I. Introduction

Breast cancer is the second commonest cause of cancer-related death in women, both in Europe and in the USA (Fornier, 2005; Mouridsen, 2005). Despite significant advances in our understanding of the molecular basis of this disease, cure remains an elusive goal with most efforts focused on clinical management- a ‘damage limitation exercise’. This article highlights current as well as well as some of the more recent drug treatment modalities for breast cancer. They are either targeted therapies aimed at inhibiting the action of defined growth modulatory genes or general cytotoxic agents that interfere with cellular proliferation in a relatively non-specific manner.

II. Endocrine therapy

Endocrine therapy is an important systemic treatment for all stages of hormone receptor-positive breast cancer. The standard treatment for early, hormone-sensitive breast cancer is surgery and when breast-conserving surgery is performed, radiotherapy. This is generally followed by adjuvant endocrine therapy given in selected cases. Following disease progression or recurrence, second-line endocrine agents are employed. In advanced stages, treatment is essentially palliative, with the goal being disease control and maintenance of quality of life (O’Shaughnessy, 2005). Sequential endocrine therapy continues as long as the patient remains hormone-sensitive. Once hormone-resistant disease develops, chemotherapy is the current alternative (Howell, 2005).

A. Selective estrogen receptor modulators (SERMs)

Endocrine therapy is based on the observation that estrogen is the major growth promoter for breast cancer cells. Tamoxifen (Novaldex^R) is one of the oldest used SERMs. It inhibits the growth of breast tumors by competitive antagonism of estrogen at its receptor site. It also exhibits partial estrogen-agonist effects. These effects can be beneficial, since they may help prevent bone demineralization in postmenopausal women, but also detrimental, since they are associated with increased risks of uterine cancer, thromboembolism, and tamoxifen resistance(Fisher, 1996; Pritchard, 1997; Hortobagyi, 1998).

In premenopausal patients, tamoxifen usage is often associated with bone loss in those who continue to menstruate after adjuvant chemotherapy. On the other hand, it decreased bone loss in women who developed chemotherapy-induced amenorrhea (Vehmanen, 2006).

Tamoxifen is normally taken orally for five years, beyond which there seems to be little additional benefit. As adjuvant therapy postoperatively it is the current standard first-line agent for patients with early, estrogen-receptor (ER) positive and/or progesterone receptor (PR) positive breast cancer. It is also indicated as adjuvant therapy in patients with metastatic disease. In the chemoprevention setting, tamoxifen is the only available endocrine option for women at high risk of breast cancer but, given that these are healthy subjects, it is associated with an unacceptable rate of adverse events (Tobias, 2004).

Toremifene (Fareston^R), another antiestrogen closely related to tamoxifen may be an option for postmenopausal women with metastatic breast cancer.

Newer SERMs, such as raloxifene (Evista^R), were initially approved to lower the risk of osteoporosis. Raloxifene's anti-cancer and chemopreventive effects are currently being investigated in the STAR (Study of Tamoxifen and Raloxifene) trial (Tobias, 2004).

B. Progestins

PR-positive advanced breast tumors can respond to the use of synthetic progesterone-like drugs such as megesterol acetate (Megace^R). Megestrol acetate was also shown to reduce the frequency of hot flushes in postmenopausal breast cancer patients (Wymenga, 2002).

Owing to its steroidal nature, Megace induces a significant increase in appetite leading to weight gain. Sometimes, it is used to reverse weight loss in patients withadvanced cancer.

Progestins are usually restricted to second or third-line therapies following aromatase inhibitors and/or antiestrogens.

C. LHRH agonists

LHRH analogs such as goserelin (Zoladex^R) and luprolide (Lupron^R) are a group of drugs that suppress ovarian estrogen production down to postmenopausal levels, essentially inducing a potentially reversible medical ovarian ablation. They are most effective in ER-positive early breast cancer in premenopausal women (von Minckwitz, 2004).

Goserelin, a principal agent of this class, is a biodegradable sustained-release 3.6mg depot administered monthly by subcutaneous injection (Mitchell, 2004). The indirect comparison of goserelin with tamoxifen as a single drug in the adjuvant setting showed similar efficacy. Furthermore, goserelin alone or in combination with tamoxifen was shown to be as effective as cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy.

Goserelin plus tamoxifen after cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) chemotherapy resulted in improved disease-free survival compared with CAF alone. Data concerning taxane-based and dose-dense chemotherapy are still lacking. Moreover, duration of therapy with LHRH analogs (2-3 years or longer) is still a matter of debate (Rody, 2005).

Early improvement in quality of life over the first 3-6 months of goserelin treatment supports its use as an alternative to chemotherapy in patients with early non-life threatening endocrine-responsive breast cancer (Mitchell, 2004).

In general, LHRH analogs are well tolerated and associated with mild effects of estrogen withdrawal such as amenorrhea, hot flushes, and vaginal dryness.

D. Aromatase inhibitors

In postmenopausal women, estrogen synthesis occurs in non-ovarian peripheral tissues. This mainly follows the route of conversion by aromatase, of the androgenic substrates androstenedione and testosterone to estrone and estradiol in the adrenal glands and adipose tissue, including that of the breast. Inhibitors of this enzyme have anti-proliferative effects presumably through suppression of this estrogen production (Smith, 2003).

In the early 1990s, third-generation aromatase inhibitors (AIs) were developed exhibiting high specificity at clinical doses, with little or no effect on cortisol or aldosterone. This class includes the reversible nonsteroidal imidazole-base inhibitors (e.g. anastrozole (Arimidex^R) and letrozole (Femara^R)), and the irreversible steroidal activators, exemestane (Aromisin^R) (Campos, 2004).

AIs are of no value in premenopausal patients where the ovaries are the primary sites of estrogen production.

Postmenopausal women with early hormone-receptor-positive breast cancer assigned to take letrozole after completing a five-year course of adjuvant tamoxifen (extended adjuvant therapy) were less likely than women on placebo to experience a recurrence, with improved four-year disease-free survival rates (Bryant, 2003; Goss, 2003).

Letrozole has been shown to be superior to megestrol acetate and aminoglutethimide as second-line treatment for advanced breast cancer. Letrozole was also superior to tamoxifen in first line-line treatment for advanced (Smith, 2003) as well as in systemic preoperative (neoadjuvant) treatment of locally advanced cancer (Mouridsen, 2005).

A recent adjuvant trial demonstrated significant superiority of letrozole over tamoxifen in disease-free survival (Mouridsen, 2005).

As first-line therapy, both anastrozole and letrozole have been shown to significantly prolong remission compared with tamoxifen in postmenopausal women with advanced breast cancer (Nabholtz, 2006).

Anastrozole has very recently been granted fast-track approval in the U.S and elsewhere for adjuvant treatment of early hormone-receptor positive breast cancer in postmenopausal women, particularly if tamoxifen is contraindicated (Bryant, 2003).

In the adjuvant setting, results of the ATAC trial showed that women taking anastrozole over a 3-year period had a 17% better disease free survival rate, compared with women taking tamoxifen. The ATAC trial has already shown superior efficacy and a number of important tolerability benefits of anastrozole versus tamoxifen for time to recurrence and incidence of contralateral breast cancer (ATAC Trialists’ Group, 2002).

The steroidal AI exemestane is highly active and well tolerated. Compared with megestrol acetate, exemestane treatment was shown to significantly prolong survival in women with progressive advanced breast cancer who experience failure of tamoxifen therapy, while at the same time, offering at least as much alleviation of pain and tumor-related signs and symptoms as megestrol acetate. Exemestane was associated with a significantly lower incidence of weight gain compared with megestrol acetate (Dixon, 2004).

Exemestane has also shown superiority when compared with tamoxifen for objective response and clinical benefit. Furthermore, exemestane appears to provide additional tolerability benefits in terms of positive androgenic effects on bone metabolism and lipid cholesterol levels, an important consideration in the treatment of early stage breast cancer.

In the first-line setting, data for exemestane have not been fully published and it is not yet approved for this indication (Nabholtz, 2006).

Third-generation AIs are given orally and appear to be generally well tolerated, though some short-term mild side effects have been recorded. The most common ones are hot flushes, vaginal dryness, musculoskeletal pain, and headache. In contrast to findings with tamoxifen, there is no evidence to suggest an increased risk of uterine carcinoma or venous thromboembolism with AIs.

Unlike tamoxifen which reduces bone demineralization through its agonist effects, AIs may enhance this process by lowering circulating estrogen levels. These undesired effects may be reduced with concurrent use of bisphosphonates such as pamidronate (Aredia^R), aledronate (Fosamax^R), or zoledronate (Zometa^R).

In light of their estrogen-lowering effects, nonsteroidal AIs are also expected to have adverse effects on blood lipids. One small study on postmenopausal women with breast cancer has reported an increase in total and LDL cholesterol after 16 weeks of letrozole treatment (Elissaf, 2001). The long-term risks of AIs remain to be fully assessed.

Currently, AIs are being evaluated for chemoprevention and in combination with chemotherapy and targeted therapies (Campos, 2004).

The ASCO panel recommends the following general guidelines for the use of AIs (Winer, 2005):

i. Postmenopausal women with ER-positive breast cancer may substitute an aromatase inhibitor for tamoxifen as initial adjuvant therapy to reduce the risk of recurrence.

ii. Postmenopausal women who are currently taking tamoxifen may consider switching to an aromatase inhibitor after two to five years.

iii. Women who switch to an aromatase inhibitor may continue this therapy for 2-3 more years, but no longer than 5 years. Women are advised that the result of treatment with an aromatase inhibitor for longer than this has not been studied and should best be taken in the context of a clinical trial.

iv. There are no data to recommend taking tamoxifen after an aromatase inhibitor.

v. In addition, women who develop invasive ER positive breast cancer while taking prophylactic tamoxifen for breast cancer risk reduction, and women who cannot take tamoxifen because of high risk of severe side effects, or who have tried tamoxifen and had to stop because of severe side effects, might be advised to consider using an aromatase inhibitor.

The ASCO panel indicates that it is not known whether AIs could be used interchangeably in clinical practice and therefore favors using the agent with the most data relevant to each individual clinical setting.

E. Estrogen receptor antagonists

An important addition to the armamentarium of endocrine therapies is the selective estrogen-receptor antagonist fulvestrant (Faslodex^R), also termed "an estrogen receptor down-regulator". With no agonist effects, it competitively binds, blocks, and degrades the ER. It was FDA approved in 2002 for treatment of ER-positive metastatic breast cancer in postmenopausal women (www.infoaging.org/d-breast). Given by injection on a monthly basis, fulvestrant 250mg is effective in the treatment of postmenopausal women with advanced breast cancer following AI failure as well as tamoxifen failure.

Fulvestrant is at least as effective as anastrozole following tamoxifen failure in terms of overall survival and shows activity after progression on AI (Tobias, 2004; Howell, 2005).

As first-line therapy, fulvestrant has been shown to be of similar efficacy to tamoxifen in patients with hormone receptor-positive tumors (Pippen, 2003), although which patient population is the most appropriate for its use in the first-line setting has yet to be determined.

Overall, the lower incidence of joint disorders compared to AIs, the absence of uterotrophic effects, the reduced incidence of hot flushes compared to tamoxifen, and the lack of cross-resistance with tamoxifen favors the use of fulvestrant in the sequential treatment of breast cancer (Howell, 2005).

II. Monoclonal antibodies

Significant advances in the use of targeted biological therapies with novel mechanisms of action over the past several years have changed, and continue to influence breast cancer treatment. The most studied are two monoclonal antibodies, trastuzumab and bevacizumab.

A. Trastuzumab

About 25-30 % of all human breast cancer patients have ER at less than 10 fmol/mg tumor protein; these invariably have the worst prognosis. In these cases, endocrine agents are generally ineffective. This has led to development of therapies aimed specifically at inhibiting the HER2/neu gene, which appears to be overexpressed in these tumors.

Trastuzumab (Herceptin^R) is the first humanized monoclonal antibody approved for treatment of HER-2 positive metastatic breast cancer. This biologic response modifier selectively binds to the extracellular domain of the HER2/neu protein, causing down-regulation of HER2/neu and inhibiting the growth of HER2/neu overexpressing tumors. It is indicated as monotherapy for patients with refractory metastatic breast cancer and in combination with paclitaxel because of their synergistic effect(Colomer, 2001). When compared to chemotherapy alone, combinations of trastuzumab plus chemotherapy lead to higher response rates, longer time to disease progression, and improved overall survival (Slamon, 2001).

A recent small study evaluated coadministration of trastuzumab and the cyclo-oxygenase (COX) 2-inhibitor celecoxib, which has shown chemoprotective and antineoplastic activity in rodent mammary carcinomas. Patients with HER-2 expression who had received trastuzumab–based therapy received celecoxib 400 mg twice a day and trastuzumab 2 mg/kg/week. To date, median time to disease progression was 9 weeks and one patient of nine (11%) had stable disease (Dang, 2002).

Trastuzumab should be given for one year with cardiac monitoring, and by either the weekly or three- weekly schedule (NCCN, 2006). The recommended initial loading dose is 4 mg/kg administered as a 90-minute infusion. The recommended weekly maintenance dose is 2mg/kg that can be administered as a 30-minute infusion if the initial loading dose was well tolerated (Genentech, 2002).

Trastuzumab, like other monoclonal antibodies is associated with infusion-related reactions, typically manifested as fever, chills, nausea, vomiting, diarrhea, and rare reports of pulmonary reactions. Trastuzumab has also been associated with an increased risk of cardiac dysfunction, primarily congestive heart failure (CHF) (Genentech, 2002). Trastuzumab is not advised to be given concurrently with an anthracycline because of cumulative cardiac toxicity.

According to the National Comprehensive Cancer network (NCCN) guidelines, trastuzumab should be incorporated into the adjuvant therapy of node-positive breast cancer that over-expresses HER-2. It should be also considered for patients with node-negative tumors greater than or equal to 1 cm and that overexpress HER-2.

B. Bevacizumab

Bevacizumab is a recombinant monoclonal antibody against vascular endothelial growth factor receptor (VEGF), a protein involved in the neovascularisation of multiple malignant tumors. In view of the known role of angiogenesis in breast cancer, two-phase III trials and three phase II trials were seeking to identify bevacizumab's effectiveness in various combinations with capecitabine, paclitaxel, and vinorelbine and as monotherapy. The only completed phase III trial compared capecitabine monotherapy with capecitabine plus bevacizumab in 462 patients with metastatic breast cancer. Inclusion criteria included prior treatment with an anthracycline and a taxane agent. No significant difference was found for time to disease progression. However, the overall response rate favored bevacizumab (19.8% versus 9.1% [p = 0.001]) (Miller, 2005).

In view of the lack of extension of the time to progression in the completed phase III trial in patients with MBC, a second phase III trial is investigating bevacizumab for locally recurrent breast cancer. Six hundred eighty-five patients are being randomized to receive paclitaxel alone or in combination with bevacizumab (Miller and Wang, 2005).

The adverse effect profile of bevacizumab includes hypertension, proteinuria, thrombosis, and epistaxis (Rugo, 2004).

At this point, data on bevacizumab are too limited to be recommended as a treatment option for breast cancer outside of a clinical trial (Motl, 2005).

III. Cytotoxic chemotherapy

Chemotherapy is administered in a series of cycles with intervals in between to minimize side effects as well as to allow time for cells in the patient’s normal tissues to recover. The number of cycles is agent dependent. Typically, 4-6 cycles for a total time of 3-6 months are employed depending on the agent used.

Several types of cytotoxic agents are used to treat breast cancer. The most common ones are doxorubicin (Adriamycin^R), pegylated liposomal doxorubicin, cyclophosphamide (Cytoxan^R), fluorouracil (5-FU), epirubicin (Ellence^R), gemcitabine (Gemzar^R), and vinorelbine (Navelbine^R).

Docetaxel (Taxotere^R), paclitaxel (Taxol^R), or albumin-bound paclitaxel (Abraxane^R) are the preferred options for patients with metastatic breast cancer that does not respond to standard chemotherapy (NCCN, 2006).

Capecitabine (Xeloda^R), an oral fluoropyrimidine carbamate, was developed as a prodrug of 5-FU with the goal of improving tolerability and intratumor drug concentrations through tumor-specific conversion to the active drug. Capecitabine is currently approved by the FDA for use (1) as a single agent in metastatic breast cancer patients who are resistant to both anthracycline- and paclitaxel-based regimens or in whom further anthracycline treatment is contraindicated and (2) in combination with docetaxel after failure of prior anthracycline-based chemotherapy. The most common dose-limiting adverse effects associated with capecitabine monotherapy are hyperbilirubinemia, diarrhea, and hand-foot syndrome (Walko, 2005).

A. Chemotherapy in early breast cancer

In early breast cancer, chemotherapy is usually applied as adjuvant treatment following local excision of the tumor, with the aim of preventing metastasis (Hennessy, 2005).

Adjuvant combination chemotherapy is the systemic treatment of choice in lymph node-positive patients with ER negative tumors, irrespective of menopausal status, and may be considered as an option in addition to endocrine therapy in patients with ER positive tumors.

For node-positive patients with no evidence of spread, anthracycline-based regimens are preferred (Table 1). Available data indicate that adjuvant chemotherapy with an anthracycline-containing regimen results in a small but statistically significant improvement in survival compared with regimens that do not contain an anthracycline (Early Breast Cancer Trialists' group, 1998).

Taxanes were recently introduced in the adjuvant setting for node-positive breast tumors. Currently available phase III data with adjuvant paclitaxel-anthracycline combinations demonstrate their significant superiority in terms of clinical outcome when compared with doxorubicin-based, non-taxane-containing combinations (Henderson, 2003).

Conventionally, lymph node-negative patients were not considered for chemotherapy, as it was widely believed that the disease was confined entirely to the breast and, therefore, would most likely be cured by local treatment. However, several large clinical trials (Early Breast Cancer Trialists’ Collaborative Group, 1998; Hennessy, 2005) showed significant improvement in disease-free survival in these patients.

The adjuvant chemotherapy options for node-negative patients include CMF (cyclophosphamide/methotrexate/5FU), FAC (5-FU, doxorubicin, cyclophosphamide), and AC (doxorubicin, cyclophosphamide).

Chemotherapy is less commonly given to older women with early stage disease (lymph node-negative), as the absolute value of chemotherapy appears to decrease with advancing age.

Neoadjuvant chemotherapy is employed to shrink the size of the tumor and allow more breast-conserving types of surgery to be undertaken or more complete excision of very large tumors. In the preoperative setting, doxorubicin, epirubicin, paclitaxel, or docetaxel-based regimens are recommended. Patients with tumors over-expressing HER-2/neu should be considered for neoadjuvant chemotherapy incorporating trastuzumab (NCCN, 2006).

B. Chemotherapy in advanced breast cancer

Approximately 30% of women initially diagnosed with earlier stages of breast cancer eventually develop recurrent advanced or metastatic disease. Cytotoxic therapy tends to be used as first-line therapy in patients with ER-negative tumors, or at a later stage in patients with initially ER-positive tumors, which eventually fail to respond to endocrine interventions.

In advanced breast cancer, the median duration of response to a chemotherapy regimen usually ranges from 6-12 months, which is generally less than that observed with hormonal therapies.

In the metastatic setting, the use of combination therapy versus monotherapy or sequential single agents remains a controversial issue. Combination therapies generally result in higher response rates and times to disease progression than sequential single agents but usually at a cost of greater toxicity (Miles, 2002).

With chemotherapy regimens, the taxanes were shown to exhibit a survival benefit of at least 20 to 30% in the majority of clinical trials. Capecitabine and gemcitabine, two antimetabolites, have shown high activity and acceptable tolerability in a range of settings for MBC. These include single-agent and combination regimens in patients with anthracycline- and/or taxane-pretreated disease. Moreover, the introduction of targeted biologics such as trastuzumab and bevacizumab in

100% of the planned dose of Abraxane^R at 100 mg/m² administered weekly over 30 minutes with no dose reduction (www.fda.gov/cder/foi/label/2005).

Paclitaxel was directly compared with albumin-bound paclitaxel (ABI-007) in 460 patients with MBC in a randomized phase III trial (Gradishar, 2005). ABI-007 was associated with a significantly greater response rate and time to disease progression than paclitaxel, but median survival rates were similar in the two treatment groups.

D. Side effects of cytotoxics

As with radiotherapy, cytotoxic agents affect all actively dividing cells in the body, both cancerous and healthy. This produces unpleasant side effects such as nausea, vomiting, alopecia, and occasionally more serious effects including neutropenia and cardiotoxicity (Partridge, 2001).

Chemotherapy will also cause ovarian failure, resulting in amenorrhea in a substantial proportion of pre-menopausal women, depending upon the treatment regimen used. It is thought that at least part of the benefits achieved with chemotherapy in pre-menopausal women could be due to their additional ‘endocrine’ effects, i.e. manifested through chemical ovarian ‘ablation’.

The side effects of chemotherapy regimens vary depending upon the particular drugs administered, the dose levels, routes of administration and duration of treatment.

Some toxic effects are specific to particular agents. For instance, vincristine and vinorelbine can produce neurological effects (loss of reflexes, parasthesia, and neuropathy). Doxorubicin and epirubicin produce cumulative cardiac effects such as congestive heart failure while methotrexate causes renal and hepatic damage (NCCN, 2006).

E. High-dose chemotherapy plus bone marrow/stem cell transplants

The necessity of bone marrow rescue is a highly controversial issue. Some studies found that high-dose chemotherapy (i.e. 2-20 times standard doses) followed by stem-cell transplantation improved survival among women with widespread cancer (Rodenhuis, 2003). Others reported that although the treatment increased time to cancer recurrence, it did not improve overall survival (www.infoaging.org/d-breast).

IV. Novel targets for breast cancer therapy

An increased understanding of the biology of breast cancer has led to the identification of novel therapeutic targets. New biological concepts may present an opportunity for the development of promising and innovative treatment paradigms that target multiple neoplastic pathways, with the goal of producing high efficacy and minimal toxicity.

A. PARP inhibitors

Women who have inherited mutations in the BRCA1 and BRCA2 genes have about an eighty per cent risk of developing breast cancer, ovarian cancer or both. During replication, these genes are involved in DNA repair by a recombination mechanism.

Cells with mutated BRCA genes cannot undergo recombination and therefore rely completely on another process involving a protein called PARP to fix the damage and continue replication.

Bryant et al reported a novel approach to treating and preventing hereditary breast cancer. They described how the use of a PARP inhibitor could specifically kill tumor cells which have a defect in the gene causing hereditary breast cancer. These findings could also lead to a prophylactic treatment for women with identified high-risk mutations in the BRCA genes.

The new treatment uses an agent that prevents PARP from repairing the DNA, making recombination essential. The breast cancer tumor cannot perform recombination and is therefore unable to replicate resulting in tumor necrosis. The beauty of this system is that only tumor cells lack BRCA genes and thus they completely rely on PARP.

Normal cells are likely to be unaffected by the treatment and continue to use recombination to repair any mistakes that may occur. Since normal cells do not need the PARP backup system to survive, PARP inhibitors could be used as a prophylactic treatment to kill BRCA deficient cells and prevent tumor formation (Bryant, 2005).

B. Farnesyltransferase inhibitors (FTIs)

Farnesyltransferase inhibitors (FTIs) are a new class of biologically active anticancer drugs. They inhibit farnesylation of a wide range of target proteins, including ras. It is thought that they block ras activation through inhibition of the enzyme farnesyl transferase, ultimately resulting in cell growth arrest (Appels, 2005). Although FTIs were originally designed to target the ras signal transduction pathway, it is now clear that several other intracellular proteins are also dependent on post-translational farnesylation for their function.

Studies with FTIs have shown promising activity in patients with breast cancer associated with ras mutations.

Preclinical data revealed that although FTIs inhibit the growth of ras-transformed cells, they are also potent inhibitors of a wide range of cancer cell lines that contain wild-type ras, including breast cancer cells. Additive or synergistic effects were observed when FTIs were combined with cytotoxic agents (in particular the taxanes and gemcitabine) or endocrine therapies (tamoxifen).

Phase I trials with FTIs have explored different schedules for prolonged administration, and dose-limiting toxicities included myelosuppression, gastrointestinal toxicity, peripheral neuropathy, and fatigue (Head, 2004).

Clinical efficacy of the FTI tipifarnib (Zarnestra^R) against breast cancer was seen in a phase II study (Johnston SRD, 2003). Seventy-six patients with advanced breast cancer were given tipifarnib orally either at a continuous dose of 300 mg twice daily (n=41) or an intermittent dose of 300 mg twice daily for 21 days followed by 7 days of rest (n=35). The trial showed nine partial responses and nine cases of stable disease (of at least 24 weeks’ duration). Although clinical efficacy was similar between patients treated intermittently and those receiving continuous dosing, the side effect profile was significantly improved by using an intermittent schedule.

Although their true mechanism of action remains unclear, ongoing clinical trials are assessing the potential of FTIs to enhance the efficacy of current endocrine and cytotoxic therapies in breast cancer. Combinations with other signal transduction inhibitors may be an additional strategy that merits further research.

C. Small molecule tyrosine kinase inhibitors

A number of low molecular–weight tyrosine kinase inhibitors (TKIs) directed at members of the ErbB family (EGFR, HER2, and HER4) is now in clinical development. None has received US FDA approval for breast cancer treatment. These small molecules compete with ATP for binding to the kinase domain of the receptor. They are orally bioavailable and generally well tolerated.

Knowing that EGFR is overexpressed in 16-48% of human breast cancers, several groups have reported an association between EGFR expression and poor prognosis. The reversible EGFR inhibitors gefitinib (Irissa^R) and erlotinib (Tarceva^R) are furthest in the course of development. Both gefitinib and erlotinib have activity against multiple breast cancer cell lines in vitro and in xenograft models. However, neither gefitinib nor erlotinib has demonstrated significant single-agent activity against refractory metastatic breast cancer (Albain 2002; Winer 2002).

Several ongoing phase II and phase III trials utilize gefitinib and erlotinib in combination with chemotherapy in MBC. Alternatively, combining antibody-based therapy with TKIs may allow for more complete blockade of erbB-mediated signal transduction pathways, and thereby delay or overcome drug resistance. This strategy is being employed in a phase II study of trastuzumab and gefitinib (Lin, 2004).

Recent data also indicate that upregulation of the ErbB receptors may mediate endocrine resistance, due to crosstalk between the ErbB and estrogen receptor (ER) signal transduction pathways (Atalay, 2003). This crosstalk has been postulated to occur via multiple mechanisms, including upregulation of EGFR and HER2 expression by tamoxifen, ligand-independent signaling of ER via PI3K, and modulation of coactivators of ER via downstream effectors of the ErbB pathway (Johnston SR, 2003).

In preclinical models, co-blockade of the EGFR and ER pathways with gefitinib and either tamoxifen or fulvestrant resulted in restoration of tamoxifen sensitivity and delay of resistance to estrogen deprivation in HER-2 overexpressing breast tumors. Based on these data, several phase II trials of gefitinib with hormonal therapy are ongoing in women with ER-positive metastatic breast cancer.

D. Rapamycin (mTOR antagonists)

Mammalian target of rapamycin (mTOR) is a serine-threonine kinase member of the cellular phosphatidylinositol 3-kinase (PI3K) pathway, which is involved in multiple biologic functions such as transcriptional and translational control.

mTOR is a downstream mediator in the PI3K/Akt signaling pathway and plays a critical role in cell survival. The mTOR signaling pathway is likely to be aberrantly activated in a substantial number of breast tumors, making mTOR an especially promising target for breast cancer therapy. In breast cancer, this pathway can be activated by membrane receptors, including the ErbB family of growth factor receptors, the insulin-like growth factor receptor, and the estrogen receptor. There is evidence suggesting that Akt promotes breast cancer cell survival and resistance to chemotherapy, trastuzumab, and tamoxifen.

Rapamycin is a specific mTOR antagonist that targets the Akt/PI3K pathway and blocks the downstream signaling elements, resulting in cell cycle arrest in the G₁phase (Carraway, 2004). Rapamycin and rapamycin analogs have emerged as promising antitumor drugs for many cancer types, including breast cancer.

When combined with other chemotherapeutic agents, rapamycin and rapamycin analogs have been reported to increase the efficacy of a variety of cytotoxic agents, including cisplatin, doxorubicin, 5-FU, and cyclophosphamide (Geoerger, 2001). Mondesire et al reported that in vitro rapamycin has a synergistic effect with paclitaxel, carboplatin, and vinorelbine and an additive effect with doxorubicin and gemcitabine. Furthermore, they showed that rapamycin in combination with paclitaxel leads to a significant reduction in tumor growth in vivo in a rapamycin-sensitive xenograft model. Their results demonstrated that rapamycin might be able to at least partially overcome resistance to paclitaxel and carboplatin in HER2/neu-overexpressing cells, suggesting a potential approach to these poorly behaving tumors. On the other hand, cell lines that were resistant to the growth-inhibitory effect of rapamycin were also resistant to rapamycin-mediated chemosensitization. This suggests that combination therapy of cytotoxic agents with rapamycin may be effective in patients selected for aberrations in the PI3K/Akt pathway (Mondesire, 2004).

In the next few years, and as trials with targeted agents mature, their role will be further defined and their mechanism of action will be more elaborated. This may help identify patients who will benefit the most from these novel therapeutic approaches.

Acknowledgements

I am highly indebted to Professor Yunus Luqmani for helpful comments and invaluable contribution to this study.

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www.infoaging.org/d-breast

Leyla Sharaf

Single agents	Doxorubicin, epirubicin, pegylated-liposomal doxorubicin, paclitaxel, docetaxel, capecitabine, vinorelbine, gemcitabine, albumin-bound paclitaxel,
Agent with Bevacizumab	Paclitaxel
Combinations	CAF/FAC, FEC, AC, EC, AT, CMF, docetaxel/capecitabine, gemcitabine/paclitaxel
Combinations with Trastuzumab	Paclitaxel ± Carboplatin Docetaxel ± Carboplatin Vinorelbine
Other active agents	Cisplatin, carboplatin, etoposide(po), vinblastine, fluorouracil continuous infusion

Review Article