Chapter 28: Metastatic Breast Cancer

Breast cancer is a significant cause of morbidity and mortality among women. In the United States, it is the most common malignancy among women. It is estimated that approximately 231,840 new cases of invasive breast cancer will have occurred in the United States in 2015 (^1,2). Although lung cancer has surpassed breast cancer as the leading cause of cancer death among women, nearly 39,620 deaths were estimated to occur from breast cancer alone in 2013 (¹).

Since the 1970s, advances in combined-modality therapies have substantially improved the outcomes of patients with breast cancer. Still, approximately 10% to 60% of patients with initial localized breast cancer will suffer a systemic relapse. Metastatic disease is diagnosed at the time of presentation in 3% to 12% of patients depending on the series (^1,3). Bone is the most common site of first distant relapse; other common sites of metastases include lymph nodes, lung, liver, and, less frequently, brain. The 5-year survival rate for localized breast cancer is 99%; for metastatic disease, this rate is only 17% to 28% (^1,2,3). As is true with cancers in general, the clinical course for patients with metastatic breast cancer (MBC) varies, but as a group, patients with MBC have a median survival of 2 years (⁴). Patients with bone-only disease tend to live longer than patients with visceral involvement. Untreated patients with MBC have a median overall survival time of 9 to 12 months. With systemic therapy, the mean survival time is 21 months for patients with visceral disease and as long as 60 months for patients with bone-only disease. Survival and response to therapy are affected by several factors, including estrogen receptor (ER), progesterone receptor (PR), and HER2/neu receptor status; performance status; site of disease; number of disease sites; and duration of disease-free interval (DFI).

The therapeutic objectives and approach to patients with advanced breast cancer is distinct from that of patients with early-stage disease. Treatment for MBC is triaged to endocrine therapy, biological therapy, or chemotherapy, depending on the hormonal and HER2/neu receptor status of the tumor, the severity of symptoms, and the site and extent of disease. Generally, breast cancer can be classified as three molecularly and clinically different syndromes: hormone-receptor positive/HER2/neu negative, Her-2/neu positive (hormone-receptor negative or positive) and triple negative breast cancer. They have different clinical courses, prognoses, metastatic patterns, and responsiveness to available therapies. Systemic treatment prolongs survival, provides palliation of symptoms, and enhances quality of life but, in general, is not considered curative. Therefore, a discussion regarding goals of care is imperative between the patient and treating oncologist. Cure in MBC is rare; less than 2% of patients with MBC may remain disease free after anthracycline-containing therapy. The overall survival of patients has improved in the last few decades due to more effective therapies. This chapter reviews standard care for patients with MBC and discusses some unique approaches used at the University of Texas MD Anderson Cancer Center (MDACC).

Once metastatic disease is suspected, careful evaluation of the primary disease history, current symptoms, and existing comorbid diseases is essential. The history of the primary disease should include a review of the initial presentation, stage of disease, histology, hormone receptor and HER2/neu status, nuclear grade, and treatment modalities employed. Knowledge of the initial tumor type may yield clues about the sites of disease as well as its biology. For instance, infiltrating ductal carcinoma most commonly involve the lungs, pleura, liver, and brain. Infiltrating lobular carcinoma may metastasize to unusual sites such as the bone marrow, meninges, peritoneum, and retroperitoneal structures, such as the ureters (⁵).

If possible, a biopsy of the metastatic or recurrence site is required to confirm the histologic type, as well as ER, PR, and HER2/neu status, because there is some evidence of significant discordance in the receptor status between the time of diagnosis of the primary tumor and the time of diagnosis of metastasis (^6,7). Changes in ER status occur in 14.5% to 40% of cases, whereas changes in HER2 expression/amplification range from 0% to 37% (⁸). Pathologic confirmation is also essential in patients suspected of having metastases if the clinical presentation or course is not typical. Such relapse scenarios include single-lesion metastasis, unusual metastatic sites, and long DFI. Solitary lesions should always be biopsied because of the possibility that the lesion may not be not malignant or may be caused by a second different primary malignancy. This occurs in up to 10% of patients with solitary lesions and would have a direct impact on the treatment selection.

In addition to a comprehensive physical examination, basic laboratory evaluation should include a complete blood count with differential, liver and renal function tests, and serum calcium determination. In addition, CA 15-3 and CA 27-29 are potentially helpful in monitoring response to therapy. The CA 15-3 test is a combination of two monoclonal antibodies bearing two reactive determinants directed against DF3 and MAM-6 antigens expressed on mammary epithelial cells (^9,10). CA 15-3 and CA 27-29, which are more sensitive than CEA, are elevated in approximately 70% of patients with MBC, but they lack sensitivity and specificity for breast cancer progression. Therefore, their prognostic significance remains indeterminate (⁹). Carcinoembryonic antigen (CEA) is elevated in 40% to 50% of patients with metastatic disease (^10,11). Current recommendations from the American Society of Clinical Oncology are that tumor markers can be used in conjunction with diagnostic imaging, history, and physical examination to monitor patients with metastatic disease during active therapy; however, data are insufficient to recommend their use alone to monitor response to treatment (¹²). Caution should be used when interpreting tumor marker levels during the first 4 to 12 weeks of a new therapy, because spurious early rises may occur (^9,12). Furthermore, the absolute value of a tumor marker measurement does not represent the extent of disease, and no therapeutic decision should be based on a single tumor marker measurement. However, trends over time are helpful to monitor clinical course. In monitoring treatment, the physician should be aware of the coefficient of variation of the assays used for CA 15-3 and CA 27-29: changes <10% fall within the accepted intra-assay variability and do not represent real change. The measurement of circulating tumor cells (CTCs) has been studied in patients with MBC. Several studies showed that high levels of CTCs (>5 cells/75 mL of blood) are correlated with poor survival in MBC and with decreased response to treatment (^13,14). However, based on current recommendations, the measurement of CTCs should not be used to make the diagnosis of breast cancer or to influence any treatment decisions. Similarly, the use of the US Food and Drug Administration (FDA)-cleared test for CTCs (CellSearch Assay) in patients with MBC cannot be recommended for routine use until further validation confirms its clinical value. An intergroup trial is under way to determine the implication of changing treatment based on the CTC level (¹²).

In most cases, we perform a baseline evaluation that also includes a computed tomography (CT) of the chest and abdomen (ultrasonography is less accurate for the chest and abdomen and would be indicated only in patients who cannot have CT or magnetic resonance imaging [MRI]), but occasionally, MRI of the abdomen may be indicated (¹⁵). The presence of bone metastases should be evaluated, and in general, we recommend a bone scan to determine the presence and extent of bone metastasis. Only 30% to 60% of patients with true-positive bone scans have increased levels of alkaline phosphatase (^16,17). Conversely, only 20% of patients with elevated levels of alkaline phosphatase are disease free (¹⁷). Impending fractures in the weight-bearing bones, such as the femur, and an unstable spine must be ruled out. The preferred test for spinal evaluation for metastases is MRI. Monitoring of bone metastases is best done with serial MRI or CT scans. Radiographic evaluations of the brain, leptomeninges, and spinal cord have low yield unless the patient is symptomatic or has abnormal neurologic findings (¹⁵). Current guidelines discourage the use of positron emission tomography (PET)/CT except in situations where other staging studies are equivocal or suspicious (¹⁵).

General Considerations

The decision whether to use chemotherapy or biological or hormonal therapy for the initial treatment of MBC should be guided by several factors including hormone receptor and HER2/neu status and the presence of symptomatic visceral disease or life-threatening disease (Fig. 28-1). Patients with moderately symptomatic visceral disease or life-threatening disease should be considered for treatment with systemic chemotherapy regardless of hormone receptor status because systemic therapy offers faster palliation of symptoms. Among women who do not have life-threatening or symptomatic visceral disease, those whose tumors are negative for ER and PR should be also considered for systemic chemotherapy. Those whose tumors are positive for ER or PR should be treated with hormonal therapy. Since the discovery of the importance of HER2 gene amplification in breast cancer and the development of anti-HER2 therapies, patients with tumors positive for HER2/neu overexpression or gene amplification should be treated with anti-HER2 therapy in combination with chemotherapy because this provides a significant survival advantage.

Multiple agents are active against hormone-responsive tumors. Endocrine therapy tends to be associated with fewer side effects and helps maintain quality of life for many patients. If the tumor does not respond to endocrine therapy or becomes unresponsive to hormonal therapy, systemic chemotherapy should be initiated. For patients with hormone receptor–positive breast cancer, endocrine therapy is at least as effective as chemotherapy.

Currently, the primary goals of chemotherapy for MBC should be palliation of symptoms attributable to cancer and prolongation of life. It is the physician’s duty to balance the benefits of therapy with possible toxic effects and to fully discuss therapeutic options with patients. The patient’s multiple previous therapies, decline in performance status, comorbid conditions, and organ function should be taken into consideration in the treatment decision. The MDACC treatment algorithm of patients with MBC is illustrated in Fig. 28-2.

Patients presenting with solitary metastases or oligometastases represent a unique subset of patients who are potentially curable and should be approached with combined-modality therapy, including surgical resection of the metastases (or radiotherapy at curative doses), combination chemotherapy before or after local treatment, anti-HER2 agents for HER2-positive MBC, and endocrine therapy for hormone receptor–positive MBC. Such patients have a 20% to 25% probability of long-term cure after such treatment.

Endocrine therapy has dramatically improved outcomes in patients with hormone receptor–positive breast cancer. It can result in significant palliation of symptoms and improvement in quality of life in patients with hormone receptor–positive MBC. Manipulation of the endocrine system as a treatment for MBC was introduced in 1896, when Beatson demonstrated objective regression of breast cancer after oophorectomy. Today, a number of endocrine therapies are used in patients with hormone-sensitive MBC; most therapies are directed at reducing the synthesis of estrogen or blocking ERs in hormone-dependent tumors.

Tumors that are positive for ER and/or PR expression do not respond to endocrine therapy, and these patients should be offered endocrine therapy (^18,19). Patients who have tumors that are both ER and PR positive have a 50% to 70% probability of receiving clinical benefit from endocrine therapy. Patients with either ER-positive or PR-positive tumors have a 30% probability of receiving clinical benefit from endocrine therapy. Of patients with a prior history of hormonal response in the metastatic setting, 30% to 50% will have a response or clinical benefit from another hormonal regimen. Patients with low-volume disease and better performance status generally have higher response rates. The duration of first response is usually 9 to 12 months, similar to that with chemotherapy. The selection of endocrine therapy depends on the menopausal status of the patient: tamoxifen and/or ovarian suppression/ablation for premenopausal women and aromatase inhibitors or selective ER downregulators (SERDs) for postmenopausal women. The side effect profile also aids in the determination of which hormonal therapy to use, because the efficacy of all agents is nearly equal (²⁰). A substantial minority of patients with hormone receptor–positive MBC will benefit from sequential single-agent endocrine therapy. Some patients might benefit from three or four lines of endocrine therapy, and a few will continue to respond to multiple lines and for many years. Additionally, for patients whose tumors are unusually sensitive to hormonal manipulation, repeated treatment with a previously effective agent may again be effective if a long interval has elapsed since it was discontinued.

The clinical criteria used to determine eligibility for endocrine therapy are longer DFI, no involvement of vital organs, no major dysfunction of the organs involved by the disease, minimal or moderate visceral involvement, and metastases confined to the soft tissue or bone.

Several types of endocrine therapy are available in managing MBC (Table 28-1). They include ovarian ablation (oophorectomy, ovarian radiation), functional suppression (luteinizing hormone–releasing hormone [LHRH] agonists), selective ER modulators (SERMs), ER downregulators, progestins, androgens, estrogens, and nonsteroidal and steroidal selective aromatase inhibitors (AIs). Medical ovarian castration obviates surgery as a first choice. There is no current indication for adrenalectomy or hypophysectomy. There are no conclusive data to support combined hormonal therapies in postmenopausal breast cancer, aside from the use of fulvestrant with AIs in the first-line setting based on a recent trial noting clinical benefit. In most trials of combinations, some minimal increases in response rates were seen, but without a significant improvement in survival. Additional toxicities are usually observed (^21,22). As the understanding of the mechanisms of resistance to endocrine-based therapies has improved, the addition of therapies targeting these pathways has resulted in improved clinical outcomes. SERMs (tamoxifen and toremifene) are effective in pre- and postmenopausal patients with breast cancer. The LHRH agonists are effective in premenopausal women only (²³), and the combination of tamoxifen and ovarian ablation is superior to ovarian ablation alone (^20,23). Estrogen biosynthesis is reduced by inhibiting the aromatase enzyme, which catalyzes the final step in estrogen production in humans. This does not completely block ovarian estrogen production in premenopausal women, and there is concern that the use of an AI as a single agent in this patient population may cause a reflex increase in gonadotropin levels and result in ovarian hyperstimulation. Thus, AIs must be used only in postmenopausal women; they are not effective in premenopausal women (^15,24,25,26). The AIs can broadly be categorized as selective and nonselective. The nonselective AIs block not only aromatase but also other enzymes in the cytochrome P450 family. Thus, they alter other steroid hormone levels and are associated with more side effects. Therefore, they are not frequently used.

Endocrine therapy is better tolerated than cytotoxic chemotherapy. However, several unique complications of endocrine therapy should be anticipated. One such complication, flare, is defined clinically by an abrupt, diffuse onset of musculoskeletal pain, increased size of skin lesions, or erythema surrounding the skin lesion within the first month of endocrine therapy. Flare may also be characterized as the worsening of bone lesions on bone scan, the reason for which bone scans may make assessing response to endocrine therapy difficult. The most serious manifestation of flare is hypercalcemia, which can be seen with several hormonal therapies except AIs and surgical castration. Hypercalcemia usually occurs in patients with bone metastases and manifests itself within the first 2 weeks after treatment. The underlying mechanism is the predominating early agonist effect of hormonal agents. Low doses of prednisone (10-30 mg/d) may abrogate the initial flare of bone pain.

Side effects of endocrine therapy, such as hot flashes and mood disturbances, are related to estrogen deprivation and are common with tamoxifen and AIs, reflecting the mechanism of action of these drugs. Tamoxifen has estrogenic effects that are beneficial in some tissues; it lowers serum cholesterol levels and protects against bone loss and cardiovascular disease but is also associated with potentially life-threatening side effects, such as endometrial cancer and thromboembolic events. AIs are associated with musculoskeletal side effects, such as arthralgias, myalgias, and bone loss. Weight gain is clearly associated with estrogens, androgens, corticosteroids, and progestins. Randomized trials of tamoxifen do not support an association with weight gain because patients on placebo experienced the same degree of weight gain as those on tamoxifen. This side effect is most common with progestins, which can cause both a true increase in weight from their anabolic effect and fluid retention secondary to their glucocorticoid effect. Progestins are the drugs most likely to cause thromboembolism; tamoxifen is the next most likely drug to cause this complication.

The preferred agent for endocrine therapy depends on the menopausal status of the patient. In premenopausal women, tamoxifen is recommended as the initial therapy, although ovarian suppression with an LHRH agonist alone or with tamoxifen can also be used. In patients who are within 1 year of antiestrogen exposure, the preferred second-line therapy is surgical oophorectomy or an LHRH agonist with endocrine therapy (¹⁵). In postmenopausal women who are antiestrogen naïve or who are more than 1 year from previous antiestrogen therapy, an AI is recommended as initial first-line therapy, but tamoxifen or the combination of fulvestrant with an anastrozole can be considered. Aromatase inhibitors appear to have superior outcome compared with tamoxifen, but differences are modest (^27,28). The use of anastrozole or letrozole as initial therapy in postmenopausal women with ER-positive tumors results in increased response rates and longer disease control (²⁹). Patients who respond to initial therapy have a higher probability of response to second- and third-line endocrine therapies. There is a partial lack of cross-resistance between steroidal and nonsteroidal AIs. These agents may provide palliation of disease if used sequentially in patients with hormone receptor–positive tumors. There is evidence that a steroidal AI (exemestane) is effective in patients who have disease progression after a nonsteroidal AI. Most patients with hormone-responsive breast cancer benefit from the sequential use of endocrine therapies at the time of disease progression. Patients who respond to endocrine therapy with tumor shrinkage or long-term disease stabilization should receive additional endocrine therapy at the time of disease progression (¹⁵).

Fulvestrant is an ER antagonist that downregulates ER and has no agonist effects. It was compared with tamoxifen in a large randomized trial involving 587 postmenopausal women with advanced breast cancer or MBC who had not previously been treated with endocrine therapy. Patients were given either fulvestrant 250 mg intramurally monthly or tamoxifen 20 mg orally (PO) daily. At a median follow-up of 14.5 months, there was no significant difference between fulvestrant and tamoxifen in time to progression (TTP; median, 6.8 vs 8.3 months, respectively) (³⁰). Fulvestrant also appears to be as effective as anastrozole in patients whose disease progressed on tamoxifen (^31,32). The clinical benefit rates of exemestane and fulvestrant observed in a phase III trial of postmenopausal women with hormone receptor–positive breast cancer who experienced disease progression on prior nonsteroidal AIs were comparable (32.2% vs 31.5%) (³³). The CONFIRM trial (n = 736) compared fulvestrant at different doses (250 and 500 mg) in postmenopausal women with advanced disease recurring or progressing after prior endocrine therapy. Response rates were similar in both groups (13.8% vs 14.6%), but TTP and overall survival (OS) were significantly longer for the patients who received 500 mg (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.68-0.94) (^33,34).

Based on preclinical studies suggesting that the combination of fulvestrant and an AI was superior compared with either agent alone, three prospective clinical trials evaluated this approach in postmenopausal women with hormone receptor–positive MBC. In the Southwest Oncology Group SO226 trial, postmenopausal women (n = 707) with previously untreated metastatic disease were randomized to anastrozole versus anastrozole and fulvestrant, with crossover to fulvestrant encouraged (³⁵). Median progression-free survival (PFS) and OS were significantly improved with the combination (median OS, 41.3 months with anastrozole vs 47.7 months with the combination; HR, 0.81; 95% CI, 0.65-1), despite the fact that 41% of patients receiving anastrozole crossed over to fulvestrant. Subgroup analysis revealed that those deriving the greatest benefit were patients who received no prior tamoxifen. The other two studies showed equivalent outcomes in patients receiving the combination. In a randomized phase III trial, Johnston et al reported that patients with hormone receptor–positive MBC who relapsed or progressed while receiving a nonsteroidal AIs had similar PFS when treated with fulvestrant plus anastrozole, fulvestrant plus anastrozole-matched placebo, or exemestane (³⁶). Another phase III trial showed no advantages in clinical efficacy for the combination of anastrozole and fulvestrant compared to treatment with anastrozole alone as first-line treatment in postmenopausal women with hormone receptor–positive MBC (³⁷). One possible reason for the difference in outcomes of the three studies is a potential imbalance in the prognostic subgroups in the SWOG study (³⁸). Given the positive phase III findings and especially the significant prolongation in OS, the combination can still be considered, especially in patients who have never received tamoxifen.

De novo and acquired resistance is a known phenomenon. Options in this setting include changing the class of AI or using a drug with a different mechanism of action, such as fulvestrant or tamoxifen. Another approach is the addition of a mammalian target of rapamycin (mTOR) inhibitor, such as everolimus. Activation of the PI3K/Akt/mTOR pathway in breast cancer has been implicated as a mechanism of resistance to endocrine therapy. Preclinical research has evaluated the molecular basis of resistance to endocrine therapy, combatting resistance by incorporating inhibitors of this pathway (³⁹). A phase II study demonstrated similar efficacy and safety with the use of everolimus in combination with tamoxifen in the treatment of of 111 patients with hormone receptor–positive, HER2-negative MBC with prior exposure to AI treatment either in the adjuvant and/or metastatic setting (⁴⁰). The study fulfilled its primary end point, with a clinical benefit rate at 6 months of 61.1% with everolimus plus tamoxifen versus 42% with tamoxifen alone (P = .045). There was a delay in time to disease progression with the combination; the TTP was 8.6 months in patients treated with everolimus plus tamoxifen versus 4.5 months in those treated with tamoxifen alone, resulting in a significant reduction in the risk of disease progression (HR, 0.54; 95% CI, 0.35-0.81; P = .002).

The BOLERO-2 study, a randomized, phase III, double-blind, placebo-controlled, multicenter trial (⁴¹), randomized 724 patients with hormone receptor–positive advanced breast cancer who had recurrence or progression after receiving previous nonsteroidal AIs to receive either exemestane or exemestane plus everolimus. The combination arm resulted in an improvement in the primary end point of PFS (10.6 vs 4.1 months; P < .001). Adverse effects of everolimus reported to affect 30% of more of patients included stomatitis, infections, rash, fatigue, diarrhea, and reduced appetite. The most common grade 3 to 4 adverse reactions affecting 2% or more of patients included infections, hyperglycemia, fatigue, stomatitis, diarrhea, dyspnea, and pneumonitis. In 2012, everolimus in combination with exemestane was approved by the FDA for the treatment of postmenopausal women with recurrent or progressive hormone receptor–positive, HER2/neu-negative disease after failure of therapy with either letrozole or anastrozole.

Enticing new options in the treatment of hormone receptor–positive, HER2-negative MBC are cyclin-dependent kinase (CDK) 4/6 inhibitors (^42,43). Together with cyclin D1, CDK4 and CDK5 are kinases that facilitate the transition of dividing cells from the G₁ phase of the cell cycle to the S phase. Preclinical studies have demonstrated that breast cancer cells rely on both CDK4 and CDK6 for division and cell growth. Inhibition of these pathways leads to cell cycle arrest at the G₁/S phase checkpoint (⁴³). Palbociclib, LEE011 (ribociclib), and LY2835219 (abemaciclib) are three selective CDK inhibitors presently under evaluation for the treatment of hormone receptor–positive MBC. In a phase I trial of LY2835219, 132 patients with five different tumor types, including MBC, received 150- to 200-mg doses of oral drug every 12 hours (⁴⁴). The overall disease control rate for the 36 patients with hormone receptor–positive breast cancer was 81%, with a median PFS of 9.1 months. Common adverse events included diarrhea, nausea, vomiting, fatigue, and neutropenia. In a phase II trial, the oral CDK4/6 inhibitor, palbociclib, resulted in a near doubling of the primary end point of PFS as compared to control in the first-line treatment of 165 postmenopausal women with hormone receptor–positive MBC (⁴⁵). Those receiving the combination of palbociclib in addition to letrozole had an objective response rate of 43% compared to 33%, with a PFS of 20.2 months versus 10.2 months (HR, 0.488; P = .0004). Common adverse events included leukopenia, neutropenia, and fatigue. The CDK inhibitors are being studied in phase III trials. The PALOMA-2 trial is testing the combination of palbociclib with letrozole in MBC in the frontline setting, and PALOMA-3 (NCT01740427) is evaluating the combination with fulvestrant in patients who have failed previous endocrine therapy. The MONALEESA-2 study is evaluating the efficacy and safety of the selective CDK inhibitor LEE011 in combination with letrozole in postmenopausal women with hormone receptor–positive MBC who have received no prior treatment for advanced disease (NCT01958021).

After third-line endocrine therapy, little high-level evidence exists to help select the optimal sequence of endocrine therapy. There are other hormonal agents available; progestins, for example, are synthetic derivatives of progesterone that have a progesterone agonist effect. Progestins such as megestrol acetate and medroxyprogesterone acetate are effective in treating MBC. These drugs are thought to have antiestrogenic properties and may result in interruption of the pituitary-ovarian axis. Androgens (eg, fluoxymesterone, danazol) have been evaluated and used in patients with MBC treated with multiple endocrine agents who still have hormone-dependent disease. Prior to the identification of hormone receptors or the development of SERMs, high-dose estrogens were commonly used to treat MBC. Their efficacy is similar to that of tamoxifen, although high-dose estrogens (eg, diethylstilbestrol, ethinyl estradiol) are associated with more severe side effects. Recent data suggest that the use of estrogens can be beneficial for patients with AI-resistant breast cancer (⁴⁶). In a phase II study, 66 patients with AI-resistant MBC were randomized to receive 6 versus 30 mg of estradiol. The clinical benefit rates were 25% with 30 mg and 29% with 6 mg. The authors concluded that 6 mg of estradiol was as effective as 30 mg with greater safety and that this regimen could be a palliative therapeutic strategy in MBC progressing after other endocrine therapies (⁴⁶). The treatment algorithm for treating patients with MBC at MDACC is illustrated Fig. 28-2.

No predictive test for response to chemotherapy has been sufficiently validated to use in a standard clinical setting. For patients with MBC not previously treated with chemotherapy, the response rates are 30% to 75%. Predictors of response to chemotherapy include DFI, sites of disease, organ function, and performance status, among others. Different biomarkers have been studied; some correlate with treatment response, but none is sufficiently accurate to help make a decision to treat or withhold therapy (⁴⁷).

Selection of Agents/Regimen

In deciding which cytotoxic regimen to use in the setting of negative ER/PR and HER2 status or in patients who have progressive disease after endocrine therapy, consideration should be given to the previous therapies, organ function, and comorbid conditions. Typically, chemotherapy within the conventional range of doses is associated with higher response rates than “low-dose chemotherapy.” As in the setting of adjuvant therapy, high-dose chemotherapy with peripheral blood/bone marrow stem cell transplantation has not been found to be of clinical benefit in randomized trials (⁴⁸).

The choice between sequential single agents and combination chemotherapy is controversial. The principle of nonoverlapping mechanisms of resistance and toxicities has been the basis of combination chemotherapy. Multiple randomized trials involving single-agent versus multiple-agent regimens in MBC have generally demonstrated that combination chemotherapy has improved response rates and TTP, but OS is not improved. Fossati et al (⁴⁹), in a systematic review that included 31,510 patients, estimated that the proportional reduction in overall mortality for combinations versus single-agent regimens is only 18%, translating to an absolute benefit in survival of 9% at 1 year, 5% at 2 years, and only 3% after 5 years. More toxicity was associated with combination therapy. In two randomized trials of combination versus single-agent therapy in MBC, formal quality-of-life analyses favored the single-agent arms, even though response rates were slightly lower (^50,51).

A Cochrane review (⁵²) including 28 trials and 5,707 patients with MBC randomly assigned to receive single-agent or combination chemotherapy found that combination therapy was associated with a higher response rate (odds ratio, 1.28; 95% CI, 1.15-1.42), longer TTP (HR, 0.78; 95% CI, 0.73-0.83), and longer OS (HR, 0.88; 95% CI, 0.83-0.94) than single-agent therapy. Most trials included in the Cochrane review did not specifically investigate the combination versus the sequential use of the single agents, and few studies reported the rate of “crossover” to an additional therapy following progression in the monotherapy arm. Therefore, the studies included evaluated the value of the use of two agents versus a single agent and do not address whether a simultaneous combination or a sequential monotherapy strategy should be pursued.

In the absence of strong evidence to guide the decision, and in agreement with different oncologic societies (⁵³), we believe that use of single-agent therapy is preferable in the absence of rapid clinical progression, life-threatening visceral metastases, or the need for rapid symptom or disease control. Ultimately the choice of the use of sequential versus combination chemotherapy depends on a careful evaluation of risks and benefits for individual patients. The other major indication for combination therapy, as in the adjuvant setting, is the treatment of oligometastases.

Duration of Chemotherapy

The optimal duration of chemotherapy for MBC is controversial. Several studies have compared continuous (maintenance) chemotherapy with intermittent therapy. Several studies found that continuous therapy was associated with a longer time to relapse (^{54,55,56,57,58}) but with worse side effects (⁵⁷). None of the individual studies comparing continuous and intermittent therapy showed prolongation of life with continuous therapy. However, a recent meta-analysis of these data showed a statistically significant improvement in survival for patients receiving chemotherapy for a longer versus a shorter time (⁵⁸). Some regimens, such as anthracycline-containing treatments, have inherent dose-limiting toxic effects that prohibit prolonged use. Other agents, such as trastuzumab, capecitabine, and, possibly taxanes given weekly, lend themselves to prolonged continued therapy. In an unplanned interim analysis, the recently presented Italian MANTA trial found no PFS or OS benefits for maintenance treatment with paclitaxel (175 mg/m² every 3 weeks for eight cycles) after first-line chemotherapy for MBC with an anthracycline/taxane-containing regimen (six to eight cycles) (⁵⁹). Many trials are designed to treat patients until they have progression of disease or for two to three cycles after maximum benefits. Currently, the optimal treatment duration is unknown. The practice at MDACC is to treat patients with MBC with continuous chemotherapy unless unacceptable toxicity arises, at least until a third-line or fourth-line regimen comes into play and/or Eastern Cooperative Oncology Group (ECOG) performance status is ≥3 in patients with MBC.

Single-Agent Chemotherapy

Anthracyclines

The introduction of anthracyclines (doxorubicin and epirubicin) in the 1970s represented a significant advance in the treatment of advanced breast cancer. In patients with MBC, response rates to single-agent doxorubicin (25-75 mg/m² every 3 weeks) ranged from 25% to 60% and were heavily influenced by patient characteristics such as prior chemotherapy exposure, performance status, and extent and sites of disease (^{60,61,62,63,64}). At MDACC, doxorubicin-containing regimens have historically been the initial treatment of choice for MBC treated previously with non–anthracycline-containing chemotherapy. Patients who received anthracyclines and had a prolonged DFI before the development of metastatic disease occasionally benefit from repeat administration of doxorubicin. However, given the increasing number of active agents available to treat MBC, repeat management with anthracyclines should be reserved for patients in whom other treatments have failed, given the potential risk of heart failure.

Epirubicin is a doxorubicin analog that has been shown to have similar efficacy and somewhat less toxicity than doxorubicin at equimolar doses. Although not designed to perform a head-to-head comparison, results from a randomized trial suggested that epirubicin might be as efficacious as doxorubicin. A formal comparison of two different anthracyclines in combination (5-fluorouracil, doxorubicin, and cyclophosphamide [FAC] vs 5-fluorouracil, epirubicin, and cyclophosphamide [FEC]) at equimolar doses found both regimens to be equally effective in terms of response rate, TTP, and survival. The FEC regimen was associated with less gastrointestinal, hematologic, and cardiac toxicity (⁶⁵).

Efforts to improve the safety profile of doxorubicin while preserving efficacy have resulted in liposomal formulations of doxorubicin. Response rates with these products appear comparable to those seen in other multicenter trials using conventional single-agent doxorubicin. In a phase III clinical trial, O’Brien et al compared the efficacy and safety of pegylated liposomal doxorubicin with those of conventional doxorubicin as first-line therapy in patients with MBC (⁶⁶). A total of 509 women received a 1-hour infusion of pegylated liposomal doxorubicin (50 mg/m² once every 4 weeks) or conventional doxorubicin (60 mg/m² once every 3 weeks). The median PFS and OS were similar in both treatment groups (6.9 vs 7.8 months and 20.1 vs 22.0 months, respectively). The rates of alopecia, myelosuppression, nausea, and vomiting were lower with pegylated liposomal doxorubicin than with conventional doxorubicin. Perhaps most notably, pegylated liposomal doxorubicin was associated with a significantly lower incidence of cardiotoxicity, even at higher cumulative doses (P < .001) (⁶⁶). The most important dose-limiting toxicity of pegylated liposomal doxorubicin is palmar-plantar erythrodysesthesia, which is both dose and duration related. The polyethylene glycol coating results in preferential concentration of the drug in the skin; this explains why small amounts of the drug can leak from capillaries in the palms and soles, resulting in redness, tenderness, and peeling of the skin that can be uncomfortable and even painful. As with all liposomal drug delivery systems, there is a low incidence of hypersensitivity reactions.

Taxanes

Taxanes (paclitaxel, docetaxel, and the nanoparticle albumin-bound [nab]-paclitaxel) are among of the most active classes of cytotoxic drugs available today for the treatment of breast cancer. They rival the anthracyclines in terms of response rates and positive impact on TTP. Taxanes are frequently used as first-line chemotherapy for treatment-naive MBC and also in MBC treated with anthracyclines or if anthracyclines are contraindicated. Response rates with paclitaxel range from 21% to 62%; in anthracycline-resistant breast cancer, response rates are 40%.

Two trials have directly compared doxorubicin and paclitaxel, using different dosing and administration schedules. In the Intergroup E1193 study (⁶⁷), similar response rates and TTP were demonstrated with doxorubicin administered at 60 mg/m² and paclitaxel at 175 mg/m² over 24 hours. Thus, paclitaxel may be as effective as doxorubicin when administered as a single agent. The dose and administration schedule may influence the response to paclitaxel. The use of weekly paclitaxel has recently become very popular due to the improvement in the toxicity profile and the ability to deliver a more dose-intensive regimen. At MDACC, the most popular taxane regimen is weekly paclitaxel 80 mg/m², commonly in a “3 weeks on, 1 week off” or “2 weeks on, 1 week off” schedule.

Docetaxel is a semisynthetic taxane with several preclinical, pharmacokinetic, biological, and clinical differences in comparison to paclitaxel. It has demonstrated a 37% to 57% response rate in patients with anthracycline-resistant tumors and was initially FDA approved for this indication at a dose of 60 to 100 mg/m² every 3 weeks. At this dose, hematologic toxicity is the greatest and the rates of neutropenia are similar to those seen when paclitaxel is given every 3 weeks. In a large clinical trial, 527 patients were randomized to receive docetaxel 60, 75, or 100 mg/m² every 3 weeks. A relationship between increasing dose of docetaxel and increased tumor response was observed, but toxicities were also related to increasing doses (⁶⁸). Docetaxel every 3 weeks at doses between 75 and 100 mg/m² are appropriate choices as first-line therapy for MBC; in most cases at MDACC, we use 75 mg/m². Compared to every-3-week paclitaxel, docetaxel 100 mg/m² was associated with longer TTP (HR, 1.64; 95% CI, 1.33-2.02) and improved OS (HR, 1.64; 95% CI, 1.33-2.02), but also greater incidence of treatment-related toxicities (⁶⁹). To place these data in context, it is important to remember that paclitaxel has greater activity when given on a weekly schedule, yet it is not clear whether docetaxel or paclitaxel provides superior outcomes when each agent is administered at its optimal dose and schedule. In patients who had received paclitaxel previously, docetaxel administration was associated with response rates of 18% to 21%, demonstrating a lack of cross-resistance between the two agents (⁷⁰).

Moderate nail changes and fatigue are commonly seen with weekly paclitaxel and docetaxel; excessive tearing due to partial or complete canalicular stenosis is seen with weekly docetaxel. Diarrhea, stomatitis, and neutropenia and its complications are uncommon with weekly taxane administration. Fluid retention is seen in patients who receive a docetaxel cumulative dose greater than 300 mg/m². Premedication with steroids greatly reduces the magnitude of fluid retention; the optimal doses and schedules for steroid administration are not well established. At MDACC, we routinely prescribe dexamethasone 4 mg PO twice a day for 3 days beginning the day before chemotherapy administration.

Nab-paclitaxel is a nanoparticle albumin-bound paclitaxel (Abraxane) that has been investigated in the treatment of MBC. In different comparisons, it has proven to be better, or at least as effective, as the other taxanes (^71,72), with the advantage that it does not require Cremophor for solubility and therefore is associated with less hypersensitivity reactions. In a phase III study, 454 patients were randomly assigned to 3-week cycles of nab-paclitaxel 260 mg/m² or paclitaxel 175 mg/m². Nab-paclitaxel demonstrated significantly higher response rates compared with paclitaxel (33% vs 19%, P = .001) and longer TTP (23.0 vs 16.9 weeks, P = .006). Grade 3 sensory neuropathy was more common with nab-paclitaxel, the incidence of grade 4 neutropenia was significantly lower with nab-paclitaxel, but the rate of febrile neutropenia was similar in both groups. A phase II four-arm study compared nab-paclitaxel (300 mg/m² every 3 weeks, 100 mg/m² weekly, or 150 mg/m² weekly) and docetaxel (100 mg/m² every 3 weeks). The weekly dose of 150 mg/m² of nab-paclitaxel demonstrated longer PFS than docetaxel (12.9 vs 7.5 months, P = .006), but no differences in PFS or response rates were seen when comparing docetaxel and the 3-week schedule of nab-paclitaxel. Grade 3 or 4 fatigue, neutropenia, and febrile neutropenia were less frequent in all nab-paclitaxel arms, but the frequency and grade of peripheral neuropathy were similar in all groups (⁷¹). At MDACC, nab-paclitaxel is frequently used as first- or second-line therapy administered in a weekly schedule, and it is preferred to paclitaxel for patients with contraindications to steroid use.

Antimetabolites

Capecitabine

Capecitabine (Xeloda) is an oral fluoropyrimidine approved by the FDA in April 1998 as single-agent therapy for the treatment of MBC resistant to anthracyclines and taxanes. In September 2001, capecitabine was approved for use in combination with docetaxel in MBC previously treated with an anthracycline. The first phase II study of capecitabine in breast cancer involved 162 patients previously treated with paclitaxel for MBC (⁷³). The majority of patients had also received previous anthracycline therapy. Capecitabine was administered at 2,500 mg/m²/d in two divided doses for 14 days, followed by 1 week of rest. Twenty-seven (20%) of 135 women with measurable disease demonstrated complete or partial responses. The median duration of response was 8.1 months, and the median survival was 12.8 months. In a phase II trial, O’Shaughnessy et al randomized patients to receive cyclophosphamide, methotrexate and 5-fluorouracil (CMF) or capecitabine in the frontline setting (⁷⁴). The overall response rate was 30% for capecitabine and 16% for CMF; no differences in TTP were seen. Similar levels of nausea, vomiting, and stomatitis were observed in both groups. More cases of grade 3 or 4 diarrhea (8%), fatigue (5%), and hand-foot syndrome (15%) were noted with capecitabine.

Capecitabine is active in the treatment of MBC, and significant response rates can be achieved in women previously treated with an anthracycline and a taxane. However, patients with triple-negative tumors do not benefit from it. The FDA-approved dose and schedule are 2,500 mg/m²/d given orally in two divided doses for 14 days, followed by 1 week of rest. Retrospective studies suggest that a lower starting dose (2,000 mg/m²/d) is better tolerated, with preserved efficacy. Capecitabine as first-line therapy for MBC results in response rates of 30% to 58%, and it is a reasonable option for some patients. At MDACC, it is often used as first-line therapy for patients who have been previously treated with anthracyclines and/or taxanes in the adjuvant or neoadjuvant setting.

Gemcitabine

Gemcitabine (Gemzar), a nucleoside analog, was approved by the FDA in April 2004 for the first-line treatment of MBC in the United States. In patients with MBC, single-agent response rates have ranged from 14% to 37% (^75,76,77). These were small trials, and the disparate results may be due to dosing differences. Generally, chemotherapy-naive patients tolerate doses of 1,000 to 1,250 mg/m²/wk on days 1, 8, and 15 every 28 days. Omitting the day 15 dose or reducing the dose in subsequent cycles of chemotherapy may improve the patient’s ability to tolerate therapy beyond the initial cycles. Pretreated patients may require dose reductions in order to decrease the risk of thrombocytopenia. Gemcitabine has been investigated in many different doublet and triplet combinations; it is a promising agent for its efficacy as a single drug, but also due to its ability to readily combine with paclitaxel, vinorelbine, docetaxel, or cisplatin/carboplatin as first- or second-line therapy. At present, gemcitabine is appropriate treatment for patients with MBC after treatment failure with standard regimens.

Other Agents

Vinorelbine

Vinorelbine (Navelbine) is a semisynthetic vinca alkaloid that interferes with microtubule assembly and is an important active agent in the treatment of MBC. Phase II trials investigating its efficacy in pretreated MBC have demonstrated response rates ranging from 25% to 47% (^78,79,80). The primary side effects are neutropenia, pain with infusion, flu-like symptoms, and gastrointestinal symptoms such as nausea or constipation. Vinorelbine is appropriate third-line (or later) therapy for patients with MBC. At MDACC, it is usually given at a dose of 25 mg/m² on days 1, 8, and 15 of 21-day cycles.

Ixabepilone

Ixabepilone (Ixempra) is an epothilone B analog that binds to microtubules and causes microtubule stabilization and mitotic arrest. It was approved by the FDA in October 2007 (alone or in combination with capecitabine) for the treatment of patients with MBC resistant to treatment with an anthracycline and a taxane or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. As a single agent, it is also indicated for patients with tumors resistant or refractory to capecitabine.

Ixabepilone monotherapy was evaluated in a single-arm trial in 126 patients who had previously received an anthracycline, a taxane, and capecitabine (⁸¹). The objective response rate was 11.5%, the median response duration was 5.7 months, and the median OS was 8.6 months. Grade 3 or 4 neutropenia was seen in 54% of patients, and grade 3 or 4 peripheral neuropathy was seen in 14%. When used as first-line therapy in patients with MBC who received anthracycline-based chemotherapy in the adjuvant setting, the response rates was 41.5%, with a median duration of response of 8.2 months and a median survival of 22 months (⁸²). At MDACC, we frequently use it in patients who have received anthracyclines, taxanes, and capecitabine. Ixabepilone is given at 40 mg/m², but based on toxicities and tolerance, it is not uncommon to reduce the dose to 32 mg/m².

Eribulin

Eribulin mesylate is a synthetic analog, a novel microtubule modulator that induces a conformational change that suppresses microtubule growth and sequestration of tubulin into nonfunctional aggregates. In the phase III study that led to its approval, 762 heavily pretreated women with locally or recurrent MBC were randomized to receive eribulin or physicians’ treatment of choice. Patients treated with eribulin had an improvement in OS (13.1 vs 10.6 months; HR, 0.81; 95% CI, 0.66-0.99) (⁸³). Asthenia, fatigue, and neutropenia were the most common side effects associated with eribulin. Peripheral neuropathy led to discontinuation of treatment in 5% of patients. Recently, a phase II study evaluated the efficacy and safety of eribulin in the treatment of HER2-negative MBC in the first-line setting (⁸⁴). Fifty-six patients were treated, with the majority having received anthracycline- and/or taxane-containing chemotherapy in the adjuvant setting. The objective response rate was 29% (95% CI, 17.3%-42.2%), the clinical benefit rate was 52%, the median response duration was 5.8 months, and the median PFS was 6.8 months.

Combination Chemotherapy

Anthracycline-Based Combination Regimens

Doxorubicin-containing combinations result in overall response rates ranging from 50% to 80%, with response durations of 8 to 15 months. The median survival with doxorubicin–alkylating agent combinations was 17 to 25 months. Although doxorubicin-containing regimens are more efficacious in the metastatic setting than are non-doxorubicin-containing combinations, anthracycline-based combinations are not commonly used because of the associated side effects.

As was discussed previously, the issue of whether combination chemotherapy is superior to single-agent chemotherapy in the treatment for MBC continues to be debated. For patients with rapidly progressing disease, treatment regimens most likely to produce an objective tumor response are highly desirable; therefore, there is still an important role for the use of combination chemotherapy. For many years, FAC (500/50/500 mg/m²) was the standard regimen for patients with MBC treated at MDACC. Several randomized clinical trials have compared different anthracycline-based chemotherapy regimens in patients with MBC. Nabholtz et al (^85,86) compared the use of docetaxel/doxorubicin/cyclophosphamide (TAC; 75/50/500 mg/m²) with FAC as first-line therapy for MBC (n = 484). The objective response rate was 55% with TAC and 44% with FAC (P = .02; HR, 1.5; 95% CI, 1.1-2.2). There was no significant difference in TTP or OS between treatment arms. Febrile neutropenia occurred more frequently with TAC than FAC (29% vs 5%), but similar rates of infection were seen. Carmichael et al reported the results of a trial comparing epirubicin and cyclophosphamide (EC) with epirubicin and paclitaxel (EP) in patients with MBC (⁸⁷). A total of 705 patients received up to six cycles of therapy. The objective response rate was higher with EP (67%) than with EC (56%). However, the TTP and OS were similar between the treatment arms. Doxorubicin and cyclophosphamide (AC) were compared to doxorubicin and docetaxel (AT) in 429 patients with MBC (⁸⁸). The AT regimen significantly improved the TTP (37.9 vs 31.9 weeks, P = .014) and overall response rate (59% vs 47%, P = .008) compared with AC, but there was no difference in OS. The AT regimen is a valid option for the treatment of MBC.

Platinum-Based Combination Regimens

As single agents, the platinum salts (primarily cisplatin and carboplatin) have had relatively limited use in the treatment of MBC. Platinum compounds have been reserved for third-line therapy or beyond. Objective responses in this setting are less than 10% (⁸⁹). In a limited number of trials of cisplatin or carboplatin first-line chemotherapy for MBC, objective responses were up to 50% (⁸⁹). The availability of many active chemotherapeutic regimens and the significant toxicities associated with platinum compounds resulted in their being largely used in the salvage setting. With the introduction of newer cytotoxic agents and preclinical data demonstrating their synergy with platinum compounds, there is renewed interest in incorporating the platinum compounds into regimens for MBC. The major reason for the revival of interest in platinum compounds is a greater understanding of the sensitivity of cells with homologous recombination deficiency, especially those with BRCA mutations, to platinum. Platinum monotherapy or platinum-based combinations are being widely tested in primary breast cancer and MBC in BRCA mutation carriers. By extrapolation, there is also much interest in testing platinum-based therapies in patients with triple-negative breast cancer and in those with HER+ tumors because in vitro synergy has been shown with anti-HER2 therapy in experimental models.

Phase II trials have been reported with the combination of paclitaxel and cisplatin. As first-line therapy for MBC, overall response rates have ranged from 50% to 90%. Trials evaluating this combination as second- or third-line therapy reported response rates of 30% to 50% (⁸⁹). These results suggest that the combination of cisplatin and paclitaxel produces response rates higher than those expected with paclitaxel alone. Perez et al reported on the combination of paclitaxel (200 mg/m²) and carboplatin (area under the curve [AUC] 6 every 3 weeks) as first-line treatment of MBC (⁹⁰). In 53 patients, an overall response rate of 62% was observed, including a complete response rate of 16%. The median TTP was 7.3 months, with a 1-year survival rate of 72%. A similar trial combining paclitaxel (175 mg/m²) and carboplatin (AUC 6) administered every 3 weeks (⁹¹) reported an objective response rate of 43% (14% complete response rate); the objective response rate was higher among patients who had received prior adjuvant therapy (76% vs 45%). A phase II study examined the combination of a platinum compound and docetaxel (⁹²). Among this previously treated group of patients, the overall response rate was 61%, the median duration of response was 8 months, and the median TTP was 10 months.

The activity of the cisplatin/gemcitabine combination in MBC had been explored with promising results. In one trial, patients previously treated with an anthracycline and/or taxane received cisplatin (30 mg/m²) plus gemcitabine (750 or 1,000 mg/m²) on days 1, 8, and 15 of 21-day cycles. The objective response rate was 50%, with 10% of patients attaining a complete response. The most common toxicities were peripheral neuropathy, nausea/vomiting, and hematologic toxicities (neutropenia, thrombocytopenia, and anemia) (⁹³). In a trial evaluating cisplatin 25 mg/m² on days 1 through 4 and gemcitabine 1,000 mg/m² on days 2 and 8 of a 21-day cycle, patients (n = 136) were divided in two cohorts according to prior treatments (heavily pretreated and not heavily pretreated). The response rate for both of the cohorts was 26%, and the median durations of response were 5.3 and 5.9 months, respectively (⁹⁴).

Platinum agents may prove to have a specific role in the treatment of triple-negative breast cancers, particularly in tumors harboring BRCA dysfunction. In preclinical and clinical studies, mutations in BRCA have greater sensitivity to DNA-damaging chemotherapeutic agents, such as platinum agents. Several studies are evaluating the safety and efficacy of platinum-based chemotherapy in combination with novel agents, particularly poly(ADP-ribose)polymerase (PARP) inhibitors. Given the similarities between triple-negative tumors and tumors harboring BRCA1 mutations, a large phase III study evaluated the combination of gemcitabine and carboplatin versus gemcitabine, carboplatin, and iniparib. The overall response rate for 258 patients treated with gemcitabine plus carboplatin was 33.7%, with a median PFS of 4.1 months and median OS of 11.1 months (⁹⁵). Unfortunately, iniparib was not an active PARP inhibitor, and the trial did not meet its primary end point. A recent meta-analysis evaluated four studies of platinum-based combination chemotherapy in the metastatic setting (⁹⁶). The overall response rates were comparable, but patients with triple-negative breast cancer treated with platinum agents had longer PFS. At present, we believe there may be a benefit in the use of platinum-based chemotherapy in all patients with triple-negative breast cancer regardless of BRCA status. Ongoing clinical trials will help clarify whether the majority of the benefit is derived from the efficacy of the platinum agents among BRCA mutation carriers.

Gemcitabine in Combination With Other Agents

Several phase II trials have investigated salvage therapy with docetaxel/gemcitabine combinations in MBC. Drug doses and schedules varied. Among previously treated patients, the objective response rates ranged from 36% to 79%. In a phase III study, the combination of gemcitabine (1,250 mg/m² on days 1 and 8) and paclitaxel (175 mg/m² on day 1) was associated with an improvement in response rate and TTP compared with paclitaxel alone (39.3% vs 25.6% and 5.4 vs 3.5 months, respectively) as first-line therapy for MBC (⁹⁷). Median OS was also significantly improved with the combination (18.6 vs 15.8 months; HR, 0.77; 95% CI, 0.62-0.95). There was more frequent grade 4 hematologic toxicity with the combination. Of note, most patients randomized to paclitaxel alone did not receive subsequent gemcitabine.

A phase III European trial found no difference between gemcitabine-docetaxel (1,000 mg/m² on days 1 and 8 and 75 mg/m² on day 1) and capecitabine-docetaxel (1,250 mg/m² twice a day on days 1-14 and 75 mg/m² on day 1) (⁹⁸). Similar PFS, OS, and response rates were seen. The toxicity profile for the gemcitabine-docetaxel combination was better.

Vinorelbine-Based Combination Regimens

A trial of single-agent doxorubicin compared to doxorubicin plus vinorelbine failed to demonstrate a superior response rate with the combination (⁹⁹). Vinorelbine has been successfully combined with taxanes. There are no phase III trials to confirm that these combinations are better than either single agent. Phase II studies combining vinorelbine and paclitaxel in MBC have been reported (¹⁰⁰). The overall response rates with first-line vinorelbine/paclitaxel are 49% to 60%. The overall response rates for second-line vinorelbine/paclitaxel and vinorelbine/docetaxel are 46% to 56% and 37% to 59%, respectively. Toxicities associated with vinorelbine/taxane combinations were myelosuppression and mild neurotoxicity (¹⁰⁰).

Capecitabine Combination Regimens

In September 2001, the FDA approved capecitabine in combination with docetaxel for patients with MBC previously treated with an anthracycline. This was based on the results of a multinational phase III trial that randomized 511 anthracycline-refractory patients to receive docetaxel 100 mg/m² or capecitabine 1,250 mg/m² twice daily for 14 days plus docetaxel 75 mg/m² intravenously every 3 weeks (¹⁰¹). The response rates for the single-agent and combination regimens were 30% and 42%, respectively (P =.006). The TTP was 4.2 and 6.1 months, respectively (P = .0001). The OS was significantly superior with the combination (HR, 0.775; 95% CI, 0.63-0.94). This is one of the few randomized trials that reported a survival benefit of one treatment over the other, but the design of the trial does not confirm that the combination is better than the sequential administration of single-agent docetaxel followed by capecitabine, or vice versa. Grade 3 treatment-related adverse events were more common with the combination versus docetaxel alone (71% vs 49%, respectively), but overall, the incidence of treatment-related adverse events was similar between the two groups (98% vs 94%, respectively).

Capecitabine in combination with ixabepilone has been approved for the management of resistant MBC or MBC progressing after anthracyclines and taxanes. The trial that led to the approval of this combination randomized 752 patients to ixabepilone (40 mg/m² intravenously every 3 weeks) plus capecitabine (2,000 mg/m² on days 1-14 of a 21-day cycle) or capecitabine alone (2,500 mg/m² on the same day schedule) (¹⁰²). Patients receiving the combination had a 25% reduction in the estimated risk of disease progression (HR, 0.75; 95% CI, 0.64-0.88). Median PFS (5.8 vs 4.2 months) and response rate (35% vs 14%) were also higher with the combination. Grade 3 or 4 treatment-related sensory neuropathy, fatigue, and neutropenia were more frequent with combination therapy, as was the rate of death as a result of toxicity (3% vs 1%). Patients with liver dysfunction were at higher risk of complications and therefore should not be treated with this regimen. Despite its toxicity, this combination represents a good alternative for patients with resistant disease previously treated with anthracyclines and taxanes and in whom a fast response is needed.

HER2/neu-Targeted Therapies

Since the introduction on anti-HER2 therapies to the treatment armamentarium of breast cancer, the outcome of patients with HER2-positive breast cancers has dramatically changed. The use of these therapies is now an integral part of the standard treatment of this subset of patients. For many years, the use of trastuzumab and a taxane was considered as the optimal first-line therapy among patients with MBC. In the past 2 years, the treatment algorithm of patients with HER2-positive MBC has dramatically changed as a result of the introduction of pertuzumab and T-DM1. In the following sections, we will review the most relevant data associated with the different anti-HER2 therapies. At MDACC, the use of trastuzumab, pertuzumab, and a taxane is considered the best regimen, and we use it as first-line therapy, followed by T-DM1 at the time of progression. For third- or fourth-line treatment, a number of different agents can be used. Commonly, we use trastuzumab and lapatinib, lapatinib and capecitabine, or another single chemotherapeutic agent in combination with trastuzumab.

Trastuzumab

The HER2/neu protein, a receptor tyrosine kinase, is overexpressed in 25% to 30% of human breast cancers and plays an important role in tumor development and progression. Trastuzumab (Herceptin) is a murine-human chimeric monoclonal antibody targeted against the HER protein. Trastuzumab was evaluated in two pivotal trials in women with HER2/neu-overexpressed MBC. In one trial, trastuzumab (4 mg/kg loading dose, then 2 mg/kg weekly) was evaluated as a single agent in 222 heavily pretreated women with MBC (¹⁰³). Nine (4%) of 213 treated patients achieved complete response, and 37 (17%) achieved partial response. The median duration of response was 9.1 months. For all treated patients, the median TTP was 3.1 months, and the median OS was 13 months. The most clinically significant adverse event was cardiac dysfunction, which occurred in 10 patients (4.7%), nine of whom had received prior anthracycline therapy. This trial demonstrated that trastuzumab can induce durable objective responses and is associated with an acceptable toxicity profile. The second pivotal trial evaluated the use of chemotherapy with or without trastuzumab in 469 patients who had not received prior chemotherapy for metastatic disease (¹⁰⁴). Women who had received an anthracycline in the adjuvant setting received paclitaxel 175 mg/m² every 3 weeks. All of the other patients received doxorubicin 60 mg/m² or epirubicin 75 mg/m² plus cyclophosphamide 600 mg/m² every 3 weeks. Trastuzumab 2 mg/kg (after a 4 mg/kg loading dose) was administered weekly until disease progression. The combination of chemotherapy plus trastuzumab resulted in a significantly higher objective response rate than chemotherapy alone (50% vs 32%). Women in the chemotherapy plus trastuzumab arm also had a significantly longer TTP and OS than those treated with chemotherapy alone. Symptomatic or asymptomatic cardiac dysfunction was seen in 27% of women treated with concurrent anthracycline/cyclophosphamide and trastuzumab. Based on the results of this trial, the FDA approved the combination of paclitaxel and trastuzumab as first-line therapy for HER2-overexpressed MBC.

The combination of trastuzumab and docetaxel has a high level of activity and an acceptable toxicity profile (^105,106). When docetaxel (100 mg/m² every 3 weeks) with or without trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly) was evaluated, the combination was significantly superior to docetaxel alone in terms of overall response rate (61% vs 34%; P = .0002), OS (31.2 vs 22.7 months; P = .032), TTP (11.7 vs 6.1 months; P = .0001), and duration of response (11.7 vs 5.7 months; P = .009). There was little difference in the number and severity of adverse events between the arms.

Given the success of the trastuzumab and paclitaxel combination, trastuzumab has been combined with other active agents against breast cancer (¹⁰⁷). A multicenter phase III study comparing trastuzumab/vinorelbine to trastuzumab/taxane (TRAVIOTA study) randomized 81 patients to receive trastuzumab with weekly vinorelbine or weekly taxane therapy (paclitaxel or docetaxel at the investigator’s choice) (¹⁰⁸). Response rates were 51% and 40% for the vinorelbine/trastuzumab arm and the taxane/trastuzumab arm, respectively. The median times to disease progression were 8.5 and 6.0 months, respectively (P = .09). Treatment with either regimen was well tolerated. Trastuzumab has also been safely combined with other agents. The trastuzumab/gemcitabine combination provides response rates of 30% to 44% in heavily pretreated patients. For patients who had disease progression on anthracyclines, taxanes, and vinorelbine, the combination of capecitabine (1,250 mg/m² divided twice a day for 14 days) and trastuzumab was shown to be very effective (^109,110). In different trials, the response rates were between 20% and 45% with clinical benefit rates of 70% to 85%. The safety profile of the combination was favorable and predictable, with a low incidence of grade 3 or 4 adverse events. This supports the use of the combination of capecitabine and trastuzumab in heavily pretreated MBC patients with tumors that have HER2 overexpression.

A number of trials evaluated triplet combinations. A phase III clinical trial evaluated the combination of trastuzumab/paclitaxel/carboplatin (TPC; trastuzumab 4 mg/kg loading dose followed by 2 mg/kg weekly, paclitaxel 175 mg/m², and carboplatin AUC 6 every 21 days) versus trastuzumab/paclitaxel. The triple combination arm had statistically significant improved response rates and PFS. Both treatments were well tolerated, but more cases of grade 4 neutropenia were seen in the triple combination arm (¹¹¹).

Pertuzumab

Pertuzumab is a humanized anti-HER2 monoclonal antibody approved by the FDA in 2012 for the treatment of advanced or late-stage (metastatic) HER2-positive breast cancer. Compared with trastuzumab, pertuzumab binds to a different extracellular dimerization subdomain of the HER2 receptor to inhibit signaling, thereby resulting in the reduction of tumor cell proliferation, invasiveness, and survival. The combination of pertuzumab, trastuzumab, and docetaxel was shown to have efficacy in the first-line treatment of HER2-positive MBC in a randomized trial known as the CLEOPATRA study (¹¹²). In this study of 800 patients, the addition of pertuzumab resulted in a PFS benefit of 18.5 months versus 12.4 months for the control group (HR, 0.62; 95% CI, 0.51-0.75; P < .001). At a median follow-up of 50 months, the addition of pertuzumab significantly improved median OS by 15.7 months (40.8 vs 56.5 months; HR, 0.68; 95% CI, 0.56-0.84; P = .0002), with a benefit consistently seen across all subgroups. The side effects profile was comparable between the two groups, although the rates of febrile neutropenia and diarrhea of grade ≥3 were higher in the pertuzumab arm. The combination of pertuzumab and trastuzumab was evaluated in a phase II study of 66 patients with progressive metastatic disease in the setting of prior trastuzumab exposure (¹¹³). The overall response rate was 24.2% and PFS was 5.5 months, with 17 patients experiencing stable disease for greater than 6 months. An ongoing study is evaluating the role of pertuzumab in patients with disease progression on trastuzumab, through a randomized phase II trial of trastuzumab/capecitabine alone or with pertuzumab for HER2-positive MBC progressing during or after trastuzumab-based first-line therapy (¹¹⁴). A nonrandomized phase II study is evaluating the efficacy of pertuzumab in combination with paclitaxel and trastuzumab in patients treated with up to one prior regimen for MBC, allowing for prior trastuzumab either in the metastatic or adjuvant setting (NCT01276041)

T-DM1

Ado-trastuzumab emtansine (T-DM1; Kadcyla) is the first HER2-antibody drug conjugate, combining trastuzumab with a linked antimicrotubule drug, maytansine (DM1). The FDA approved it in 2013 for the treatment of patients with metastatic HER2-positive breast cancer previously treated with trastuzumab and taxanes. The initial phase I study conducted in heavily pretreated patients with HER2 overexpression showed clinical activity, leading to a single-arm phase II study in 112 patients who progressed on trastuzumab, lapatinib, or both. A response rate of 25.9%, clinical benefit rate of 34%, and PFS of 4.6 months were observed (¹¹⁵). Hypokalemia (8.9%), thrombocytopenia (8%), and fatigue (4.5%) were the most common grade 3 or 4 toxicities. The EMILIA trial was an open-label, phase III study comparing T-DM1 versus capecitabine/lapatinib in trastuzumab pretreated HER2-positive patients with advanced/metastatic breast cancer (n = 980) (¹¹⁶). A significant improvement in PFS was observed with T-DM1 (9.6 vs 6.4 months; HR, 0.650; 95% CI, 0.549-0.771; P < .0001). The OS at 2 years was 65.4% with T-DM1 compared to 47.5% with capecitabine/lapatinib. An added benefit is the favorable safety profile of T-DM1 and the potential role of T-DM1 in treating brain metastasis. A phase II trial evaluated the role of treatment with T-DM1 in the first-line setting as compared to trastuzumab and docetaxel, resulting in an improvement in PFS (¹¹⁷). At a median follow-up of 14 months, the median PFS was 9.2 months with trastuzumab plus docetaxel and 14.2 months with T-DM1 (HR, 0.59; 95% CI, 0.36-0.97). The overall response rate with T-DM1 was 64.2% (95% CI, 51.8%-74.8%) versus 58% (95% CI, 45.5%-69.2%) with trastuzumab plus docetaxel. In the TH3RESA trial, 602 patients previously treated with two or more HER2-directed therapies were randomized to receive T-DM1 or treatment of physician’s choice (¹¹⁸). The PFS was significantly improved with T-DM1 compared with physician’s choice (median, 6.2 vs 3.3 months; HR, 0.528; 95% CI, 0.422-0.661; P < .0001). An interim OS analysis showed a trend favoring T-DM1. A lower incidence of grade 3 or worse adverse events was reported with T-DM1 than with physician’s choice treatment.

The MARIANNE trial is a phase III randomized trial evaluating the efficacy of T-DM1 with or without pertuzumab compared with trastuzumab plus taxane for first-line treatment of HER2-positive MBC (NCT01120184). A second phase III trial is seeking to compare T-DM1 to physician’s choice of treatment in patients with HER2-positive unresectable locally advanced or metastatic breast cancer treated with at least two prior anti-HER2 regimens (NCT01419197). Finally, a phase IB/II trial is evaluating the role of T-DM1 in combination with pertuzumab in patients with HER2-positive advanced breast cancer previously treated with trastuzumab (¹¹⁹).

Lapatinib

Lapatinib (Tykerb) is a selective, reversible dual EGFR-HER2 inhibitor. Phase II trials of single-agent lapatinib have shown modest clinical benefit in patients with HER2-positive breast cancer. Lapatinib in combination with capecitabine was approved by the FDA in 2007 for the treatment of advanced or HER2-overexpressing MBC previously treated with an anthracycline, a taxane, and trastuzumab. The trial that led to the approval showed that patients treated with lapatinib and capecitabine had a significant increase in PFS compared to capecitabine alone (¹²⁰). The study was closed prematurely because the first interim analysis showed that the addition of lapatinib was associated with a 51% reduction in the risk of disease progression. The median TTP for patients treated with lapatinib plus capecitabine compared with capecitabine plus placebo was 8.4 versus 4.4 months (HR, 0.49; 95% CI, 0.34-0.71). In a phase II study of patients with HER2-positive breast cancer and brain metastasis treated with lapatinib, 6% of patients had an objective response, defined as ≥50% volumetric reduction of the brain metastasis (¹²¹), suggesting that lapatinib could be of help in the treatment of patients with central nervous system metastasis.

Preclinical studies have shown a synergistic interaction between trastuzumab and lapatinib in HER2-overexpressing breast cancer cell lines and tumor xenografts. Results of a randomized phase III trial combining lapatinib with trastuzumab compared with lapatinib alone in heavily pretreated HER2-positive MBC (n = 296) demonstrated synergy and improved response rates and PFS in the combination arm. Despite a high crossover rate, there was a significant improvement in OS with the lapatinib and trastuzumab combination (HR, 0.71; 95% CI, 0.54-0.93) (¹²²).

Lapatinib has also been combined with hormonal agents. In a preclinical model, lapatinib restored tamoxifen sensitivity in tamoxifen-resistant breast cancer (¹²³). The EGF3008 trial, a phase III study combining letrozole plus lapatinib versus letrozole, demonstrated a 29% reduction in risk of disease progression and an improvement in median PFS (¹²⁴). A summary of some of the trials evaluating different anti-HER2 therapies is shown in Table 28-3.

Vascular Endothelial Growth Factor–Targeted Therapies

Bevacizumab

Bevacizumab (Avastin), a monoclonal antibody against all vascular endothelial growth factor (VEGF)-A isoforms has single-agent response rates of 9% in patients with refractory MBC. In a randomized phase III trial comparing capecitabine with or without bevacizumab in patients previously treated with an anthracycline and a taxane, the addition of bevacizumab produced a significant increase in response rates but no improvement in in PFS or OS (¹²⁵).

The ECOG 2108 trial randomized 680 patients with previously untreated locally recurrent breast cancer or MBC to receive weekly paclitaxel (90 mg/m² on days 1, 8, and 15) with or without bevacizumab (10 mg/kg on days 1 and 15) in 4-week cycles until progression (¹²⁵). The overall response rate (29.9% vs 13.8%, P = .0001) and the PFS (11.4 vs 6.11 months; HR, 0.51; 95% CI, 0.43-0.62) were significantly better with combination therapy; no OS differences were seen. Based on this trial, the combination of bevacizumab and paclitaxel was approved for first-line therapy of MBC. Several phase III studies using bevacizumab combined with different chemotherapy agents have shown improvements in PFS but failed to demonstrate a survival benefit with the addition of bevacizumab. Based on these studies, the FDA revoked the indication of bevacizumab in breast cancer. At MDACC, we have occasionally continued to use bevacizumab in addition to paclitaxel in very selected patients who need to achieve a rapid response and in whom the benefits associated with bevacizumab use outweigh the risks.

Bone Agents

Bisphosphonates are analogs of pyrophosphates that bind to hydroxyapatite crystals and inhibit bone resorption by osteoclasts. They are widely used to prevent skeletal complications in patients with bone metastases. Clinical trials have shown that the use of pamidronate or zoledronic acid is associated with fewer skeletal-related events and pathologic fractures and less need for radiation therapy and surgery to treat bone pain, with some suggesting that zoledronic acid is superior (¹²⁶). During bisphosphonate treatment, monitoring of renal function is needed. Physicians should also be aware of the risk of developing osteonecrosis of the jaw, a rare but serious complication of bisphosphonate therapy. Trial results support the use of bisphosphonates for 2 years, but there are limited long-term safety data. The OPTOMIZE-2 trial evaluated the frequency of zoledronic acid administration in 403 women with bone metastasis who previously received at least nine doses of intravenous bisphosphonate. The study showed that giving zoledronic acid 4 mg intravenously every 3 months was as effective as giving it monthly, with a rate of skeletal-related events of 22% in the monthly group versus 23.2% in the every-3-months group. The less frequent dosing corresponded to lower rates of renal failure and osteonecrosis of the jaw (¹²⁷).

Denosumab is a fully human monoclonal antibody that targets RANK ligand, a protein that acts as the primary signal to promote bone removal. Denosumab is being used in the treatment of osteoporosis, treatment-induced bone loss, and bone metastases. A large (n = 2,033), randomized, placebo-controlled trial evaluated denosumab (120 mg subcutaneously) versus zoledronic acid (4 mg intravenously) in patients with MBC and bone metastases (¹²⁸). Denosumab was superior to zoledronic acid in delaying or preventing skeletal-related events and delayed or prevented hypercalcemia, radiation to bone, and bone pain, suggesting that monthly denosumab is a viable option for the management of bone metastases. An advantage of denosumab therapy is that it is given as a subcutaneous injection. At MDACC, all patients with MBC and bone metastasis who do not have a contraindication to receive bone agents are treated with zoledronic acid or denosumab.

Despite therapeutic advances, the prognosis for many women with breast cancer is still poor. Investigational therapies for MBC include new molecules and agents with novel mechanisms of action.

In breast cancer, epidermal growth factor receptor (EGFR) plays a major role in promoting cell proliferation and malignant growth. Multiple studies evaluating the use of tyrosine kinase (TK) inhibitors in MBC are ongoing. Phase II studies of gefitinib (Iressa) used as a single agent or in combination with chemotherapy or endocrine therapy have been completed. Single-agent gefitinib showed minimal clinical benefit; no improvement in response rates was seen when it was used in combination. An exploratory analysis of two randomized phase II trials compared anastrozole or tamoxifen plus gefitinib versus single-agent anastrozole or tamoxifen plus placebo (¹²⁹). In both trials, among endocrine-naïve patients, gefitinib was associated with improved PFS when combined with hormonal therapy compared to anastrozole or tamoxifen alone. Erlotinib (Tarceva) is a small molecule that reversibly inhibits the EGFR TK and prevents receptor autophosphorylation. Combinations of erlotinib with drugs known to be active in breast cancer have been conducted. In a dose-escalation study of capecitabine, docetaxel, and erlotinib in patients with MBC, the overall response rate was 67% (¹³⁰). The regimen was well tolerated; manageable skin and gastrointestinal problems were the most common treatment-related adverse effects.

Multikinase inhibitors that inhibit VEGF receptors are under investigation. Sunitinib malate (Sutent) is an oral TK inhibitor that targets several receptor TKs, including VEGFR-1, -2, and -3. In a phase II trial in MBC previously treated with anthracyclines and taxanes (n = 64), sunitinib was associated with a clinical benefit rate of 16% (¹³¹). In a phase II randomized study, 46 patients with HER2-negative MBC were randomized to receive paclitaxel (90 mg/m² weekly), bevacizumab (10 mg/kg every 2 weeks), and sunitinib (25 mg daily for 21 days) as first-line chemotherapy. High rates of dose modification and treatment discontinuation due to toxic effects were seen, leading to the study closure. In previously treated MBC patients, sunitinib (37.5 mg PO daily dose) was compared to capecitabine (n = 482); no differences in PFS or OS were seen, and capecitabine was better tolerated.

Sorafenib (Nexavar) has been evaluated in patients with MBC refractory to anthracyclines and taxanes. Results from the SOLTI-0701 trial evaluated the combination of sorafenib (400 mg PO bid) and capecitabine (1,000 mg/m² on days 1-14 of a 21-day cycle) versus capecitabine and placebo in HER2-negative MBC (¹³²). Similar response rates were seen (38.3% vs 30.7%), but improved PFS (6.4 vs 4.1 months, P < .001) was observed with sorafenib and capecitabine. The combination treatment was associated with a 45% rate of grade 3 hand-foot syndrome. The Trials to Investigate the Effects of Sorafenib in Breast Cancer program evaluated the combination of sorafenib and paclitaxel versus paclitaxel and placebo in the frontline setting. The TTP and overall response rate, but not PFS, were improved with the combination. There was also an increase in cases of grade 3 toxicities and an imbalance in the number of deaths due to unusual causes in the paclitaxel and sorafenib group. Other VEGF TK inhibitors such as vandetanib (Zactima), valatinib, and axitinib are currently being tested.

Ongoing research is evaluating insulin-like growth factor inhibitors (CP-751, 856, AMG-479, IMC-A12), RAS/MEK/ERK (tipifarnib), and PI3K/AKT/mTOR pathway inhibitors. The PARP inhibitors are agents that have shown promise, particularly in the setting of metastatic triple-negative breast cancer associated with BRCA mutations; PARP-1 is a critical enzyme of cell proliferation and DNA repair. In addition, PARP-1 and -2 are fundamental in the repair of single-stranded DNA breaks (¹³³). Olaparib, a PARP inhibitor, has shown single-agent activity in patients with BRCA1/2 mutations, with little activity in sporadic breast cancer. Single-agent response rate was 41% in the phase I trial, with a median TTP of 5.7 months. Higher doses of 400 mg twice daily correlated with higher response rates. In a phase II randomized study of triple-negative MBC (n = 123), BSI-201 (iniparib) added to gemcitabine plus carboplatin showed significantly higher objective response rates and survival (¹³⁴). However, the phase III trial revealed modest improvement in PFS/OS that was not statistically significant. The phase III study (n = 519) compared chemotherapy alone versus chemotherapy plus iniparib in the treatment of triple-negative MBC (⁹⁵). Several studies of PARP inhibitors in the setting of BRCA-associated MBC are under way. At MDACC, we offer such patients clinical trials that include new and promising molecules.

Retrospective studies have suggested a potential survival benefit from complete tumor excision in selected patients with MBC. Substantial selection biases exist in all of these reports that likely confound the results. Recently, two trials evaluated the role of locoregional therapies in women with MBC. In a trial by Indian investigators, 350 patients with MBC and intact primary tumor were randomized to mastectomy followed by complete axillary dissection and radiation therapy versus no locoregional treatment (¹³⁵). All patients received anthracyclines with or without taxanes, with stratification by hormone receptor status, metastatic site, and number of metastases. No difference in OS was noted in the surgical versus nonsurgical group at 72 months. Although the local PFS was better in the surgical group, distant PFS was worse. In a second trial conducted by Turkish investigators, no difference in OS at 40 months was noted between patients with MBC randomized to upfront surgery followed by chemotherapy and patients assigned to chemotherapy alone (¹³⁶). A subgroup analysis identified an apparent survival benefit in women with solitary bone metastases. In the United States, ECOG 2108 is a randomized phase III trial presently evaluating early local therapy for the intact primary tumor in patients with MBC (NCT01242800). According to the most recent guidelines, patients with MBC and an intact primary should be treated systemically. Consideration for surgery for palliation is indicated in women with impending complications that may compromise quality of life such as skin ulceration, bleeding, fungation, and pain. Surgery in such cases should be performed only if complete local tumor resection can be achieved and if other disease sites are not immediately life threatening. Such surgery requires the collaboration between the breast surgeon and the reconstructive surgeon to provide optimal cancer control and wound closure. Alternatively, radiation therapy may be considered.

Despite great advances in the treatment of MBC, this conditions remains largely incurable, with a median survival of 2 to 3 years. The therapeutic concepts in MBC have changed with the realization that breast cancer is a conglomerate of several molecularly defined subtypes, each with a distinct prognosis, clinical course, and sensitivity to existing therapeutics. Treatment for MBC has dramatically evolved, incorporating new hormonal therapies, cytotoxic agents, and monoclonal antibodies. Refinements of chemotherapy with different combinations of newer agents along with modulating agents and growth factor support have allowed further advancement in the treatment of MBC. Despite great enthusiasm for targeted therapies, these agents have exhibited modest activity when used as single agents. A better understanding of the molecular biology of signaling pathways and the discovery of new biomarkers will help select patients who benefit from specific treatments.