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Systemic Treatment of Breast Cancer

Systemic Treatment of Breast Cancer

Over the past 20 years we have witnessed the emergence of a new generation of aromatase inhibitors as valuable antiestrogens in the management of both advanced and early-stage breast cancer. In addition, the list of cytotoxic chemotherapeutic agents useful in the control of breast cancer has grown considerably. The emergence of anthracyclines was a major chemotherapeutic step forward in the 1980s, and the taxanes have clearly been the agents with the greatest impact on breast cancer treatment over the past decade. The end of the past 2 decades has been characterized by a greater understanding of the molecular biology of breast cancer, rational drug design, and the development of agents that disrupt specific cellular targets and pathways. The development of better prognostic and predictive assays that employ a panel of genes involved in the malignant and metastatic phenotype promises to allow clinicians to better select patients who could forgo adjuvant chemotherapy. Finally, adjunctive and supportive therapy of breast cancer has evolved substantially over the past 20 years. This review will highlight some of the landmark accomplishments during this time, and offer a glimpse at where we might be 20 years from now.

The first observations of hormone-dependency of breast cancer were made over a century ago, when ovarian ablation was observed to cause regression of systemic disease.[1] The past 2 decades have witnessed the emergence of a new generation of aromatase inhibitors as valuable antiestrogens in the management of both advanced and early-stage breast cancer. The role of ovarian function suppression in the adjuvant treatment of premenopausal women with hormone-sensitive breast cancer is only now being prospectively investigated in randomized trials, after Beatson's early observation. Progress in the development of effective nonantiestrogen therapy (eg, cytotoxics and targeted agents) for breast cancer has been indeed much more contemporary. The past 2 decades constitutes about one-half of what most would consider to represent the "chemotherapy era."

The list of cytotoxic chemotherapeutic agents useful in the control and cure of breast cancer is long, and growing (Table 1). A high level of evidence-based medicine supports the use of sequential single-agent chemotherapy for metastatic disease, with judicious use of combination chemotherapy arguably indicated for selected patients.[2] Just as the emergence of anthracyclines was a major chemotherapeutic step forward in the 1980s, the taxanes have clearly been the agents with the greatest impact on breast cancer treatment over the past decade. Dose escalation of cytotoxic chemotherapeutic agents into the realm of myelosuppression requiring autologous bone marrow and peripheral blood stem cell support did not improve survival for patients with either metastatic or early-stage disease[3-5]—this was a lesson learned the hard way. More modest dose escalation of agents such as paclitaxel and docetaxel (Taxotere) has not prolonged time to disease progression.[6,7] More frequent dosing of paclitaxel has proven superior to standard every-3-week dosing,[8] and indeed dose-dense chemotherapy with anthracycline and taxane improves disease-free and overall survival as compared to conventional every-3-week dosing.[9]

The end of the past 2 decades has been characterized by a greater understanding of the molecular biology of breast cancer, rational drug design, and the development of agents that perturb specific, often premeditated cellular targets and pathways. The emergence of trastuzumab (Herceptin)[10-12] and, in the near future, lapatinib (Tykerb),[13,14] agents that improve outcomes for patients with HER2-overexpressing breast cancers, is one obvious example. The benefit observed for the addition of the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (Avastin) to weekly paclitaxel in metastatic breast cancer as reported in Eastern Cooperative Oncology Group (ECOG) 2100 represents another.[15] Whether the target is angiogenesis, HER-family signaling, apoptosis, or other pathways, numerous agents in development are likely to emerge from ongoing clinical trials, and optimizing their use in combinations with both cytotoxics and other targeted agents will remain a challenge as we begin to morph beyond the chemotherapy era.

It is well recognized that in the effort to cure early-stage breast cancer, many women will receive adjuvant chemotherapy without deriving benefit. The development of better prognostic and predictive assays that employ a panel of genes involved in the malignant and metastatic phenotype promises to allow clinicians to better select those patients who cold forego adjuvant chemotherapy.[16-19] One such assay, the Oncotype DX 21-gene reverse transcriptase polymerase chain reaction assay is already used in the clinic and is being further studied in a randomized phase III trial.[19,20]

Finally, adjunctive and supportive therapy of breast cancer has evolved substantially over the past 20 years. The use of granulocyte colony-stimulating factor (G-CSF, Neupogen) has ameliorated neutropenic complications of chemotherapy (and facilitated dose-dense chemotherapy), erythropoietin has mitigated against anemia, and bisphosphonates have reduced skeletal complications. Newer generation antiemetics have lessened chemotherapy-induced nausea and vomiting. Ongoing trials are examining pharmacologic means of preventing peripheral neuropathy, mucositis, and cognitive dysfunction.

This review will highlight some of the landmark accomplishments of the past 20 years, and offer a glimpse at where we might be 20 years from now.

Adjuvant Chemotherapy

Over the past 2 decades, numerous clinical trials have established the benefit of anthracycline-based chemotherapy over non-anthracycline-containing chemotherapy, a finding that has been substantiated by a meta-analysis showing a decline in breast cancer mortality during that time (Figure 1).[21] More recent analysis of outcomes from several of these trials suggests that the differential benefit of anthracycline-containing chemotherapy may be confined to or largely derived in those patients with HER2-overexpressing tumors.[22,23] Current investigation focuses on whether amplification of the topoisomerase II-alpha gene may be a useful aid in predicting for greater anthracycline benefit.[24]

Numerous trials have demonstrated the benefit of the addition of paclitaxel and docetaxel in improving disease-free and overall survival in early breast cancer,[25-28] and these agents have become standard components in the adjuvant and neoadjuvant therapy of early-stage disease. The recently reported ECOG 1199 adjuvant trial showed no significant difference in efficacy between these two taxanes, with less toxicity noted for paclitaxel (Table 2).[29]

A recent report indicates the feasibility of integrating nanoparticle albumin-bound paclitaxel (Abraxane) into dose-dense adjuvant chemotherapy.[30] Ongoing Intergroup studies are comparing paclitaxel to doxorubicin-cyclophosphamide for lower-risk early-stage disease, and weekly to every-2-week paclitaxel. Examination of the potential contribution of agents not currently considered standard in the adjuvant setting, such as gemcitabine (Gemzar) and capecitabine (Xeloda), is also ongoing.

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