Systemic treatment for metastatic breast cancer: General principlesAuthorDaniel F Hayes, MDSection EditorJulie R Gralow, MDDeputy EditorDon S Dizon, MD, FACPDisclosuresAll topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Nov 2012. | This topic last updated: Δεκ 6, 2012.

INTRODUCTION — Although metastatic breast cancer is unlikely to be cured, meaningful improvements in survival have been seen, coincident with the introduction of newer systemic therapies [1-3]. Median overall survival approaches two years, with a range from a few months to many years [4].

The selection of a therapeutic strategy depends upon both tumor biology and clinical factors, with the goal being a tailored approach. Although a subset of patients with oligometastatic disease may benefit from an intensified locoregional approach, most patients with metastatic breast cancer receive systemic medical therapy, consisting of chemotherapy, endocrine therapy, and/or biologic therapies, and supportive care measures [5,6].

General principles of management of metastatic breast cancer are presented here. Details of single agent and combination chemotherapy, endocrine therapy, biologic therapy, and how to select among them, as well as locoregional approaches, osteoclast inhibitors (bisphosphonates and receptor activator of nuclear factor kappa-B [RANK] ligand inhibitors), and supportive care, are discussed separately.

(See "Systemic treatment for metastatic breast cancer: Endocrine therapy".) (See "Systemic treatment for metastatic breast cancer: Single agent

chemotherapy".) (See "Systemic treatment for metastatic breast cancer: Combination

chemotherapy".) (See "Systemic treatment for metastatic breast cancer: Biologic therapy".) (See "Systemic treatment for metastatic breast cancer: Selection of

chemotherapy regimen".) (See "Metastatic breast cancer: Local treatment".) (See "Treatment of metastatic breast cancer in older women".) (See "Osteoclast inhibition in the management of bone metastases from breast

cancer".)

THERAPEUTIC GOALS — The primary goals of systemic treatment for metastatic breast cancer are prolongation of survival, alleviation of symptoms, and maintenance or improvement in quality of life, despite the toxicity associated with treatment [7-9]. The median survival for metastatic breast cancer is 18 to 24 months, though this varies widely based on subtype of tumor, sites of metastatic involvement, and burden of metastatic disease, and some patients experience long-term survival [1-4,10].

No prospective randomized clinical trials have demonstrated that systemic therapy prolongs survival compared to best supportive care alone [7]. However, median survival for patients with metastatic breast cancer appears to have improved over time, a trend which has been attributed to the availability of new, more effective agents, including taxanes, aromatase inhibitors, and trastuzumab [1,2,11-13]. As an example, patients from the British Columbia Breast Cancer Outcomes Database who were diagnosed between 1997 and 2001 had better two-year overall survival than patients diagnosed between 1991 and 1995 (45 versus 34 percent) [1].

The optimal measure of therapeutic efficacy is debated. Overall survival is the gold standard for comparing therapies, but it requires prolonged follow-up and may be diluted by the effects of subsequent treatment. However, no other endpoint, including progression-free survival, time to tumor progression, or objective response rate, has been shown to be a good surrogate for overall survival [14]. Comparisons of objective response rates are often used to determine relative treatment efficacy, but high response rates do not necessarily translate into clinically meaningful increases in survival [14-16]. In addition, symptom relief without measurable disease response and achievement of stable disease as compared to disease progression may be clinically important [17].

TUMOR BIOLOGY AND RISK ASSESSMENT — Biologic markers, such as hormone receptor status, human epidermal growth factor receptor 2 (HER2) overexpression, and tumor burden, have both prognostic and predictive value and are important factors in selecting appropriate treatment.

Disease assessment — Complete evaluation for the extent of metastatic disease includes confirmatory biopsy of suspected lesions and reassessment of molecular markers, particularly estrogen receptor (ER), progesterone receptor (PR), and HER2 overexpression. This is especially important if the primary cancer was deemed negative for ER, PR, and or HER2, since a conversion to positive would dramatically change therapy.

There is a possible discordance of these markers between primary and metastatic disease [18-22]. As an example, in a pooled analysis of two prospective studies, the rates of discordance in ER, PR, and HER2 between the primary and recurrent disease were 13, 28, and 5 percent, respectively [19]. In this study, the number needed to biopsy to alter immediate patient management was 6.3. However, it is not clear that verifying receptor status in new metastases and the resultant management changes will ultimately lead to improvements in patient quality of life and survival.

Prognosis — Clinical factors that predict the rate of progression and survival include the interval between initial therapy and relapse, the number of metastatic sites, the presence or absence of visceral involvement, and biologic markers. As examples:

Relapse-free interval of ≥2 years is more favorable than a shorter time to relapse [23-26].

Patients with metastases involving the chest wall, bones, or lymph nodes may have prolonged progression-free survival, while those with hepatic and/or lymphangitic pulmonary disease have shorter progression-free and overall survival [23,24,27]. Patients with lymphangitic lung metastases, bone marrow

replacement, carcinomatous meningitis, or significant liver metastases are described as having visceral crisis [28]. Patients without visceral crisis but with poor prognostic features represent an intermediate phenotype.

Patients with hormone receptor positivity generally have a more favorable prognosis, and patients with ER- and PR-positive tumors have significantly longer survival than single hormone receptor-positive tumors (ER+/PR- or ER-/PR+) [29]. Patients with either HER2 overexpression or triple (ER, PR, HER2)-negative metastatic breast cancer have a shorter median survival [25,30,31]. The prognosis associated with particular molecular phenotypes is discussed separately. (See "Molecular intrinsic subtypes of breast cancer".)

Other adverse prognostic features include weight loss, poor performance status (table 1), and elevated serum lactic dehydrogenase [23,32]. Age less than 35 years old is a poor prognostic factor for women with early stage breast cancer, but the effect of age on survival after recurrence is not established [25,33]. Similarly, the stage at diagnosis does not reliably indicate prognosis after relapse.

Prediction of response — Hormone receptor status and HER2 overexpression are the most important predictors of treatment response in patients with metastatic breast cancer.

Hormone receptors — Hormone receptor status is the most important predictive factor for response to hormone therapy [34,35]. The likelihood of response is 70 percent in patients with tumors that express both ER and PR, 40 percent in tumors that are ER-positive/PR-negative or ER-negative/PR-positive, and less than 10 percent in ER-negative/PR-negative tumors [36,37]. The molecular basis by which ER status predicts response to endocrine therapy is discussed separately. (See "Hormone receptors in breast cancer: Clinical utility and guideline recommendations to improve test accuracy".)

Additional features that predict responsiveness to hormone therapy in patients with metastatic breast cancer include a long relapse-free interval, isolated bone and soft tissue involvement, and prior response to endocrine therapy [38,39].

There are some data suggesting that patients with ER-positive tumors are less likely to respond to cytotoxic chemotherapy than those with ER-negative tumors [35,40-42].

HER2-overexpression — Overexpression of HER2 predicts response to therapies that target HER2, such as the humanized monoclonal antibody trastuzumab and the small molecule tyrosine kinase inhibitor lapatinib. These drugs are only effective for tumors that have high levels of HER2 expression (3+ by immunohistochemistry) or gene amplification (as detected by fluorescence in situ hybridization [FISH]).

Some evidence suggests that tumors with HER2 overexpression are less responsive to endocrine therapy, although the available data are not sufficient to use HER2 status to predict resistance to endocrine therapy [43,44].

Details of HER2 testing and the role of HER2-status in predicting the response to HER2-directed therapy, chemotherapy, and endocrine therapy are discussed separately. (See "HER2 and predicting response to therapy in breast cancer".)

Chemotherapy response — Consistent predictors of poor chemotherapy response are progression with prior chemotherapy for advanced disease, relapse within 12 months of completing adjuvant chemotherapy, poor performance status, and multiple disease sites, especially visceral involvement [23,24,32,45-52].

Markers of increased cellular proliferation, such as high S-phase fraction by flow cytometry, increased uptake of radiolabeled thymidine, and immunohistochemical staining for the proliferation antigen Ki67, are all associated with higher chemotherapy response rates [53-55]. In contrast, breast cancers that overexpress p-glycoprotein (gp170), a drug efflux pump that mediates multidrug resistance (MDR), or have a mutated p53 gene may be less likely to respond to chemotherapy [56-59]. At present, none of these markers should be used to make clinical decisions.

Another possible approach is the use of chemotherapy sensitivity and resistance assays [60-62]. However, the clinical utility of these assays remains unclear [56,63,64]. The detection and monitoring of circulating tumor cells during treatment for metastatic breast cancer is discussed below. (See 'Circulating tumor cells' below.)

TREATMENT SELECTION — Key points described above are important to keep in mind when selecting treatment for metastatic breast cancer. These include:

The aim of treatment is to palliate symptoms, prolong survival, and maintain quality of life.

Patients with visceral metastases and a short disease-free interval generally have an aggressive phenotype, while patients with soft tissue and bone metastases have a more indolent phenotype.

Hormone receptor status and human epidermal growth factor receptor 2 (HER2) overexpression are important in estimating prognosis and the likelihood of response to therapy.

Hormone receptor (estrogen receptor [ER] and/or progesterone receptor [PR]) status is the major determining factor for response to endocrine therapy.

Likewise, HER2 overexpression is required for response to HER2-directed therapies.

Based upon these principles, selection of treatment can be individualized. Endocrine therapy is best used for patients with hormone receptor-positive breast cancer and not for patients with hormone-negative breast cancer. HER2-directed therapy is only appropriate for patients with tumors that overexpress HER2. Lastly, chemotherapy is indicated for hormone-insensitive metastatic breast cancer (ie, patients with hormone-receptor-negative breast cancer and those with hormone-receptor-positive breast cancer who have become resistant to endocrine therapy). It is less clear is when to use endocrine therapy versus chemotherapy as initial treatment for patients with hormone receptor-positive metastatic breast cancer. Likewise, it is less obvious when to use single agent versus combination chemotherapy, how to best incorporate biologic therapies, and whether combined modalities are of benefit.

Endocrine therapy versus chemotherapy — It is commonly thought that chemotherapy results in higher response rates and more rapid responses than endocrine therapy, and is often used as the initial treatment for patients with hormone receptor-positive

metastatic breast cancer with a poor prognosis, especially those with visceral metastases. A meta-analysis that included eight small randomized trials, all published prior to 1995, compared the response rates for chemotherapy alone with those of endocrine therapy alone [65]. The pooled estimate of response rates showed an advantage for chemotherapy over endocrine therapy (relative risk 1.25, 95% CI 1.01 to 1.54), although the two largest trials had opposite findings [66,67]. No significant difference was seen in overall survival (hazard ratio, HR 0.94, 95% CI 0.79 to 1.12), and on subset analysis, there was no obvious trend to suggest an effect of age, menopausal status, or pattern of metastatic disease on the efficacy of either therapy. There was minimal and contrasting information on quality of life and toxicity.

A major limitation to these findings is that most patients in these trials had tumors of unknown hormone receptor status, since the predictive value of hormone receptor status on response to endocrine therapy was not yet appreciated. Nevertheless, chemotherapy remains the preferred modality for initial treatment of patients with rapidly progressive symptomatic disease or visceral crisis (end-organ dysfunction), given the higher likelihood of achieving a response with chemotherapy.

No survival benefit has been seen when chemotherapy and endocrine therapy were combined.

Sequential single agents versus combination chemotherapy — When compared in a meta-analysis published in 2005, combination chemotherapy was associated with significantly higher overall response rates (odds ratio [OR] 1.28, 95% CI 1.15-1.42) and improved overall survival (hazard ratio [HR] for death 0.88, 95% CI 0.83-0.93), and a significantly lower rate of disease progression (overall hazard ratio HR 0.78, 95% CI 0.73-0.83) [68]. However, this modest survival improvement came with the cost of significantly worse toxicity, including leukopenia, nausea, and vomiting.

The findings of this meta-analysis are limited in that modern chemotherapy agents were not well represented in the included trials and that the rate of cross-over was not known.

Clinical trials with newer agents, such as capecitabine, docetaxel, vinorelbine, and gemcitabine, have either found no difference in overall survival between combination and single agent chemotherapy, or a modest improvement of a few months, and again, worse toxicity [69-71].

Most trials compare single agent therapy to a combination of two drugs, rather than comparing the combination to sequential use of the two single agents. The modest survival benefits favoring combination chemotherapy may not have been seen if crossover to the experimental agent had been allowed. Several trials that directly compared combination versus sequential therapy failed to show a survival benefit for initial combination therapy [72-75].

As an example, Eastern Cooperative Oncology Group (ECOG) trial E1193 randomly assigned 739 patients with metastatic breast cancer to doxorubicin alone, paclitaxel alone, or the combination [72]. Patients receiving single agent therapy crossed over to the alternative agent at the time of progression. Although initial combination therapy with doxorubicin and paclitaxel, compared to either agent alone, was associated with a significantly higher response rate (47 versus 36 and 34 percent)

and time to treatment failure (8 versus 5.8 and 6 months), median overall survival was similar for all three (22, 19, and 22 months, respectively).

Without an appreciable survival advantage with combination chemotherapy, sequential therapy with single agents is often preferred. Toxicity is less with single agent therapy and quality of life appears better [76-78]. For patients in need of quick symptom control or those with rapidly progressive disease or visceral crisis, however, combination therapy may be a more appropriate first-line choice because of the greater likelihood of an objective response in a shorter time.

Adding more agents to combination regimens has not led any further improvements in time to progression or overall survival [79]. In fact, a review of all randomized trials comparing chemotherapy regimens for metastatic breast cancer that were reported between 2000 and 2007 found little evidence of major survival differences among many common chemotherapy regimens [80].

Combining treatment modalities — In theory, combining chemotherapy, biologic therapy, and/or endocrine therapy might have additive efficacy, but it might also lead to increased toxicity. Clinical trials have failed to show a survival advantage for the concurrent administration of chemotherapy and endocrine therapy over either single modality [7,67,81].

However, HER2-directed therapy, namely, trastuzumab and lapatinib, has been successfully combined as individual agents with chemotherapy and endocrine therapy, and with each other.

Biologic therapy — At present, the molecularly targeted agents (or biologic therapy) that have proven efficacy in metastatic breast cancer are the HER2-directed agents, trastuzumab and lapatinib, and bevacizumab. The use of these biologic agents in metastatic breast cancer is discussed in detail separately. (See "Systemic treatment for metastatic breast cancer: Biologic therapy".)

Osteoclast inhibitors — Patients with bone metastases should be treated with osteoclast inhibitors (bisphosphonates or RANK ligand inhibition) as these agents have been shown to reduce the risk of skeletal related events, such as fractures, the need for surgery or radiation to bone, spinal cord compression, and hypercalcemia of malignancy. (See "Osteoclast inhibition in the management of bone metastases from breast cancer".)

TREATMENT ALGORITHMS — The issues discussed above can be summarized and clarified into treatment recommendations for patients with metastatic breast cancer according to the hormone receptor and human epidermal growth factor receptor 2 (HER2) status of their tumors.

Hormone receptor-positive HER2-negative patients — The evidence, despite limitations described above, suggests that chemotherapy has higher response rates than endocrine therapy. Therefore, patients with rapidly progressive, symptomatic disease or visceral metastases with end-organ dysfunction may be best treated with first-line chemotherapy. After chemotherapy response stabilizes (usually four to six months), a switch to maintenance endocrine therapy is a commonly employed

strategy, which can reduce the treatment side effects without compromising overall survival [7,82,83].

Given its generally favorable toxicity profile, first-line endocrine therapy may be more appropriate for patients with asymptomatic or minimally symptomatic disease and those without visceral involvement. If the disease progresses rapidly (within a few months) following initiation of first-line endocrine therapy, chemotherapy is generally recommended as a second-line rather than switching to another endocrine strategy. If time to progression on first-line endocrine therapy is prolonged (greater than six months), then a switch to second-line endocrine therapy at progression is reasonable.

Selection of endocrine therapy is discussed separately. (See "Systemic treatment for metastatic breast cancer: Endocrine therapy".)

Selection of chemotherapy regimen is discussed separately. (See "Systemic treatment for metastatic breast cancer: Selection of chemotherapy regimen".)

Hormone receptor-positive HER2-positive patients — Therapeutic options for these patients include chemotherapy, endocrine therapy, and HER2-directed therapy. HER2 directed therapy has demonstrated improved survival for patients with tumors that overexpress HER2 and thus should be part of first-line therapy for these patients.

Whether it is better to use HER2-directed therapy combined with chemotherapy versus endocrine therapy as first-line treatment is unclear. HER2-directed therapy combined with chemotherapy or endocrine therapy are discussed separately.

(See "Systemic treatment for metastatic breast cancer: Biologic therapy", section on 'HER2-directed therapy'.)

(See "Systemic treatment for metastatic breast cancer: Endocrine therapy".)

Hormone receptor-negative HER2-negative patients — Many patients with triple- (ER-, PR-, HER2-) negative breast cancer have a particularly aggressive subtype, and first-line chemotherapy is recommended. Whether chemotherapy agents are given in combination or sequentially should be determined based on symptoms and location and burden of disease, as well as patient-related factors (ie, preferences, goals, and overall health).

Triple-negative breast cancer is discussed in detail separately. (See "Epidemiology, risk factors and the clinical approach to ER/PR negative, HER2-negative (Triple-negative) breast cancer".)

Selection of chemotherapy regimen is discussed separately. (See "Systemic treatment for metastatic breast cancer: Selection of chemotherapy regimen".)

Hormone receptor-negative HER2-positive patients — The combination of HER2-directed therapy and chemotherapy is recommended for these patients.

Regimens combining HER2-directed therapy with chemotherapy are discussed separately. (See "Systemic treatment for metastatic breast cancer: Biologic therapy", section on 'HER2-directed therapy'.)

MONITORING THERAPY — Careful assessment of the response to therapy will assist in decisions for duration of treatment and in selection of subsequent treatments. However, the best approach for monitoring patients with metastatic breast cancer is not well established.

History and examination — If symptom palliation is the main objective, clinical history alone may suffice to determine the success of therapy. Physical examination may allow response quantitation if disease is easily accessible (eg, chest wall nodules, palpable lymphadenopathy). With a dramatic reduction in symptoms that were clearly disease-related or obvious shrinkage of palpable lesions, serum markers and radiographic tests are likely to be irrelevant.

However, many patients have more subtle disease signs or symptoms that may be confused with treatment toxicity or other nonmalignant conditions. In addition, disease is not measurable by physical examination in nearly half of patients with metastatic breast cancer. In these patients, serial changes in tumor markers or radiographic studies are essential in establishing the response to therapy.

Tumor markers — Serial assay of serum tumor markers (eg, CA15-3 and CA27.29, both products of the MUC-1 gene, and CEA) can aid in response assessment, particularly if disease sites are not assessable by usual criteria [43,84]. Judicious use of serial tumor marker measurements may decrease the need for periodic radiographic evaluation [85].

Guidelines from the American Society of Clinical Oncology (ASCO) expert panel suggest that it is reasonable to evaluate one of the MUC-1 assays and CEA initially in patients with metastatic disease [43]. If the MUC-1 assay is elevated, there is no role for monitoring CEA, but if not, then serial CEA levels may be useful.

Elevated tumor markers may occasionally be spurious. Up to 20 percent of patients successfully treated with systemic therapy may experience a transient increase (marker "flare") during the first one or two months after treatment initiation, presumably due to release of antigen by cytolysis [86,87]. Patients with abnormal liver function may also have falsely elevated marker levels because they are cleared by the liver [86]. CA 15-3 levels may be aberrantly elevated in patients with vitamin B12 deficiency and megaloblastic anemia, as well as in patients with thalassemia or sickle cell disease [88-90].

Radiographic studies — Serial plain radiographs, computed tomography (CT) scan, or magnetic resonance imaging (MRI) can permit assessment of tumor response. Periodic scintigraphic bone scans, while helpful, may also be misleading. Technetium (Tc99) phosphonate accumulates in areas of osteoblastic activity rather than in cancer cells. In a patient experiencing a response to therapy, a "scintigraphic healing flare" may appear as early as two months, and persist for as long as 12 months after initiating therapy [91,92].

Integrated positron emission tomography (PET)/computed tomography (CT) is popular as a whole-body examination in monitoring response to therapy in metastatic breast cancer, as it has demonstrated high sensitivity and specificity in detecting metastatic disease and can reliably assess response to therapy [93-95]. There is also

some evidence that metabolic changes in bone metastases in response to systemic therapy (ie, a change in standardized uptake value [SUV]) can predict response duration or time to progression [96-98]. However, many integrated PET/CT scanners in clinical use provide a limited CT scan primarily for orientational purposes (determining where the PET abnormality is) and not a higher resolution, fine cut, contrast-enhanced CT scan. This should be kept in mind when evaluating response between modalities (standard CT and PET/CT).

Circulating tumor cells — Detection of circulating tumor cells (CTCs) in blood samples of patients with metastatic breast cancer (≥five CTCs) has been shown to be a predictor of progression-free survival (PFS) and overall survival [99-105]. Immunological and RNA-based methods are used to detect CTCs in breast cancer. Although multiple commercially available methods for isolating CTCs exist, the CellSearch system (Veridex Corporation, Warren, NJ) is the only system approved in the US for clinical use to detect the presence of CTCs in patients with breast cancer. In a prospective trial of 177 patients who were beginning a new therapy for metastatic breast cancer [100], elevated CTCs at baseline (defined as ≥5 CTCs per 7.5 mL of blood) compared with the finding of fewer or no detectable CTCs predicted a significantly shorter PFS (3 versus 7 months) and overall survival (10 versus 22 months). Patients with elevated CTCs at the first follow-up visit (within three to five weeks of initiating therapy) also had a worse PFS (2 versus 7 months) and overall survival (8 versus greater than 18 months), whereas those with a decrease in the number of CTCs from baseline had improved PFS and overall survival. Subsequent analyses from this trial and others have suggested that elevated levels of CTCs at any time point during treatment are associated with tumor progression and that CTC levels may reliably estimate disease progression earlier than imaging studies [102,105,106].

An ASCO expert panel on tumor markers in breast cancer, when convened in 2007, concluded that the data were insufficient and needed further validation prior to recommending routine measurement of CTCs in patients with metastatic breast cancer [43]. A prospective randomized trial is underway to test the clinical utility of changing therapy for patients with metastatic breast cancer who have not cleared CTCs after only one cycle of a new, first-line therapy [107].

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Beyond the Basics topics (see "Patient information: Treatment of metastatic breast cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS — The goals of systemic treatment for metastatic breast cancer are prolongation of survival, alleviation of symptoms, and maintenance or improvement in quality of life.

Hormone receptor status, human epidermal growth factor receptor 2 (HER2) overexpression, tumor burden, and disease-free interval have prognostic and predictive value and are important determinants in selecting appropriate treatment.

Given the importance of hormone receptor and HER2 status in selecting treatment, hormone receptor and HER2 testing should be repeated upon diagnosis of metastatic breast cancer in case there is discordance in expression between the primary site and metastases, especially if the primary cancer was deemed negative, since a conversion to positive would dramatically change therapy.

For patients with hormone-positive metastatic breast cancer with rapidly progressive, symptomatic disease or visceral metastases with end-organ dysfunction, we recommend first-line treatment with chemotherapy rather than endocrine therapy (Grade 1B). All other patients with hormone-positive metastatic breast cancer should be treated first with endocrine therapy.

We suggest sequential single agent chemotherapy for most patients with metastatic breast cancer who require chemotherapy (Grade 2B). Combination chemotherapy may be preferable for select patients with rapidly progressive disease, visceral crisis, or if quick symptom control is desired.

We recommend that patients with HER2-positive breast cancer, regardless of their hormone receptor status, receive HER2-directed therapy as first-line treatment (Grade 1A). (See "Systemic treatment for metastatic breast cancer: Biologic therapy", section on 'HER2-directed therapy'.)

Careful assessment of the response to therapy will assist in decisions for treatment continuation and in selection of subsequent treatments. Tools that are potentially useful to monitor treatment response include history and physical examination, radiographic imaging, and assay of serum tumor markers and/or circulating tumor cells (CTCs). (See 'Monitoring therapy' above.)

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107. Information on SWOG trial 0500 available online at http://clinicaltrials.gov/ct2/show/NCT00382018 (Accessed on April 28, 2011).