Introduction
Article Outline
Breast cancer is one of the most frequently diagnosed types of cancer and a leading cause of cancer death in women.1 Approximately 5% of patients with breast cancer have clinically detectable metastases at the time of initial diagnosis; a further 30% to 40% of patients who appear clinically free of metastases harbor occult metastases, many of whom will relapse and die despite appropriate adjuvant systemic therapy.2 The vast majority of these deaths are caused by recurrent metastatic disease.
Treatment of metastatic breast cancer (MBC) has evolved significantly over the past two decades, a result of both the transition of previous metastatic agents to the adjuvant setting and the discovery of new agents (and new classes of agents). Patients relapsing in this decade will frequently have received multiple prior agents (chemotherapy, hormonal therapy, and trastuzumab-based therapy) in the adjuvant setting, complicating treatment issues.
In general, however, therapy is based on tumor biology, with steroid receptor-positive metastatic disease being a candidate for initial hormonal therapy, human epidermal growth factor receptor (HER)2-positive patients receiving trastuzumab-based therapy, and almost all patients being candidates for chemotherapy at some point in the natural history of their disease. Despite the many new agents introduced in the past decade (eg, hormonal agents such as fulvestrant, HER2-targeting agents such as trastuzumab, and chemotherapeutics such as gemcitabine and capecitabine), the ultimate fate of the average patient with MBC remains largely unchanged. Therefore, it is clear that novel approaches to targeting MBC are required.
This supplement to Seminars in Oncology reviews current and evolving therapies for the treatment of MBC. Novel approaches to treatment are being developed to enhance responses to standard therapy, interfere with resistance mechanisms, and improve treatment outcome. To individualize treatment more effectively, these new treatment approaches will need to consider the heterogeneity of the disease and predictors of benefit.
The first article, by Roy and Perez, provides an overview of new therapies for treating breast cancer. Among the advances being made in chemotherapy, combinations of fulvestrant or letrozole plus inhibitors of growth-signaling pathways are being investigated. Other advances include the development of albumin-bound paclitaxel and new agents such as ixabepilone and vinflunine. Developments in targeted therapies include inhibitors of angiogenesis (bevacizumab and vascular endothelial growth factor [VEGF]-trap), epidermal growth factor receptor inhibitors (trastuzumab, pertuzumab, lapatinib, and erlotinib), Raf/mitogen-activated protein kinase and extracellular signal-regulated kinase pathway inhibitors (tipifarnib), and mammalian target of rapamycin inhibitors (rapamycin). Several other agents (alone and in combination) are also being investigated, and are expected to lead to the evolution of more effective therapies.
In the second article, Cristofanilli discusses the potential benefit of using circulating tumor cells (CTCs) for predicting the prognosis of breast cancer patients. The presence of CTCs in MBC patients about to start a new line of treatment has been shown to predict progression-free survival and overall survival, and is also a better method for predicting patient outcome than site of metastasis, type of therapy, and length of time to recurrence after definitive primary surgery. Because CTCs are detectable in MBC, irrespective of the site of metastasis, line of therapy, and initial hormone receptor status, the author suggests that CTC detection in combination with other MBC diagnostic technologies can allow early identification of disease, providing an opportunity for prompt intervention in patients at high risk, and appropriate patient selection and treatment. Combining CTC detection with other diagnostic technologies will help us to further understand the complex and heterogeneous tumor phenotype and its relationship with tumor-related immunity.
Sledge and Gökmen-Polar review the involvement of protein kinase C-β (PKC-β) and its splice variant PKC-βII in breast cancer, and discuss the potential for targeting PKC-β to control tumor growth and proliferation. The authors highlight the importance of angiogenesis as a therapeutic target in breast cancer, and discuss PKC-β-specific inhibitors, such as enzastaurin, and their effect on disease outcome. Inhibition of PKC-β with enzastaurin has been shown to block VEGF and basic fibroblast growth factor-stimulated angiogenesis. Although, to date, there have been no trials of enzastaurin in MBC, this drug has entered phase I trials, both as monotherapy and in combination with gemcitabine and cisplatin, and is in phase II studies for treatment of glioma and lymphoma and colon, prostate, non–small cell lung, ovarian, and pancreatic cancers, as well as chronic lymphocytic leukemia. Enzastaurin has also entered a phase III trial for glioblastoma. Preliminary results from these trials have shown that enzastaurin has promising activity and is well tolerated. These studies will also help to determine whether specific agents targeting PKC-β (such as enzastaurin) will be of benefit to MBC patients.
In his review of the use of single-agent gemcitabine for treating breast cancer, Smith assesses several studies that have investigated combinations of gemcitabine plus paclitaxel or docetaxel, as well as triplet combinations of gemcitabine plus paclitaxel plus trastuzumab, or gemcitabine plus paclitaxel plus an anthracycline. The combination of gemcitabine plus paclitaxel has been shown to be superior to paclitaxel alone as first-line therapy for metastatic disease without significant increased toxicity. On this basis, the author also suggests that gemcitabine should be considered an established first-line treatment option for patients with advanced breast cancer who have already received anthracyclines as adjuvant therapy. Novel, alternate-week gemcitabine plus paclitaxel and gemcitabine plus docetaxel combinations are being investigated.
The final article, by Dittrich, looks at the use of pemetrexed in breast cancer. Single-agent pemetrexed has shown remarkable activity, with significant toxicity reduction in treated patients. Pemetrexed has been examined in combination with several agents, including gemcitabine, carboplatin, and cyclophosphamide, and has shown promising results. The combination of pemetrexed plus gemcitabine proved to be active in patients who had previously been treated with an anthracycline plus a taxane. An ongoing prospective, randomized phase II study is presently investigating a combination of pemetrexed plus cyclophosphamide, the development of which will soon be assessable.
We wish to thank the authors for their valuable contributions to this supplement. Eli Lilly and Company is also gratefully acknowledged for providing an educational grant to support the supplement and for making its publication possible.
References
- National Cancer Institute: SEER Cancer Statistics Review (1975-2000). Available at: http://seer.cancer.gov/csr/1975_2000 (Accessed September 2005)
- . Radioimmunodetection and therapy of breast cancer . Semin Nucl Med . 2005;35:143–151
PII: S0093-7754(06)00140-0
doi:10.1053/j.seminoncol.2006.03.021
© 2006 Elsevier Inc. All rights reserved.
