Breast cancer is a heterogeneous disease which begins in the breast tissue and is characterized by uncontrolled cell division/proliferation and growth leading to the formation of a lump or a mass called a "tumor" (1). Breast cancer is the most common cancer among women and is one of the leading cause of death among women worldwide (2). Breast cancers may be classified as in situ when the cancer is localized within the ducts, lobules of the breast tissue or infiltrating/invasive when the cancer cells have broken the walls of the ducts, lobules and spread to other parts of the breast or other tissues of the body such as bone, lung, liver and brain by the process of metastasis (1). Breast cancer accounts for one in four cases of cancer diagnosed among women in the US and 192,370 new cases of invasive breast cancer were estimated for 2009-10 (1).
It has been suggested that the primary breast tumors originate when cells acquire mutations in the genes that are responsible for cell cycle progression, mitotic check point regulation, telomere maintenance, and centrosome function which leads to a disruption of the normal cell cycle and differentiation (3). In the case of metastatic breast cancer (MBC), these cells lose certain important properties of normal cells including anchorage dependence and contact inhibition which creates an ideal environment for metastasis to ensue. The process of metastasis occurs when tumors cells from the primary breast tumor become highly aggressive in their proliferation and migrate to form secondary tumors at other sites in the body (4). Metastasis is a complex process involving several changes including loss of cell-cell adhesion, loss of cell-extracellular matrix adhesion, invasion of cancerous cells into the neighboring tissue, disruption of basement membrane, invasion into the blood and lymphatic vessels and establishment of distant metastases and formation of new blood vessels by the process of angiogenesis (4-8). The deregulation of several pathways in cell differentiation, cell cycle progression, apoptosis, and angiogenesis helps maintain the process of metastasis. Even though there has been a significant progress in early detection and with the development of molecular targeted therapeutic agents, metastatic breast cancer is still incurable.
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1.1.2 Therapeutic options
Over the last two decades, there has been a significant progress in the early diagnosis and treatment of metastatic breast cancer. This is reflected by the decrease in the number of incidences of MBC (9) and an increase in the survival duration of patients diagnosed with MBC(10). These improvements can be attributed to the availability of newer chemotherapeutic agents, molecular targeted therapy, combination therapy and novel diagnostic methods. Despite these advances, statistics shows that the overall survival of women diagnosed with MBC is still less than 2 years (11-12) and only 20% of the patients diagnosed with distant metastasis will survive beyond a period of 5 years (12-13). Once the tumor cells have escaped from the primary site in the breast tissue and have started to metastasize, breast cancer (MBC) is a virtually incurable disease; most of the treatment provided is of palliative nature with the aim of increasing progression free survival (PFS), overall survival (OS) and improving the quality of life (QOL) of the patient (13-14).
The treatment of metastatic breast cancer include chemotherapy, radiation therapy, hormonal therapy, targeted biological therapy or a combination of the above and in certain cases may also involve the surgical removal of the primary tumor or metastatic tissue(12).
Over the last four decades, the taxanes or anthracycline combinations have been frequently used as the first line of therapy for patients diagnosed with MBC (15-16) . Endocrine therapy as first line of treatment for MBC depends on the hormone receptor status of the patient. Considering the heterogeneous nature of the disease the choice of treatment depends on the individual patient characteristics, pre-existing disease conditions and drug treatments(17). Physicians also depend on important prognostic markers such as the expression of the estrogen receptor (ER), progesterone receptor (PR) and the human epidermal growth factor receptor - 2 (HER-2)(17). For pre and postmenopausal women with estrogen receptor positive breast cancer, Selective Estrogen Receptor Modulator (SERM), Tamoxifen alone or in combination with third-generation selective aromatase inhibitors (AI) such as anastrozole, letrozole and exemestane are among the most effective agents used for adjuvant endocrine therapy(18). The menopausal status of the patient helps in deciding the sequence of first line and adjuvant treatment in endocrine therapy(18). For pre and post-menopausal women with hormone receptor positive breast cancers, sequential endocrine therapy administered in correlation with their menopausal status has shown to have equal or improved overall survival in comparison to polychemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil (CMF)(19-21) . In pre-menopausal women with estrogen receptor positive breast cancer ovarian ablation has also shown to improve the overall survival of the patient (19-20). Only 30% of the ER positive breast cancer patients treated with first line endocrine therapy respond positively and have a median progression time of 9-11 months (22). The decreased response rate and progression free survival period may be attributed to the development of resistance to endocrine therapy. One of the mechanisms of inherent or acquired resistance to Tamoxifen in patients with ER positive and HER-2 positive breast cancer is due to the continued cross talk between the ER , EGFR and HER-2 signaling cascades, where there occurs an increase in growth factor signaling upon prolonged repression of the mitogenic estrogen receptor genomic signaling by Tamoxifen(23). Genetic polymorphisms in drug metabolizing cytochrome P450 enzymes, drug-drug interactions are also responsible for the development of resistance to endocrine therapy (24).
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Patients who are not eligible for endocrine therapy (ER negative, PR negative, endocrine resistant), cytotoxic combination chemotherapy is the obvious choice for first line of treatment (25). However only 30-65% of the patients respond to first line anthracycline or taxanes based chemotherapy and these patients have a median time to progression period of 7-8 months (16, 26). Also, it has been observed that, once hormone receptor negative MBC patients stop responding to one line of chemotherapy, their response to other chemotherapeutic agents and progression free survival period decreases (16, 26). The most important factor decreasing the effectiveness of chemotherapy is the development of drug resistance (27). Multi drug resistance (MDR) may be acquired by one of several mechanisms which include overexpression of drug efflux proteins (E.g. ABC transporter proteins P-glycoprotein, BCRP, MRP-1 etc), epigenetic phenomenon such as DNA methylation and phosphorylation, activation or inactivation of drug and alterations in the drug target(27). The taxanes, anthracyclines, anti-metabolites and vinca-alkaloids that are widely prescribed chemotherapeutic agents for MBC are substrates of P-glycoprotein (28). One way to overcome drug resistance
Several of the currently prescribed chemotherapeutic drugs Combination chemotherapy with more than may be one of the options to delay
Chemotherapy with more than two
is decreased patients who do not respond to one line of chemotherapy have a much lesser response to other chemotherapeutic agents For patients with hormone receptor negative (ER negative, PR negative) MBC, hormonal therapy is not an option for treatment. Irrespective of the stage of the breast cancer and metastasis, these patients are treated with
Irrespective of the hormone receptor status of the patient, cytotoxic chemotherapeutic agents such as the anthracyclines and taxanes apart from other newer cytotoxic
Cytotoxic chemotherapeutic agents such as the taxanes and anthracyclines have been the first line
Breast cancers are classified based on the hormone receptor status of
1.1.2 Currently available therapeutic options
1.1.3 Targeted therapy for breast cancer
Targeted therapy for breast cancer aims at
Look at the receptor status of the tumor, ER-ve, fewer therapeutic options. 20% of the tumors are HER-2 positive or over expressing.
1.1.5 Phage display
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