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Facts and Controversies in Systemic Treatment of Metastatic Breast Cancer

Jules Bordet Institute, Brussels, Belgium

Correspondence: Martine J. Piccart, M.D., Ph.D., Department of Medical Oncology, Jules Bordet Institute, Boulevard de Waterloo, 125, 1000 Brussels, Belgium. Telephone: 32-2-541-32-06; Fax: 32-2-538-08-58; e-mail: martine.piccart{at}bordet.be

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Which Patients Benefit From... Which Is the Best... What Is the Role... What Is the Best... CT Tailoring Biological Therapies What Is the Background... Conclusions References

 
After completing this course, the reader will be able to:

1. Describe the roles of hormonal treatment, chemotherapy, and biological agents in the therapy of metastatic breast cancer patients.
   
2. Explain how to select the best available treatment for a metastatic breast cancer patient.
   
3. Discuss the controversies and future developments of treatment modalities for metastatic breast cancer patients.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Which Patients Benefit From... Which Is the Best... What Is the Role... What Is the Best... CT Tailoring Biological Therapies What Is the Background... Conclusions References

 
The management of metastatic breast cancer remains an important and controversial issue. The systemic therapy, comprising endocrine, cytotoxic and biological agents, can be administered sequentially or in combination. Few drugs or combinations provide a significant improvement in survival and, therefore, in the great majority of cases, treatment is given with a palliative intent. With the exception of first-line therapy, for which general agreement exists, currently there is no consensual standard of care. This review will summarize the current knowledge and outline the controversial issues related to systemic therapy of metastatic breast cancer, with emphasis on treatment tailoring. The potential role of tumor molecular profile(s) in the selection of patients that could benefit the most from each strategy/agent will be discussed.

Key Words. Breast cancer • Endocrine therapy • Chemotherapy • Biological therapy • Tailoring therapy

	INTRODUCTION

Top Learning Objectives Abstract Introduction Which Patients Benefit From... Which Is the Best... What Is the Role... What Is the Best... CT Tailoring Biological Therapies What Is the Background... Conclusions References

 
Approximately 10% of newly diagnosed breast cancer patients have locally advanced and/or metastatic disease, and 20%–85% of patients, depending on the initial stage, tumor biology, and treatment strategy used [1], who are diagnosed with early breast cancer will later develop recurrent and/or metastatic disease. Despite more than 3 decades of research, metastatic breast cancer (MBC) remains essentially incurable and, after documentation of metastasis, the median survival time is approximately 2 years. At the present time, clinicians can use three different systemic treatment modalities for advanced breast cancer: endocrine therapy (ET), chemotherapy (CT), and biologic targeted therapy (BT). This review will summarize up-to-date knowledge and outline controversial issues related to systemic therapy of MBC.

	WHICH PATIENTS BENEFIT FROM SYSTEMIC THERAPY?

Top Learning Objectives Abstract Introduction Which Patients Benefit From... Which Is the Best... What Is the Role... What Is the Best... CT Tailoring Biological Therapies What Is the Background... Conclusions References

 
The optimal management of MBC remains a significant therapeutic challenge; the selection of the most appropriate medical therapy for the individual patient must currently be based on breast cancer risk evaluation, predictive factors, toxicity risk, and patient preferences. Following the assessment to determine the extent of the disease, the presence of life-threatening lesions (i.e., presence of visceral metastases and/or rapid progressive disease), or imminent complications that require aggressive management and urgent tumor control, patients can be classified in two groups: low risk of recurrence (usually hormone responsive) or high risk of recurrence (usually hormone nonresponsive) (Fig. 1) [2]. Since trastuzumab has proven added survival benefit to CT in patients with HER-2-overexpressed/amplified tumors [3], treatment tailoring in 2004 requires HER-2 status determination.

View larger version (16K): [in this window] [in a new window]   Figure 1. Optimal standards of care in breast cancer risk evaluation in metastatic breast cancer.

	WHICH IS THE BEST SYSTEMIC THERAPY?

Top Learning Objectives Abstract Introduction Which Patients Benefit From... Which Is the Best... What Is the Role... What Is the Best... CT Tailoring Biological Therapies What Is the Background... Conclusions References

 
Endocrine Therapy
ET remains the most important approach to the treatment of hormone-sensitive non-life-threatening MBC. This systemic therapy has the advantage of combining efficacy, minimal toxicity, and good quality of life. ET use in clinical practice is based on a positive estrogen receptor (ER) and/or progesterone receptor (PgR) status of the primary tumor or, if at all possible, of an easily accessible metastasis [11]. This type of therapy is usually the first choice when the risk of rapid disease progression is low, i.e., there is no life-threatening disease. The selection of the most appropriate ET takes into account the menopausal status of the patient, the type of adjuvant ET received, and past medical history of thromboembolic disease.

What Type of ET Should Be Used?
Historically, tamoxifen, the first systemic ET approved for the treatment of MBC, was the gold standard hormonal agent for first-line treatment with hormone-sensitive breast cancer for more than 25 years. Because of its partial-agonist properties and the frequent emergence of resistance, alternative ET has been developed and has successfully challenged the role of tamoxifen: aromatase inhibitors (AIs) and pure antiestrogens.

The first AI used in MBC, aminoglutethimide (AG), has now been practically abandoned, due to its low potency and frequent side effects [12]. Second-generation agents are also seldom used because of their inconvenient way of administration (formestane) and side effects (fadrozole) [13]. Third-generation AIs, either nonsteroidal (letrozole, anastrozole, and vorozole), or steroidal (exemestane), are more potent, more selective, and better tolerated, inhibiting the sites of estrogen synthesis in postmenopausal patients. Randomized clinical trials have compared third-generation AIs to megestrol acetate and to AG as second-line therapy for MBC (Table 1) [14–22]. All of the trials showed significantly reduced toxicity and, at least, similar efficacy. Due to these highly consistent results providing level-1 evidence, AIs (anastrozole, letrozole, and exemestane) became the recommended second-line ET after tamoxifen. Next, a direct comparison of AIs to tamoxifen as first-line ET has shown prolonged time to treatment progression (TTP) with anastrozole in the subgroup of ER/PgR-positive patients, and improved response rate (RR), TTP, time to treatment failure (TTF), and overall survival (OS) up to 2 years with letrozole over tamoxifen (Table 2) [23–27]. Preliminary data of a phase III trial comparing exemestane with tamoxifen also seem very promising [27]. These first-line data taken together (level-2 evidence) have led to another change in standard clinical practice, even before final results of the exemestane trial. Since the late 1990s, AIs have established themselves as the new gold standard for first-line ET in postmenopausal MBC patients.

Which Is the Best Sequence of ET?
With the approval of third-generation AIs as first-line hormonal therapy for postmenopausal MBC patients, the question of the best sequence of ET remains open. Indirect observations, such as the benefit limited to the first 2 years seen on the survival curves of the letrozole/tamoxifen trial, seem to suggest that tamoxifen may not be the best option after AI failure. With the more common use of AIs in earlier stages of breast cancer, as first-line treatment for advanced disease, and eventually adjuvant therapy, data on the efficacy of fulvestrant after AIs are essential to determine the most appropriate sequence. On the other hand, a retrospective analysis showed that MBC patients progressing on fulvestrant remain sensitive to subsequent ET with anastrozole or letrozole [31].

Sequencing data for anastrozole and tamoxifen have shown that tamoxifen is likely to be effective after progression on anastrozole. Indeed, combined analysis of two international randomized, double-blind trials of 1,021 patients has shown that 48% of patients gained clinical benefit with sequential administration of first-line anastrozole followed by tamoxifen [32].

What Is the Best ET for Premenopausal Patients?
For premenopausal women with ER- and/or PgR-positive MBC, the available ET options are ovarian ablation through surgery, RT, or luteinizing hormone releasing hormone (LHRH) analogues; tamoxifen; or a combination of ovarian ablation with tamoxifen. Only a few studies so far have looked at the combination of AIs with LHRH agonist suggesting efficacy, but these data are not conclusive [33–36]. Tamoxifen has shown at least equal efficacy when compared with ovarian ablation in this setting [37–41], as did LHRH agonists [42]. A meta-analysis comparing the combination of tamoxifen and LHRH analogues to LHRH analogues alone has shown favorable results for the former, with an increase in RR of 31%, an improvement in progression-free survival (PFS) (p = 0.001), and in survival (p = 0.02) [43]. Notably, however, no crossover was mandatory in three of the four pooled studies.

ET Tailoring
Finally, an attractive possibility for the near future could be the selection of an optimal ET sequence based on the genetic/molecular profile of each tumor. Several preclinical and some clinical studies (see below) suggest that endocrine resistance, especially to antiestrogens, could be related to an increased signaling through the HER-family pathway, due to the intense crosstalk between ER and HER-2 pathways [44]. Therefore, it is possible to hypothesize that a strategy involving a rapid decrease of estrogen levels could be most useful in patients with HER-2-overexpressing/amplified tumors. The results of two studies of neoadjuvant ET seem to support this hypothesis. In the first study, postmenopausal patients with ER- and/or PgR-positive primary breast cancer ineligible for breast-conserving surgery were randomly assigned to 4 months of neoadjuvant letrozole or tamoxifen in a double-blinded study [45]. Letrozole yielded a higher RR both in the entire population (55% versus 36%, p < 0.001) and in the population with ER/PgR status centrally reviewed (124 versus 126 patients, respectively, 60% versus 41%, p = 0.004). In a translational research substudy, the ER, HER-1, and HER-2 statuses were correlated with the clinical response and rate of breast-conserving surgery [46]. The differences in RR and breast-conserving surgery rate between letrozole and tamoxifen were particularly striking in the subgroup of tumors ER and HER-1 and/or HER-2 positive (88% versus 21%, p = 0.0004 and 48% versus 36%, p = 0.036, respectively). This prospective study suggests that HER-1 and HER-2 signaling through ER may be ligand dependent and that the growth-promoting effects of these receptor tyrosine kinases on ER-positive breast cancer can be inhibited by potent estrogen deprivation. The second study, presented at the 2003 San Antonio Breast Cancer Symposium, evaluated the potential predictive value of Ki67 in the relapse-free survival of 259 patients included in the IMPACT trial, which compared anastrozole to tamoxifen or to the combination as neoadjuvant ET [47]. The RRs were similar between anastrozole and tamoxifen, although there was a trend towards a superiority of the AI, and a higher rate of breast-conserving surgery. The fact that anastrozole had a greater antiproliferating effect than tamoxifen suggests that Ki67 could be used as a predictive marker.

Chemotherapy
For women with ER- and HER-2-negative, endocrine-resistant disease, CT is currently the only therapeutic option. Many cytotoxic agents have been available for more than 4 decades for the management of MBC. The most active drugs are the anthracyclines and the taxanes, followed by alkylating agents, antimetabolites, and vinca alkaloids. Used as single agents, they produce objective RRs of 20%–80% [48–50]. However, the rare complete responses are short lived, and progression of disease is almost inevitable [1, 51]. While the benefit of first-line CT for MBC is unanimously accepted, the value of second-lines of CT is more controversial, particularly in terms of survival benefit [51]. The true impact of CT on survival and quality of life of MBC patients is still debated.

Poly- or Mono-Chemotherapy?
For the treatment of ER/PgR-negative MBC patients, the medical oncology community is divided between two major strategic options: one that favors combination regimens in all endocrine-resistant patients, and another that prefers the use of single agents in sequence, unless symptoms or signs of life-threatening disease exist. The optimal schedule of CT administration in MBC, i.e., concurrent versus sequential, remains controversial, and the decision must be individualized for each patient. A landmark study is the randomized phase III trial by O’Shaughnessy et al., which reported improved RR, TTP and, most importantly, OS for the combination of docetaxel and capecitabine when compared with single-agent docetaxel [52]. However, the lack of built-in cross-over, which resulted in only 17% of patients initially treated with docetaxel subsequently receiving capecitabine at progression, makes the survival superiority of the combination less relevant, since it does not allow an accurate comparison between the concurrent and sequential administration of both drugs. Data concerning cyclophosphamide/methotrexate/5-fluorouracil (CMF) and anthracycline-containing regimens (5-fluorouracil/doxorubicin/cyclophosphamide [FAC], 5-fluorouracil/epirubicin/cyclophosphamide [FEC]) indicate that polyCT produces higher RRs than single agents [53]. What is not yet completely clear is whether the same agents administered sequentially would have yielded similar results [54–60]. An important trial addressing this issue has been performed by Sledge et al. [60]. A total of 739 chemotherapy-naïve patients were randomized to doxorubicin (and paclitaxel at progression), or paclitaxel (and doxorubicin at progression) or a combination. Although RR and TTF were improved by the combination, OS was comparable between the two arms.

What Is the Optimal CT Regimen?

Anthracycline-Based CT
Since its introduction in the early 1970s, doxorubicin has been considered one of the most active cytotoxic agents for the treatment of breast cancer. In randomized trials, anthracycline-containing regimens have proven superiority to regimens that do not include anthracyclines, while no randomized study has shown superior results of CMF over FAC [53, 61]. Several issues remain controversial regarding the best use of anthracyclines in MBC.

Which is the most effective anthracycline? Epirubicin, a semisynthetic derivative of daunorubicin, is approved for use in the metastatic setting only in Europe. A meta-analysis of studies comparing epirubicin and doxorubicin showed equivalence in terms of efficacy at equivalent doses, with less toxicity for epirubicin [62].

Which is the optimal schedule, dose, and duration of therapy? A randomized trial compared single-agent epirubicin at 75 mg/m² with two regimens of FEC with epirubicin at two different doses: 75 mg/m² (FEC-75) and 50 mg/m² (FEC-50) in 412 MBC patients. The combination regimens were superior to the single agent, and an advantage was seen in RR and OS for FEC-75 over FEC-50 [63]. The optimal duration of FEC therapy in the metastatic setting was evaluated in 392 MBC patients randomized between 11 cycles of FEC-75, four cycles of FEC-100 followed by eight cycles of FEC-50, and four cycles of FEC-100, then restarting the same regimen at disease progression in case of prior response or stabilization. While the RR was higher using the FEC-100 regimen, the OS rate was similar for the three groups [64].

Taxane-Based CT
The introduction of paclitaxel and docetaxel in the 1990s has led to additional improvement in the management of MBC. The now common use of anthracyclines in earlier stages of breast cancer (i.e., in the adjuvant setting) has increased the likelihood of anthracycline-resistant MBC. In light of this situation, taxanes have become the current standard of care. More recently, the taxanes have started to be used earlier in MBC management, in patients with no or minimal prior anthracycline exposure and/or in combination with anthracyclines. Some of the still controversial issues regarding the use of taxanes in MBC are discussed below.

When Should Taxanes Be Used?
For more than a decade, taxanes have been evaluated in numerous clinical trials, either as single agents or in combination. The results can be interpreted according to previous anthracycline exposure [65]. For the post-anthracycline-exposure (anthracycline-resistance or failure) category, there are no paclitaxel-based phase III trials (Table 3) [52, 56, 66, 67]. On the other hand, four trials have used docetaxel: three as monotherapy [56, 66, 67] and one in association with capecitabine [52]. About half of the patients included in these trials had anthracycline-resistant disease. Despite being underpowered and lacking cross-over, these trials provide highly consistent results, with a gain in RR, TTP and, most importantly, a survival advantage in two of the trials [52, 56]. Therefore, docetaxel can now be considered as the new standard of care for MBC after anthracycline resistance.

At the present time, in case of minimal or no previous anthracycline exposure, there is no standard of care, even after enrolling more than 4,300 patients in randomized clinical trials (Table 4) [57, 60, 69–78]. The small sample size of the trials makes them underpowered, and there is a lack of built-in or allowed cross-over in many of these trials, which better reflects routine clinical practice with sequential CT regimens at disease progression. Furthermore, only one trial addresses the important question of taxane mono- versus combination therapy [60]. While docetaxel yielded improved RR in all of the trials and improved TTP in most of them, these advantages did not translate into any survival benefit [69, 71–74]. The paclitaxel-based trials generate conflicting results in terms of RR and TTP, which translate into a survival benefit in two of the studies however [57, 60, 70, 75–78]. Therefore, a meta-analysis of all the randomized phase III trials evaluating docetaxel and paclitaxel as first-line treatment for MBC is of extreme importance in order to reach a definite conclusion. This is currently being planned.

What Is the Best Schedule of Administration?
Both taxanes have two main schedules of administration: 3-weekly and weekly, and, to date, there are no clear data concerning their relative efficacy. The 3-weekly schedule has been extensively studied for both taxanes. General consensus exists for docetaxel best dose and infusion time (100 mg/m² in 1 hour), while for paclitaxel, despite several prospective studies involving more than 1,500 patients comparing different doses (ranging from 135–250 mg/m²) and different infusion times (ranging from 3–96 hours), none has shown so far a clear advantage over the registered dose and schedule (175 mg/m² as a 3-hour infusion) [80–82]. There has been a growing interest in weekly taxane administration as a way to increase efficacy and/or decrease toxicity. While the only advantage for weekly docetaxel seems to be reduced myelosuppression, weekly paclitaxel is extremely well tolerated [83], and available results suggest that it may have improved activity [84, 85] compared with the 3-weekly regimen. Of note, preclinical and clinical data have shown that the cross-resistance between the two taxanes is only partial; consequently, their sequential use a few months apart is possible, in particular for patients who are initially taxane sensitive [86, 87]. More recently, epothilones, a new class of antitubulin agents that lack cross-resistance with the taxanes, have been developed in the metastatic setting, with promising results [88].

	What Is the Role of Anthracycline/Taxane Combinations?

Top Learning Objectives Abstract Introduction Which Patients Benefit From... Which Is the Best... What Is the Role... What Is the Best... CT Tailoring Biological Therapies What Is the Background... Conclusions References

 
Although there is no documented synergy in preclinical experiments between anthracyclines and taxanes, their empirical combination was a natural step, given that they are the two most active classes of cytotoxic agents for breast cancer. Phase III trials comparing anthracycline/taxane combinations with anthracycline-combination regimens without taxanes have not consistently shown superiority of the former [60, 71, 72, 75–78], and improvement in survival has been reported so far in only one trial [75] (Table 4). The higher RR has been considered a consequence of the pharmacokinetic interaction between docetaxel [89, 90] or paclitaxel [91] and doxorubicin. Due to the lack of consistent survival benefit, these regimens might be reserved for patients where a rapid and higher RR is needed, such as rapidly advancing and/or symptomatic disease. The above-mentioned meta-analysis could also provide a definite answer regarding this issue.

	What Is the Best Treatment for Anthracycline- and Taxane-Resistant Patients?

Top Learning Objectives Abstract Introduction Which Patients Benefit From... Which Is the Best... What Is the Role... What Is the Best... CT Tailoring Biological Therapies What Is the Background... Conclusions References

 
No standard of care exists for subsequent lines of CT, particularly after failure of both anthracyclines and taxanes, and treatment options for these patients are limited. The most commonly used are chosen in view of their manageable toxicity profile and reasonable efficacy.

Capecitabine is the first oral fluoropyrimidine approved by the Food and Drug Administration (FDA) for the treatment of patients with MBC who failed prior anthracycline- and taxane-based CT [92–94]. This drug has the great advantage of a convenient oral administration. The FDA-approved dose and schedule are 2,500 mg/m²/day given orally for 14 days followed by 1 week of rest. However, retrospective studies suggest that a slightly lower starting dose (2,000 mg/m²/day) is better tolerated with preserved efficacy [95, 96].

Vinorelbine, delivered intravenously at 25–35 mg/m² on days 1 and 8 of a 3-week cycle, has shown variable RR (10%–20%) after anthracycline or taxane failure [97, 98] with low incidence of nonhematological toxicities. Of note, an oral formulation of vinorelbine was recently evaluated as first-line chemotherapy for MBC, and the results suggest that it is an effective and well-tolerated agent, offering an alternative to the intravenous route [99].

A direct comparison between capecitabine and vinorelbine is currently being done in a randomized phase II trial coordinated by the European Organization for Research and Treatment of Cancer.

Gemcitabine has been studied as first-line MBC treatment in combination with the major drugs. GET (gemcitabine/epirubicin/paclitaxel) compared with FEC failed to demonstrate a statistically significant benefit, revealing, in fact, worse acute toxicity [100]. As described above, the combination gemcitabine/paclitaxel yielded statistically significant improved RR, TTP, and survival in relation to paclitaxel alone [68]. Interestingly, the addition of gemcitabine was associated with improvement in analgesic level, pain relief, and quality of life.

	CT Tailoring

Top Learning Objectives Abstract Introduction Which Patients Benefit From... Which Is the Best... What Is the Role... What Is the Best... CT Tailoring Biological Therapies What Is the Background... Conclusions References

 
Despite several years of intense translational research, no predictive factors of response to CT are currently recommended for routine clinical use. Among the evaluated markers, HER-2 is the one for which the largest amount of data has been gathered, and it seems to be associated with a higher likelihood of response to anthracyclines and taxanes and a lower likelihood of response to CMF [101–104]. Other promising potential predictive markers are topoisomerase II alpha for response to anthracyclines [105–107], p53 [108] and microtubule-associated parameters [109] for taxanes, and thymidylate synthase and thymidine phosphorylase for fluorouracil-based CT [110, 111]. The main disadvantages of the published literature are the lack of prospective studies, needed to clarify definitely the merits of each investigated marker, and the loss of reproducibility of the assessment methods across different laboratories. Moreover, new techniques, namely the use of cDNA microarrays, hold the hope of allowing not only better biologic characterization and even new classification of breast cancer, but also better treatment tailoring based on distinct molecular profiles with prognostic and/or predictive value. These hypotheses are being tested in a new generation of prospective biologically based studies, and their results may radically change the management of breast cancer in the near future.

	Biological Therapies

Top Learning Objectives Abstract Introduction Which Patients Benefit From... Which Is the Best... What Is the Role... What Is the Best... CT Tailoring Biological Therapies What Is the Background... Conclusions References

 
With the growing understanding of the biology of breast cancer and the advent of new techniques such as genomics and proteomics, multiple new targets for anticancer therapy are identified every year. These molecules are implicated in several molecular pathways relevant to the biology of the breast cancer cell, such as the signal transduction pathway, the cell cycle, the apoptotic pathway, and the angiogenesis/metastases pathway. To date, one biological agent has been approved for the treatment of MBC: trastuzumab, the monoclonal antibody against the HER-2 receptor. Many of the other new drugs under evaluation target receptors either in the cancer cell or in the stromal cell. None of these antireceptor agents has yet completed phase III studies, and, therefore, their future role in breast cancer management is still unknown. Surprisingly, bevacizumab, a monoclonal antibody against the vascular endothelial growth factor (VEGF) receptor that has shown impressive results in colon cancer, has yielded somewhat disappointing results so far in MBC [112, 113], suggesting that targeted therapy may not only be target-individual specific but also disease specific. Nevertheless, bevacizumab evaluation in breast cancer continues in women with less resistant or less heavily pretreated disease. Gefitinib (Iressa^®) is a synthetic drug that specifically inhibits epidermal growth factor receptor tyrosine kinase (EGFR-TK), with modest activity in solid tumors mainly in non-small cell lung cancer. In the MBC setting, two trials have used gefitinib as second-line treatment with rare objective responses and some stable diseases observed [114, 115]. An important drawback of these trials is the lack of patient selection; these targeted therapies are unlikely to benefit the entire MBC population but rather a subset of patients, identified for instance through some predictive marker expression. Some recent preclinical data suggest that VEGF expression may be a better predictive marker for gefitinib efficacy than EGFR expression (personal communication, Folkman J. [October 2003]).

What Is the Optimal Use of Trastuzumab?
As monotherapy, trastuzumab produces antitumor response in patients with HER-2-amplified/overexpressing MBC who have failed anthracyclines and taxanes [116, 117]. In this population, the addition of trastuzumab to taxane-based CT improves RR, duration of response, and survival in comparison with CT alone [3, 118]. Since trastuzumab is one of the few agents that led to an improvement in OS in MBC, HER-2 status evaluation became indispensable for optimal treatment decision-making in breast cancer. However, several issues regarding the clinical use of trastuzumab are still debatable and the subject of ongoing research, such as the method used for HER-2 status assessment; the optimal schedule of trastuzumab administration, dose, and duration; the mechanism of cardiotoxicity; and the emergence of resistance.

Currently, there are two techniques available for HER-2 status determination. The first one, immunohistochemistry (IHC), which determines the HER-2 protein status, is a nonstandardized technique with high levels of interlaboratory variability due to the type of antibody and the optional use of antigen retrieval procedure. The second, fluorescence in situ hybridization (FISH), which evaluates the HER-2 gene status, has been considered a more reliable technique although more expensive and not as widely available. Furthermore, false results have also been reported with FISH [119, 120]. At present, screening by IHC for HER-2 protein, backed by rigorous quality controls and FISH confirmation of equivocal cases with intermediate staining intensity or FISH testing in cases with no staining but an aggressive clinical course, remains a reasonable approach [121]. Trastuzumab therapy can be considered for breast cancer patients with tumors that demonstrate 3+ overexpression by IHC or 2+ and a FISH-positive test.

The most common schedule of administration of trastuzumab is the weekly intravenous infusion dose of 2 mg/kg after a loading dose of 4 mg/kg. However, since this drug has a prolonged half-life of approximately 28 days, an alternate dosing regimen with a loading dose of 8 mg/kg followed by a maintenance dose of 6 mg/kg given every 3 weeks has been studied and seems to be as effective and more convenient [122–124]. Trastuzumab is commonly used until disease progression, since the significant clinical benefit has been demonstrated in clinical trials with such designs. However, preclinical data and retrospective studies suggest a rationale for using trastuzumab beyond disease progression [125, 126], particularly if combined with a (different) cytotoxic agent.

Trastuzumab is generally well tolerated, and its most important side effect, with the exception of hypersensitivity seen mainly with the first infusion, is congestive heart failure. Although the rate of trastuzumab-related cardiotoxicity is well established, the question of its pathogenesis is not yet answered [127], and biological markers that could predict cardiotoxicity of trastuzumab are urgently needed.

Finally, a critical issue is the identification of the potential mechanisms of resistance to trastuzumab [128], both de novo and acquired, since about 60% of HER-2-positive patients do not respond to this treatment and, when response is seen, its median duration, when given as single agent, is around 9 months. One approach, known as multitargeted therapy, advocates the blockage of the same pathway at different sites or the blockage of different pathways simultaneously. Drugs that target multiple receptors and combinations of two biological agents, such as trastuzumab and gefitinib [114], are currently being studied in several phase I and II trials.

BT Tailoring
The recently published gene expression analysis studies [129, 130] seem to confirm what clinical practice has been suggesting for quite some time, which is the fact that HER-2-overexpressing breast cancer could well be a distinct disease entity requiring a separate approach in terms of treatment both in the adjuvant and the metastatic settings. Important issues are: A) the early use of trastuzumab, alone or in combination with cytotoxic agents such as paclitaxel or paclitaxel/carboplatin, in MBC; B) careful cardiac monitoring due to risk of cardiotoxicity, particularly when other risk factors are present such as prior anthracycline exposure and advanced age (evaluation of left ventricular ejection fraction is currently recommended every 3 months) [131]; C) special attention to central nervous system (CNS) symptoms/signs, due to the propensity of brain metastasis in this type of breast cancer (about one-third of HER-2-positive breast cancer patients develop CNS metastases at a median of 6 months from the beginning of trastuzumab therapy [132] and the role of brain magnetic resonance imaging in the follow-up of responding patients will require prospective evaluation).

	What Is the Background for Combined Modality Therapy?

Top Learning Objectives Abstract Introduction Which Patients Benefit From... Which Is the Best... What Is the Role... What Is the Best... CT Tailoring Biological Therapies What Is the Background... Conclusions References

 
Combined HT and CT
This association is not recommended in advanced breast cancer based on the lack of evidence of survival improvement in 19 trials conducted between 1977 and 1996 [53]. However, all these trials had a small sample size, and none included a third-generation AI or a pure antiestrogen. It could be interesting to re-explore this concept with these more active agents in large, well-designed trials.

Combined CT and BT
As discussed above, the combination of trastuzumab with CT in the pivotal phase III first-line study produced significant clinical benefits compared with CT alone [3], including increased overall RR (p < 0.05) and TTP (p < 0.001). In the same way, a phase II study comparing trastuzumab plus docetaxel versus docetaxel alone in 188 MBC patients has shown a statistically significant difference in terms of overall RR (61% versus 36%, p = 0.001), TTP (10.6 versus 6.1 months, p = 0.0001) and OS (24.1 versus 13.2 months, p = 0.0001) in favor of the combination from the beginning [118].

In vitro and in vivo data show that trastuzumab has additive and even synergistic effects in combination with various cytotoxic agents as a single-agent or doublet, including docetaxel [118, 132, 133], vinorelbine [134, 135], gemcitabine [136], capecitabine [137], and paclitaxel/carboplatin [138, 139]. These combinations have demonstrated efficacy and acceptable toxicity in several phase I and II trials. However, since no direct comparisons between the various trastuzumab/CT associations have been made, there is still no standard combination.

A recent study evaluated the effect of adding carboplatin to the combination trastuzumab/paclitaxel, based on interesting synergistic effects seen preclinically. This triple regimen has shown significantly improved RR (52% versus 36%, p < 0.01) and TTP (11.2 versus 6.9 months, p = 0.004) in 194 MBC patients [138]. Based on these promising results, the U.S. North Central Cancer Treatment Group started a trial evaluating the role of the schedule of administration when using this three-drug combination; in this prematurely interrupted phase II study, 70 MBC patients were randomized between a weekly regimen of paclitaxel/carboplatin and a 3-weekly regimen of the same drugs, while receiving concomitant weekly trastuzumab [139]. The weekly regimen showed a marked improvement in both RR (78% versus 50%) and median PFS (13.4 versus 8.8 months), leading to study closure and strongly suggesting that schedule of administration is an important variable to consider, particularly in the case of paclitaxel.

Both trials of trastuzumab/paclitaxel and of trastuzumab/docetaxel [118] strongly suggest that trastuzumab should be administered early in the evolution of the disease. The question that remains open is the one addressing the issue of initiating trastuzumab as monotherapy and adding CT at progression, as compared with the strategy of using combination treatment from the start, since to date no trial has directly compared these two approaches.

Combined HT and BT
This attractive strategy of combining ET with biological antitumor agents is based on the hypothesis that it could delay the onset of hormone resistance due to the complex and intense cross-talk between the ER and signal transduction pathways [44, 140, 141]. Currently, several trials are exploring this notion: A) randomized phase II/III trial comparing the effectiveness of anastrozole or letrozole plus trastuzumab in MBC postmenopausal women; B) randomized phase II trial of anastrozole with or without the EGFR-TK inhibitor gefitinib; C) tamoxifen with or without gefitinib; and D) combined BT. However, further data are needed before these attractive but expansive strategies can be advocated in routine clinical practice.

	CONCLUSIONS

Top Learning Objectives Abstract Introduction Which Patients Benefit From... Which Is the Best... What Is the Role... What Is the Best... CT Tailoring Biological Therapies What Is the Background... Conclusions References

 
The optimal management of MBC remains a significant therapeutic challenge. MBC therapy is becoming more complex with the development of a large number of agents, namely biological agents with original mechanisms of action. The phase III data generated over the past decade have suffered from clinical trial design limitations and, consequently, did not provide us with a consensual new standard of care for MBC treatment. Exceptions may be the use of anastrozole and letrozole as first-line therapy for postmenopausal hormone-sensitive MBC patients, of docetaxel in anthracycline-resistant endocrine nonresponsive disease, and of trastuzumab in HER-2-positive MBC women. Clinicians should keep in mind that in the palliative metastatic setting, issues of tolerability and quality of life are crucial. The development of new technologies, such as genomics and proteomics, will most likely provide the possibility of improved treatment tailoring and important changes in the standard of care of MBC within the next 5 years.

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Top Learning Objectives Abstract Introduction Which Patients Benefit From... Which Is the Best... What Is the Role... What Is the Best... CT Tailoring Biological Therapies What Is the Background... Conclusions References

 

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