Breast cancer cytotoxic therapy

Cytotoxic drugs that have been used alone and in combination as adjuvant therapy in breast cancer include doxorubicin, epirubicin, cyclophosphamide, methotrexate, fluorouracil,... 

The goal of therapy with early and locally advanced breast cancer is to cure the disease. Breast cancer is currently incurable after it has advanced beyond local-regional disease. The goal of treatment of metastatic breast cancer is to improve symptoms, maintain quality of life, and extend survival. Thus it is important to choose therapy with good activity while minimizing toxicities. Treatment of metastatic breast cancer with either cytotoxic or endocrine therapy often results in regression of disease and improvements in quality of life. 

Cytotoxic chemotherapy is eventually required in most patients with metastatic breast cancer. Patients with hormone-receptor-negative tumors require chemotherapy as initial therapy of symptomatic metastases. Patients who respond initially to hormonal manipulations eventually cease to respond and go on to require chemotherapy. The median duration of response is 5 to 12 months, but some patients will have an excellent response to an initial course of chemotherapy and may live 5 to 10 years or longer without evidence of disease. In general, median survival of patients after treatment with commonly used drug combinations for metastatic breast cancer is 14 to 33 months. The median time to response has ranged from 2 to 3 months in most studies, but this period depends in large part on the site of measurable disease. The median time to appearance of response is between 3 and 6 weeks in patients whose disease is primarily in the skin and lymph nodes, 6 to 9 weeks in patients with metastatic lung involvement, 15 weeks in patients with hepatic involvement, and nearly 18 weeks in patients with bone involvement. Thus it is often the case that an immediate response to therapy is not... 

Finally, therapeutic sequencing of different hormonal agents is fast becoming a common clinical practice, and fulvestrant is a good treatment choice to extend the opportunity for using endocrine therapies before reliance upon cytotoxic chemotherapy is necessary. Further research is required in order to evaluate the optimal sequence, both in clinical practice as well as in the laboratory, to choose the correct treatment of breast cancer in each person after the appearance of tamoxifen-induced drug resistance (Robertson 2004 Osipo et al. 2004 Johnston 2004 Robertson et al. 2005). 

The same is true with cytotoxic (anticancer) drugs, which have many adverse effects. Many neoplastic diseases (leukemia, breast cancer, etc.) show definite rhythms in presenting their symptoms. Thus, if the therapy is tuned according to these rhythms, not only is the disease better treated, but the patient also is protected from side effects. Thus the drug delivery should be programmed according to the disease condition. 

Early Breast Cancer Trialists Collaborative Group 1992. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 339, 1-15. 

Tamoxifen is beneficial in postmenopausal women when used alone or when combined with cytotoxic chemotherapy. The present recommendation is to administer tamoxifen for 5 years of continuous therapy after surgical resection. Longer durations of tamoxifen therapy do not appear to add additional clinical benefit. Results from several randomized trials for breast cancer have established that adjuvant chemotherapy for premenopausal women and adjuvant tamoxifen for postmenopausal women are of benefit to women with stage I (node-negative) breast cancer. While this group of patients has the lowest overall risk of recurrence after surgery alone (about 35-50% over 15 years), this risk can be further reduced with adjuvant therapy. 

Park BJ, Whichard ZL, Corey SJ (2012) Dasatinib synergizes with both cytotoxic and signal transduction inhibitors in heterogeneous breast cancer cell lines—lessons for design of combination targeted therapy. Cancer Lett 320(1) 104-110... 

In summary, capecitabine (1), an A -carbamate pyrimidine nucleoside prodrug of cytotoxic antimetabolite 5-fluorouracil, is an FDA-approved anticancer drug that can be administered orally. This compound uses a multilayer of prodrug strategies that not only avoids side effects arising from exposure of toxic metabolites to healthy tissue but is converted to 5-fluorouracil only by enzymes preferentially expressed in many cancer cell types, thus resulting in selective delivery of the drug to tumors. Capecitabine is marketed under the trade name of Xeloda for use in the treatment of metastatic colorectal and breast cancers and metastatic breast cancer that is resistant to paclitaxel or anthracycline therapies. 

We have examined the effects of llavonoids and isoflavonoids on the P-gp-and MRP- mediated MDR mechanisms in both mouse lymphoma and human breast cancer cell lines. The interactions of the drug transporters P-gp or MRP with flavonoids or isoflavonoids might be worth their use as anticancer agents, such as a single administration or a combination cancer therapy with cytotoxic agents such as mitomycin C (MMC). Differences in the activities of the P-gp and the MRP-mediated efflux pump could be found in the presence of flavonoids and isoflavonoids. 

Cytotoxic drags that have been used alone and in combination as adjuvant therapy in breast cancer include doxorubicin, epirubicin, cyclophosphamide, methotrexate, fluorouracil, paclitaxel, docetaxel, melphalan, prednisone, vinorelbine, and vincristine. The most common combination chemotherapy regimens employed in the adjuvant and metastatic setting are listed in Table 125-11. 

The prognostic usefulness of ERP in predicting response to cytotoxic chemotherapy was studied (H7) in pre- and postmenopausal women with advanced disseminated breast cancer and in patients receiving postsurgical adjuvant therapy. In both sets of patients, the response or failure to respond to chemotherapy was independent of ERP status. 

Trastuzumab (Herceptin) is a humanized monoclonal antibody against the HER2/neu (ErbB-2) member of the epidermal growth factor family of cellular receptors. The internal domain of the HER2/neu glycoprotein encodes a tyrosine kinase that activates downstream signals and enhances metastatic potential and inhibits apoptosis. HER2/neu is overexpressed in up to 30% of breast cancers and is associated with clinical resistance to cytotoxic and hormone therapy. A number of mechanisms of action have... 

Approximately two-thirds of primary breast cancers are ER -i- [45]. Oestrogen receptor status is important, as it determines whether or not the patient can benefit from hormonal therapy and also provides information on the history of the cancer, since ER -i- patients show a longer disease-free interval and total survival than ER - patients. About 60% of ER -I- patients and 10% of ER- patients may respond to hormonal therapy [45, 46]. Patients with ER - tumours have very little chance of remission with endocrine therapy ablative procedures are avoided and replaced by cytotoxic therapy [47]. 

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