for metastatic  breast cancer can be defined as novel interventions directed toward the more effective treatment of secondary, progressively growing tumors distant from the primary site of the breast. Experimental therapies may include newly developed drug agents or may be different modalities for existing agents, such as the novel indication of a drug in the setting of breast cancer or the combination of approved single agents.

Characteristics

Breast cancer affects one in four women and is the second leading cause of cancer mortality among women in the United States. Globally, breast cancer is the leading cause of cancer mortality in women. Approximately 1% of all cases of breast cancer occur in men. The majority of mortality associated with the disease is due to the advanced, metastatic form of breast cancer, characterized by progressively growing tumors distant from the primary site. Approximately 40% of patients that initially present with localized disease develop metastatic disease. In those cases where the breast cancer has spread to distant sites, the 5-year survival rate is 27% in sharp contrast to 98% and 84% survival rates for localized and regional breast cancer, respectively. Risk factors for breast cancer reflect the influence of genetics, hormonal status, and environment on the development of the disease. These risk factors include age, gender, a personal or familial history of breast cancer, known genetic risk factors such as  BRCA1 and BRCA2 mutations, radiation exposure,  obesity,  alcohol consumption, postmenopausal hormone therapy, and age at menarche, menopause onset, and having a first child. Once a primary tumor has been surgically removed, risk can be stratified into three categories (low, intermediate, and high) determined by the calculated risk of recurrence, tumor size, histopathological grade,  invasion into the vasculature, lymph node involvement, presence of  estrogen receptor/progesterone receptor, and status of the epidermal growth factor receptor  HER2. Treatment for metastastic breast cancer typically involves a combination of surgical resection, radiotherapy,  chemotherapy, and, depending on hormonal sensitivity and  HER2 status,  endocrine therapy and biological agents, such as  trastuzumab and lapatinib. As much of metastatic breast cancer is incurable and there exist few proven standards of care, novel treatment agents and strategies are currently under experimental and clinical investigation to improve clinical outcome.

Gene Therapy

A promising avenue for the use of  gene therapy is to elicit a more potent immune response, either by being directly targeted to an individual’s cancer cells or as part of a vaccine therapy. Although there are a variety of gene therapy vectors available,  adenoviruses are the preferred gene delivery vectors due to their high ability to transduce both dividing and nondividing cells and an almost negligible integration potential. A phase I  clinical trial is being conducted to evaluate the safety and efficacy of an adenoviral vector delivery of the immune system stimulating  cytokine, interleukin-12 cDNA, intratumorally (NCT008494590).

Vaccine Therapy

Vaccine therapies are intended to bolster the immune system response against specific breast cancer antigens. Immune cells can be stimulated with tumor-specific cell-surface antigens, such as  HER2 or MUC-1, delivered by allogeneic cell lines engineered by  gene therapy to express the antigen or via direct injection of an immunogenic portion. In other trials, allogeneic tumor cells lines are engineered to secrete granulocyte-macrophage colony-stimulating factor, an immune stimulating cytokine that is currently being used in vaccines against a variety of cancers. Most often, these therapies are combined with other anticancer agents such as  interferon-alpha,  cyclophosphamide, and/or  trastuzumab. Vaccine-based therapies against metastatic breast cancer are currently in stage I or II clinical trials to test dose, safety, and efficacy.

Chemotherapeutic and Biological Agents

A large number of clinical trials are currently investigating the use of FDA-approved drugs in combination to more effectively treat the secondary tumor by targeting multiple pathways involved in cancer. Combinations often include the pairing of an anti-angiogenic (e.g.,  bevacizumab) or antiproliferative (e.g.,  everolimus, exemestane,  trastuzumab, sunitinib, or  imatinib) agent with a second antimitotic drug that directly results in cell death (e.g.,  paclitaxel, capecitabine, vinorelbine, and  gemcitabine).

 Bevacizumab is a humanized monoclonal antibody that binds and inhibits  vascular endothelial growth factor A, thereby inhibiting  angiogenesis. Phase III  clinical trials have combined bevacizumab with a variety of  chemotherapy agents in both first-line and second-line settings. A previous phase III clinical trial showed the combination of bevacizumab and capecitabine to result in significantly increased response rates when compared to capecitabine alone, although there was no difference in the endpoints of longer progression-free or overall survival. Based on these and other data, a phase II study is being conducted to investigate this combination as first-line therapy and in the adjuvant setting.

Several phase III trials are also examining the combination of  bevacizumab and  paclitaxel, a mitosis inhibitor. These studies (NCT00028990, NCT00600340, and NCT00600340) differ in comparators, paclitaxel alone or combination bevacizumab and capecitabine, the restriction of study groups to HER2-negative metastatic breast cancer patients, and the primary endpoint of either time to progression or overall survival. Nab-paclitaxel (Abraxane; Abraxis Oncology, Los Angeles, CA) is a newly developed solvent-free formulation of paclitaxel that yields higher levels of paclitaxel and an improved adverse-event profile. Trials are underway to examine the combination of nab-paclitaxel and bevacizumab and nab-paclitaxel and  gemcitabine.

 Everolimus is an orally active  mammalian target of rapamycin (mTOR) inhibitor that is being combined with a variety of agents in advanced clinical trials including the  aromatase inhibitor exemestane (Phase III, NCT00863655), both  trastuzumab and  paclitaxel (Phase III, NCT00876395), and  trastuzumab with vinorelbine (Phase III, NCT01007942).  Gefitinib, an epidermal growth factor inhibitor (EGF), is similarly being used in combination with chemotherapeutic or hormone therapy to target cancer cell proliferation.

Sunitinib is a multitargeted  receptor tyrosine kinase that has been shown to have both anti-angiogenic and antiproliferative effects. Early clinical trials are underway to evaluate the efficacy of sunitinib in the setting of metastatic breast cancer either in comparison to chemotherapy or in addition to either hormonal or chemotherapeutic agents for advanced disease.  Imatinib, another tyrosine kinase inhibitor, is also under evaluation in combination therapy with vinorelbine (Phase II/Phase III, NCT00372476).

Histone Deacetylase (HDAC) Inhibitors

Unlike chemotherapeutic, hormonal therapy, and biological agents, histone deacetylase inhibitors are not thought to directly cause cell death or inhibit  angiogenesis or proliferation. Rather, inhibitors such as  vorinostat (Zolinza, Merck & Co., Inc., White House Station, NJ) are proposed to act by relieving epigenetic silencing of  tumor suppressor genes. Vorinostat is currently in early clinical trials for the treatment of advanced breast cancer in combination with chemotherapeutic agents.

Conclusion

Because of the difficulty in treating metastatic disease, experimental therapies are using multipronged approaches to enhance an individual’s immune response, to directly cause cell death, and to target signaling cascades and cellular processes involved in tumor growth. The use of combination therapy and the development of novel gene therapy and vaccine approaches are yielding promising results. However, continued research of the underlying molecular mechanisms of cancer is required to suggest novel targets and new avenues of treatment.

Cross-References

References

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See Also

  1. (2012) Adjuvant. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 75. doi:10.1007/978-3-642-16483-5_107Google Scholar
  2. (2012) Allogeneic. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 138. doi:10.1007/978-3-642-16483-5_194Google Scholar
  3. (2012) EGF. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 1211. doi:10.1007/978-3-642-16483-5_1824Google Scholar
  4. (2012) Exemestane. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 1357. doi:10.1007/978-3-642-16483-5_6752Google Scholar
  5. (2012) Interleukin. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 1892. doi:10.1007/978-3-642-16483-5_3094Google Scholar
  6. (2012) Lapatinib. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 1980. doi:10.1007/978-3-642-16483-5_3277Google Scholar
  7. (2012) Monoclonal Antibody. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 2367. doi:10.1007/978-3-642-16483-5_6842Google Scholar
  8. (2012) Proliferation. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 3004. doi:10.1007/978-3-642-16483-5_4766Google Scholar
  9. (2012) Progesterone Receptor. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 2990. doi:10.1007/978-3-642-16483-5_4754Google Scholar
  10. (2012) Sunitinib. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 3562. doi:10.1007/978-3-642-16483-5_5575Google Scholar
  11. (2012) Vaccine Therapy. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 3879. doi:10.1007/978-3-642-16483-5_6147Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Ocular Molecular Genetics InstituteHarvard Medical School, Massachusetts Eye and Ear InfirmaryBostonUSA