Stages III and IV Breast Cancer

Metastatic Breast Cancer

Patients with metastatic cancer can be divided into two groups: those with stage IV disease at presentation and those who develop metastases after primary treatment. Biopsy is highly recommended for pathologic confirmation of presumed metastatic breast cancer and for marker investigations. Alterations in hormone receptor and HER2 status occur throughout tumor progression, and discordance between the primary and metastatic disease can significantly influence patient management and possibly survival. The management of stage IV disease depends on the site and extent of metastases, comorbid conditions, and clinical tumor characteristics.

Patients with delayed metastatic disease can be divided into two groups, that is, so-called low-risk and/or high-risk patients, based on the biologic aggressiveness of the disease. As shown schematically in Figure 2, the management approach for these two groups differs.

Low-risk patients

The low-risk group includes patients who develop metastatic disease after a long disease-free interval (ie, a long disease-free interval from primary breast cancer diagnosis to presentation with metastasis), those whose tumors are positive for hormone receptors (estrogen and progesterone(Drug information on progesterone)), those with bone-only disease, and those without extensive visceral organ involvement.

FIGURE 2 Treatment approach to metastatic cancer

Hormone therapy. Low-risk patients who have hormone receptor-positive (ie, ER-positive and/or PR-positive) tumors should be treated with a trial of hormone therapy. Ovarian suppression, with either an LHRH agonist or bilateral oophorectomy, is an effective modality of hormone therapy in premenopausal women.

• First-line hormonal therapy—First-line hormonal therapy consists of an aromatase inhibitor or tamoxifen(Drug information on tamoxifen), with careful serial assessment of clinical and disease responses.

Hormone therapy may be associated with a "flare" response, a temporary worsening of signs and symptoms of disease within the first few weeks of treatment. This response generally means clinical benefit will follow.

TABLE 2 Doses and schedules of hormonal agents commonly used in patients with metastatic breast cancer

If the tumor responds initially to first-line hormone therapy and then progresses, a second hormonal manipulation is warranted. Various hormonal agents are available (Table 2). They may be used sequentially and may provide disease palliation for prolonged periods of time in some patients.

• Second-line hormonal agents—The choice of second-line endocrine therapy depends on the front-line endocrine agent used. Typically, if tamoxifen was used, the second-line agent includes an aromatase inhibitor or fulvestrant (Faslodex) for postmenopausal women. For premenopausal women, the choice may be megestrol(Drug information on megestrol) (Megace) or induction of menopause with an LHRH (luteinizing hormone–releasing hormone) agonist with or without an aromatase inhibitor. If aromatase inhibitors were used as front-line agents for postmenopausal women, second-line options can be to change treatment to include another class of aromatase inhibitor, or fulvestrant, or tamoxifen.

EFECT (Evaluation of Faslodex versus Exemestane(Drug information on exemestane) Clinical Trial) was a randomized, double-blind, placebo-controlled, multicenter trial comparing the efficacy and tolerability of fulvestrant vs exemestane (Aromasin) in postmenopausal women with hormone receptor-positive advanced breast cancer following nonsteroidal aromatase inhibitor therapy. This was the first phase III trial to specifically evaluate endocrine therapeutic options following disease progression/recurrence occurring during nonsteroidal aromatase inhibitor therapy. A fulvestrant loading-dose regimen was utilized (via IM injection): 500 mg on day 0, followed by 250 mg on days 14 and 28, and every 28 ± 3 days thereafter. Exemestane was given as a 25-mg capsule PO once daily. Treatment was administered until disease progression or death, or withdrawal for any other reason. This trial includes 693 women, ~60% of whom have received at least two prior endocrine therapies.

In the primary analysis (median follow-up of 13 months), the median time to disease progression was 3.7 months in both the fulvestrant and exemestane groups (HR = 0.963; 95% CI, 0.819–1.133; P = .06531). Objective response and clinical benefit rates were also similar between groups, although the median duration of response (n = 38; from randomization: 13.5 months vs 9.8 months) and clinical benefit (n = 172; 9.3 months vs 8.3 months) appeared slightly longer in patients receiving fulvestrant. Overall survival data were immature at the time of the primary analysis. However, in a recent update with a median follow-up of 20.9 months, 209 patients (59.5%) in the fulvestrant group and 197 (57.9%) in the exemestane group had died. Median overall survival was not significantly different between treatments (24.3 months vs 23.1 months in the fulvestrant and exemestane groups, respectively [HR = 1.012; 95% CI, 0.833–1.229; P = .9072]).

FACT (Fulvestrant and Anastrozole(Drug information on anastrozole) in Combination Trial) was a multinational trial that enrolled women with ER-positive metastatic/recurrent breast cancer in the first-line setting. Patients were randomized to either anastrozole (Arimidex) at 1-mg orally each day (control arm) or anastrozole plus fulvestrant at 500 mg on day 0, at 250 mg on days 14 and 28, and monthly thereafter. The primary endpoint was time to progression (TTP); 258 women were enrolled in the fulvestrant-plus-anastrozole group and 256 were in the anastrozole-alone group. The study found no significant differences between the treatment groups with respect to the number or percentage with progression or the median TTP or overall survival (37.8 months vs 38.2 months, respectively; HR = 1; 95% CI, 0.76–1.32; P = 1.00). Receptor status, visceral involvement, age, and measurable disease were not associated with a greater benefit with combination therapy.

CONFIRM (Comparison of Faslodex in Recurrent or Metastatic Breast Cancer) is a randomized, double-blind, parallel-group, multicenter, phase III trial comparing fulvestrant at 500 mg (500 mg intramuscularly on day 0, then 500 mg IM on days 14 and 28 and every 28 days thereafter) with the approved dose of fulvestrant at 250 mg per month for treatment of postmenopausal women with ER-positive advanced breast cancer who experienced progression after prior endocrine therapy. Progression-free survival was significantly longer for women who received fulvestrant at a dose of 500 mg (n = 362) compared with 250 mg (n = 374) (HR = 0.80; 95% CI, 0.68–0.94; P = .006), corresponding to a 20% reduction in risk of progression. The objective response rate was similar for fulvestrant doses of 500 mg and 250 mg (9.1% vs 10.2%, respectively). The clinical benefit rate was 45.6% for fulvestrant at 500 mg and 39.6% for fulvestrant at 250 mg. Durations of clinical benefit were 16.6 months vs 13.9 months, respectively, whereas overall survival times were 25.1 vs 22.8 months in the 500-mg and 250-mg groups, respectively. Fulvestrant at a dose of 500 mg was well tolerated, with no dose-dependent adverse events. Quality of life was similar for patients in both arms.

Clinical efficacies in premenopausal metastatic breast cancer patients with combined letrozole(Drug information on letrozole) (Femara) and goserelin(Drug information on goserelin) (Zoladex) therapy were comparable to those in postmenopausal patients treated with letrozole alone. In a study of 73 patients with hormone-responsive metastatic breast cancer, 35 premenopausal patients received goserelin (3.6-mg subcutaneously every 28 days) plus letrozole (2.5-mg orally daily), and 38 postmenopausal patients received letrozole alone as their first-line endocrine therapy in a metastatic setting. Baseline characteristics were similar in the two groups, except for a younger age (median, 41 years vs 53.5 years; P < .001) and a shorter disease-free interval (median, 1.8 vs 3.3 years; P = .03) in the premenopausal group. Clinical benefit rates were comparable between the two groups (77% vs 74%; P = .77). At the median follow-up of 27.4 months, there was no statistical difference in the median TTP between the two groups (9.5 months [95% CI, 6.4–12.1 months] vs 8.9 months [95% CI, 6.4–13.3 months]). In patients who did not receive bisphosphonate, letrozole with or without goserelin caused a greater loss of bone mineral density at 6 months compared with that of patients receiving bisphosphonate treatment (premenopausal group, −16.7% vs 53.9%, P = .002; and postmenopausal group, −13.3% vs 17.4%, P = .04 at the lumbar spine). Although letrozole +/− goserelin resulted in a modest increase in bone resorption, concurrent treatment with bisphosphonate could prevent bone loss at 6 months.

The most commonly used second-line hormonal agents had been progestational drugs, such as megestrol (Megace). Recent randomized trials have indicated that fulvestrant or the aromatase inhibitors, such as anastrozole (Arimidex), letrozole, and exemestane (Aromasin), are equally effective for palliation of metastatic disease, have less toxicity, and may provide a survival advantage compared with megestrol. Therefore, they are the drugs of choice for second-line therapy following tamoxifen administration. Tamoxifen may also be considered as second-line therapy for patients initially treated with an aromatase inhibitor.

Hormonal therapy continues until evidence of disease progression or drug-related toxicity precludes further therapy with the same agent. If a partial or complete response to the first hormonal treatment is documented at the time of disease progression, a second hormonal agent may provide further palliation of symptoms and avoid the initiation of systemic chemotherapy. Subsequent hormonal responses tend to be of shorter duration, however, and, ultimately, the disease will become refractory to hormonal treatment.

Growing evidence supports a close interaction between the mammalian target of rapamycin (mTOR) pathway and ER signaling, and an emerging mechanism of endocrine resistance is aberrant signaling through the mTOR signaling pathway. Everolimus (Afinitor, Zortress) inhibits mTOR through allosteric binding to mTORC1. The BOLERO-2 (Breast Cancer Trials of Oral Everolimus 2) trial investigated the effect of the addition of everolimus in postmenopausal women with ER-positive, HER2-negative advanced breast cancer whose disease was refractory to previous letrozole or anastrozole. This phase III randomized trial compared everolimus and exemestane vs exemestane and placebo (randomly assigned in a 2:1 ratio) in 724 patients with hormone-receptor–positive advanced breast cancer who had recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor. The median patient age was 62 years, 56% had visceral involvement, and 84% had hormone-sensitive disease. Previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). Everolimus combined with exemestane improved median progression-free survival compared with exemestane plus placebo (10.6 months and 4.1 months, respectively, according to central assessment; HR = 0.36; 95% CI, 0.27–0.47; P < .001). The most common grade 3 or 4 adverse events were stomatitis (8% in the everolimus-plus-exemestane group vs 1% in the placebo-plus-exemestane group), anemia (6% vs < 1%), dyspnea (4% vs 1%), hyperglycemia (4% vs < 1%), fatigue (4% vs 1%), and pneumonitis (3% vs 0%).

Sidebar: There was renewed interest in combined endocrine therapy when the phase III trial, SWOG (Southwest Oncology Group) S0226, was reported by Mehta and colleagues. This study demonstrated improved progression-free and overall survival among postmenopausal women with hormone receptor–positive breast cancer who were given front-line treatment with anastrozole plus fulvestrant, compared with those given anastrozole alone. Prior adjuvant tamoxifen was allowed, and prior adjuvant aromatase inhibitor therapy was allowed if completed at least a year earlier. After stratification by receipt of adjuvant tamoxifen, patients were randomly assigned in balanced fashion to treatment with anastrozole with or without fulvestrant. Those in the anastrozole-only arm were strongly encouraged to switch to fulvestrant at progression, and ultimately 41% did. A total of 694 patients were included in the study; median age was 65 years. Only a minority had received adjuvant tamoxifen (40%), chemotherapy (33%), and aromatase inhibitors (2%). Patients in the anastrozole/fulvestrant arm had significantly better progression-free survival than the anastrozole only arm (15 vs 13.5 months; HR = 0.80; P = .007). In subgroup analyses, the difference was significant among those who had not received adjuvant tamoxifen (17 vs 12.6 months; HR = 0.74) but not among those who had. Patients in the anastrozole/fulvestrant arm also had significantly better overall survival (47.7 vs 41.3 months; HR = 0.81; P = .049). This benefit likewise appeared to be restricted to those who had not received adjuvant tamoxifen (47.7 vs 39.7 months; HR = 0.74). (Mehta RS et al: SABCS 2011, abstract S1-1).

Cytotoxic agents. Hormone-refractory disease should be treated with systemic cytotoxic therapy. Often sequential single-agent treatment regimens are administered. Patients should stay on each therapy until they either have progression of disease or too much toxicity from it. Chemotherapeutic doses and schedules, including those for combination regimens commonly used for metastatic breast cancer, are outlined in Table 1. (For a more detailed discussion of these agents, see section on "Intermediate-risk or high-risk patients.")

A prospective, multicenter study assessed the role of circulating tumor cells (CTCs) in predicting survival in 177 metastatic breast cancer patients before the start of a new treatment. Patients with levels of CTCs greater than five per 7.5 mL of whole blood had a shorter median progression-free survival (progression-free survival; 2.7 vs 7 months; P < .001) and shorter overall survival (10.1 vs > 18 months; P < .001) than did those with fewer than 5 circulating tumor cells per 7.5 mL of whole blood. Of all the variables in the statistical model, the levels of CTCs at baseline and at the first follow-up visit were the most significant predictors of progression-free and overall survival in this group of patients.

Intermediate-risk or high-risk patients

Intermediate-risk or high-risk patients include those with rapidly progressive disease or visceral involvement and those with disease shown to be refractory to hormonal manipulation by a prior therapeutic trial.

Anthracycline-containing combinations. Regimens containing an anthracycline, such as FAC (see Table 1), are preferred for these patients. However, newer combinations of doxorubicin(Drug information on doxorubicin) and a taxane are gaining favor for use in patients who have not received > 450 mg/m² of an anthracycline and whose relapse has occurred more than 12 months after the completion of adjuvant therapy.

Single agents. Many single cytotoxic drugs have shown some activity in metastatic breast cancer. They include paclitaxel(Drug information on paclitaxel), ixabepilone (Ixempra), capecitabine(Drug information on capecitabine) (Xeloda), vinorelbine, and gemcitabine(Drug information on gemcitabine) (see Table 1), as well as vinblastine(Drug information on vinblastine), mitomycin(Drug information on mitomycin), and thiotepa(Drug information on thiotepa).

Paclitaxel. One of the most active agents is paclitaxel. It has demonstrated antitumor activity in patients with anthracycline-resistant disease and in those who have received three or more prior chemotherapy regimens for metastatic disease.

High-dose paclitaxel (250 mg/m² over 3 hours) has not been shown to be superior to 175 mg/m² over 3 hours. The higher dose regimen is associated with greater hematologic and neurologic toxicities.

In a study to determine whether weekly infusion of paclitaxel improves response rates vs the standard 3-hour infusion (Cancer and Leukemia Group B [CALGB] protocol 9840), 577 patients with metastatic breast cancer who had received one or two prior regimens were randomized to receive standard (175 mg/m²) or weekly (80 mg/m²) paclitaxel. Weekly paclitaxel was shown to be superior with respect to response rate (40% vs 28%; P = .017), TTP (9 months vs 5 months; P = .0008), and overall survival (24 months vs 16 months). The authors concluded that weekly paclitaxel is superior to standard paclitaxel in the management of metastatic breast cancer. Weekly paclitaxel caused more grade 3 sensory/motor neuropathy and less grade 3 granulocytopenia.

Nab-paclitaxel. In a clinical trial, the tumor response rate was nearly double for patients who received nanoparticle albumin-bound paclitaxel (nab-paclitaxel [Abraxane]) compared with those who received solvent-based paclitaxel. The proposed mechanism of delivery of this nab-driven chemotherapy is thought to be by targeting an albumin-specific (Gp60) receptor-mediated transcytosis path through the cell wall of proliferating tumor cells, using caveolin-1 activated caveolar transport. Once in the stromal microenvironment, the albumin-bound drug may be preferentially localized by SPARC, a protein secreted into the stroma by tumor cells. The resulting collapse of stroma surrounding the tumor cell may thus enhance the delivery of the nab-chemotherapeutic to the intracellular core of the tumor cell itself. Another advantage of nab-paclitaxel is its ease of use. Since it does not contain solvents like Cremophor, it eliminates the need for premedication with steroids or antihistamines for hypersensitivity reactions caused by these solvents. Furthermore, in contrast to solvent-based paclitaxel, which requires up to 3 hours for IV administration, nab-paclitaxel can be administered in 30 minutes.

Docetaxel. Approved by the US Food and Drug Administration (FDA) for anthracycline-resistant locally advanced or metastatic breast cancer, docetaxel(Drug information on docetaxel) has demonstrated overall response rates of 41% in patients with doxorubicin-resistant disease. It has been shown to be superior to mitomycin/vinblastine in patients who experienced disease progression after being treated with an anthracycline-based chemotherapy regimen. Docetaxel as a single agent has been shown to produce objective responses in up to 60% of patients with metastatic breast cancer that had not previously been treated with chemotherapy.

The recommended starting dose of docetaxel—100 mg/m² as a 1-hour IV infusion—requires premedication with dexamethasone(Drug information on dexamethasone) to avoid fluid retention and the capillary leak syndrome. The usual regimen of dexamethasone is 8 mg twice daily for a total of 3 days, beginning 24 hours prior to the administration of docetaxel.

Although 100 mg/m² is the dose of docetaxel approved by the FDA, many recent trials have demonstrated a high rate of grade 4 hematologic toxicity at this dose level; a dose of 60 to 70 mg/m² may achieve equivalent therapeutic benefit with improved safety. As with paclitaxel, the docetaxel dosage must be modified in patients who have hepatic impairment, manifested by elevated transaminase or alkaline phosphatase levels.

Capecitabine. An orally active fluorinated pyrimidine carbonate, capecitabine has a substantial antitumor effect in patients whose disease has recurred or progressed after prior anthracycline or taxane therapy. Prolonged survival, limited toxicity, and response in visceral as well as soft-tissue disease add to the benefit of capecitabine. Toxicities include diarrhea, stomatitis, and hand-foot syndrome.

Ixabepilone. Ixabepilone was approved for the treatment of advanced breast cancer after failure of an anthracycline and a taxane, either as monotherapy or in combination with capecitabine. Its approval was based upon the results of two pivotal trials. One phase II study evaluated the efficacy and safety of ixabepilone in patients with metastatic breast cancer resistant to an anthracycline, a taxane, and capecitabine. Ixabepilone (at 40 mg/m²) was administered as a 3-hour IV infusion on day 1 of a 21-day cycle. A total of 113 patients were assessable for response; the overall response rate (ORR) was 11.5% (95% CI, 6.3%–18.9%) as assessed by an independent radiology facility. A total of 50% of patients achieved stable disease; 14.3% achieved stable disease for longer than 6 months. The median duration of response and progression-free survival were 5.7 and 3.1 months, respectively. The median overall survival was 8.6 months. Grade 3/4 treatment-related events included peripheral sensory neuropathy (14%), fatigue/asthenia (13%), myalgia (8%), and stomatitis/mucositis (6%). Resolution of grade 3/4 peripheral sensory neuropathy occurred after a median of 5.4 weeks.

The second study was a randomized, phase III trial evaluating the efficacy and safety of ixabepilone used in combination with capecitabine. This trial included 752 patients who were previously treated with anthracyclines and taxanes and whose tumors had demonstrated prior resistance to these therapies. Ixabepilone plus capecitabine prolonged progression-free survival relative to capecitabine (median, 5.8 months vs 4.2 months), with a 25% reduction in the estimated risk of disease progression (HR = 0.75; 95% CI, 0.64–0.88; P = .0003). The objective response rate was also increased (35% vs 14%, respectively; P < .001). Grade 3/4 treatment-related sensory neuropathy (21% vs 0%), fatigue (9% vs 3%), and neutropenia (68% vs 11%) were more frequent with combination therapy, as was the rate of death as a result of toxicity (3% vs 1%, with patients with liver dysfunction [≥ grade 2 liver function tests] at greater risk). Capecitabine-related toxicities were similar for both treatment groups.

New approaches. Multiple new approaches to treating metastatic breast cancer are being explored. Weekly schedules of the various taxanes (paclitaxel, nab-paclitaxel, and docetaxel) have been reported to produce high response rates and lower toxicity than have 3-week schedules. Substantial antitumor activity has also been shown with combinations of doxorubicin with paclitaxel or docetaxel; and with capecitabine and docetaxel; carboplatin(Drug information on carboplatin) and paclitaxel; and gemcitabine and cisplatin(Drug information on cisplatin). Several biologic/targeted agents are also being investigated, either as monotherapy or in combination with chemotherapy or endocrine therapy. Taking further advantage of the growing knowledge about the biology of breast cancer, trials are increasingly designed to target specific breast cancer subsets rather than treating all comers. These newer combinations need to be compared with standard AC or FAC (CAF) regimens in phase III trials. Recent studies also suggest that sequential weekly chemotherapy may be as effective as more intensive combinations with respect to overall survival in patients with metastatic breast cancer.

Key enzymes involved in the DNA repair pathway are PARP-1 and PARP-2, which are two of a number of members of the PARP, or poly(ADP-ribose) polymerase, family of nuclear enzymes. The presence of PARP renders the cells repairable and therefore contributes to their survival. Inhibition of PARP would result in unrepairable damage and cell death. In the cancer cells of mutation carriers, all BRCA-1 or BRCA-2 function is absent, and when PARP-1 is inhibited, cancer cells are unable to repair DNA damage by homologous recombination or base-excision repair, and cell death results (ie, synthetic lethality).In a randomized phase II study in patients with metastatic triple-negative breast cancer (TNBC), O'Shaughnessy et al suggested that iniparib (I), added to gemcitabine/carboplatin (GC) improved overall survival without potentiating GC toxicity. Unfortunately, a subsequent phase III study reported at ASCO in 2011, evaluating the safety and efficacy of GC with or without I in a similar metastatic TNBC population, failed to demostrate a significant improvement in overall survival or progression-free survival. The median overall survival was 11.1 and 11.8 months for GC and GCI, respectively (HR = 0.876; 95% CI, 0.687–1.116; P = .284). The median progression-free survival was 4.1 and 5.1 months for GC and GCI, respectively (HR = 0.794; 95% CI, 0.646–0.976; P = .027) A number of PARP inhibitors (including iniparib, olaparib,veliparib, among others) are in various stages of development and are being investigated primarily for the treatment of TNBC.

Alterations in the PI3K pathway include deregulation of PTEN, or PI3K pathway mutations or hyperactivation. The pathway to mTOR activation is activated downstream of PI3K, and everolimus is an oral inhibitor of mTOR. Everolimus has been reported to enhance activity, reverse resistance to trastuzumab(Drug information on trastuzumab) (Herceptin), and provide synergistic activity with paclitaxel. At the 2010 ASCO meeting, several presentations were related to the use of everolimus in combination with trastuzumab and/or other agents in patients with HER2-positive/overexpressing metastatic breast cancer. In a phase II study, the efficacy and safety of everolimus in combination with trastuzumab plus paclitaxel was assessed in 37 evaluable patients with trastuzumab and taxane-resistant HER2-positive MBC. Patients received everolimus at a dosage of 10-mg daily, trastuzumab at a 4 mg/kg IV loading dose then 2 mg/kg weekly, and paclitaxel at 80 mg/m² IV on days 1, 8, and 15, every 4 weeks. Of 25 efficacy-evaluable patients, 20% (n = 5) had a confirmed partial response, 56% (n = 14) had stable disease and 24% (n = 6) had progressive disease. Grade 3/4 neutropenia occurred in 32% (n = 12), with one case of febrile neutropenia, grade 3 stomatitis in 13% (n = 5), and grade 3 asthenia/fatigue in 5% (n = 2).

Monoclonal antibodies and other targeted agents

Trastuzumab. Trastuzumab is a humanized monoclonal antibody that selectively binds to the extracellular domain of the HER2 receptor. In women with surgically resected breast cancer that overexpresses HER2, trastuzumab combined with chemotherapy improves disease-free and overall survival. Trastuzumab treatment decreases the risk of death by one-third (P = .015) in HER2-positive breast cancer. It is approved for use as a single agent in second- and third-line therapy in the metastatic setting. A pivotal randomized trial in 469 women showed that the combination of trastuzumab with chemotherapy yielded a 45% ORR, as compared with a 29% rate with chemotherapy alone—a 53% increase. Addition of trastuzumab had the greatest impact on response when combined with paclitaxel. Among the study group as a whole, 79% of women treated with trastuzumab plus chemotherapy were alive at 1 year, as compared with 68% of those given chemotherapy alone. An update of these data has shown a superior median overall survival with chemotherapy plus trastuzumab compared with chemotherapy alone (25.4 months vs 20.9 months). The survival advantage was seen with both AC plus trastuzumab and paclitaxel plus trastuzumab. In another single-arm trial involving 222 women who had not responded to prior chemotherapy, trastuzumab shrunk tumors by 50% in 14% of women, with a median duration of response of 9 months. Overall, trastuzumab was well tolerated in both trials.

Because of an increased risk of cardiac dysfunction observed in women treated with trastuzumab plus an anthracycline, trastuzumab should not be used in combination with this drug class outside of a clinical trial. Finally, essentially all of the clinical benefit of trastuzumab (alone or in combination) is confined to patients whose breast cancer expresses high levels of the HER2 oncoprotein (ie, 3+ by immunohistochemistry [IHC] or amplified by fluorescence in situ hybridization [FISH]). Thus, outside of a clinical trial, its use should be limited to patients whose tumors overexpress HER2.

One study explored the relationship between circulating HER2 extracellular domain (ECD) and tissue HER2 status and examined its predictive value in a cohort of MBC patients treated with weekly trastuzumab and paclitaxel. A retrospective analysis of patients treated on a previous trial evaluated the associations between pretreatment serum HER2 ECD and tissue HER2 status and the change in serum HER2 ECD after 12 weeks of therapy and response. Stored serum samples were available for 55 of 95 patients (58%). A statistically significant association was found between HER2 status and baseline serum HER2 ECD level. Patients whose ECD normalized after 12 weeks of therapy had a higher response proportion than did those with persistently high ECD levels (68% vs 15%; P = .005). A relative decline of more than 55% from baseline ECD predicted response to trastuzumab-based therapy.

The FDA recently approved pertuzumab (Perjeta) for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for their disease. Pertuzumab is an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization of HER2 with other HER family members, including EGFR, HER3, and HER4. The phase III study leading to approval of pertuzumab included 808 patients with HER2-positive metastatic breast cancer, who were randomly assigned to receive either placebo plus trastuzumab plus docetaxel (control group) or pertuzumab plus trastuzumab plus docetaxel (pertuzumab group) as first-line treatment until disease progression or unmanageable toxicity. The primary endpoint was independently assessed progression-free survival. Secondary endpoints included overall survival, progression-free survival as assessed by the investigator, ORR, and safety. The median progression-free survival was 12.4 months in the control group, as compared with 18.5 months in the pertuzumab group (HR = 0.62; 95% CI , 0.51–0.75; P < .001). The interim analysis of overall survival showed a strong trend in favor of the pertuzumab group. The safety profile was generally similar in the two groups, with no increase in left ventricular systolic dysfunction. The rates of grade 3 or 4 febrile neutropenia and diarrhea were higher in the pertuzumab group than in the control group.

Treatment of HER2-overexpressing breast cancer is a very active area of research in both the neoadjuvant/adjuvant and metastatic settings, with many active drugs being studied.

Sidebar: Until the recent approval of pertuzumab (Perjeta), the only approved combination for trastuzumab-refractory HER2+ metastatic breast cancer (MBC) has been capecitabine (Xeloda, X) plus lapatinib (Tykerb, L) (XL). T-DM1 is an antibody–drug conjugate comprising trastuzumab (T), a stable linker, and the cytotoxic agent DM1. EMILIA (Open-Label Study of Trastuzumab Emtansine [T-DM1] vs Capecitabine + Lapatinib in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer) is a randomized study of T-DM1 (3.6 mg/kg IV q3w) vs XL (X at 1,000 mg/m² PO bid, days 1–14 q3w + L at 1,250 mg PO daily) in MBC patients previously treated with T and a taxane. Patients received T-DM1 until progressive disease (PD) or unmanageable toxicity. A total of 991 patients were enrolled; 978 received treatment. Median durations of follow-up were 12.9 months for patients treated with T-DM1 and 12.4 months for those treated with XL. There was a significant improvement in progression-free survival favoring T-DM1 (9.6 vs 6.4 months; HR = 0.650; 95% CI, 0.549–0.771; P < .001). The median overall survival was not reached in the T-DM1 group vs 23.3 months with XL (HR = 0.621; 95% CI, 0.475–0.813; P = .0005); the interim efficacy boundary was not crossed. T-DM1 was well tolerated. The most common grade ≥ 3 adverse events for patients treated with T-DM1 were thrombocytopenia (12.9% vs 0.2% with XL), increased AST (aspartate aminotransferase; 4.3% vs 0.8%, respectively), and increased ALT (alanine aminotransferase; 2.9% vs 1.4%, respectively), and for patients treated with XL were diarrhea (20.7% vs 1.6% with T-DM1), palmar plantar erythrodysesthesia (16.4% vs 0, respectively), and vomiting (4.5% vs 0.8%, respectively). The authors concluded that T-DM1 conferred a significant and clinically meaningful improvement in progression-free survival compared with XL and that the results support T-DM1 as an active and well-tolerated novel therapy for HER2+ MBC (Blackwell KL et al: J Clin Oncol 30[suppl]: abstract LBA1, 2012).

Eribulin (Halaven). Eribulin is a synthetic analog of halichondrin B. It binds to a unique site on tubulin and suppresses microtubule polymerization, sequesters tubulin into nonfunctional aggregates, and creates irreversible mitotic block. An open-label, phase III, randomized multicenter trial of eribulin in women with locally recurrent or metastatic breast cancer who had received two to five prior chemotherapy regimens (73% of patients had received prior capecitabine) was reported in 2011 (EMBRACE [Eisai Metastatic Breast Cancer Study Assessing Physician's Choice versus E7389]). The primary endpoint was overall survival with progression-free survival, with ORR and safety as secondary endpoints. Women were randomized in a 2:1 ratio to eribulin at 1.4 mg/m², infused as a 2- to 5- minute IV on days 1 and 8 of a 21-day cycle, or to the treatment of physician's choice. The treatment of physician's choice could be any cytotoxic, hormonal, or biological monotherapy, or supportive care only. A total of 762 patients were enrolled: 508 to eribulin and 254 to physician's choice. The median number of prior chemotherapy regimens was four in each treatment arm. Disease characteristics were also similar, with approximately 67% being ER-positive. In the physician's-choice arm, 96% received chemotherapy, with a wide range of agents being used. Overall survival was significantly longer with eribulin vs physician's choice (HR = 0.81; 95% CI, 0.66–0.99; P = .041 by stratified log-rank test). In those given eribulin, median survival was 13.12 months, with 53.9% having a 1-year survival. Median survival was 10.65 months in the physician's choice treatment arm, with 43.7% having a 1-year survival. Median progression-free survival for eribulin was 3.7 months vs 2.2 months for physician's choice (HR = 0.87; 95% CI, 0.7–1.05; P = .14). A significant benefit was observed in the ORR, with 22.6% vs 16.8% of women having a clinical benefit (CR + PR + stable disease for at least 6 months). The overall incidence of adverse events was similar between the treatment arms: 98.8% and 93.1%, respectively, as were serious adverse events and those leading to treatment interruption, discontinuation, dose reduction, or dose delay.

Lapatinib (Tykerb). Lapatinib is a potent and specific reversible oral small molecule dual tyrosine kinase inhibitor of both HER2 and epidermal growth factor receptor (EGFR). It is active in combination with capecitabine in women with HER2-positive metastatic breast cancer. Women with HER2-positive, locally advanced, or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab were randomly assigned to receive either lapatinib (at a dose of 1,250 mg/d continuously) plus capecitabine (at a dose of 2,000 mg/m² of body surface area) on days 1 through 14 of a 21-day cycle or monotherapy with capecitabine alone (at a dose of 2,500 mg/m²) on days 1 through 14 of a 21-day cycle.

The interim analysis of TTP met specified criteria for early reporting on the basis of superiority in the combination-therapy group. The HR for the independently assessed TTP was 0.49 (95% CI, 0.34–0.71; P < .001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median TTP was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group. This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events. In March 2007, lapatinib in combination with capecitabine was approved by the FDA for treatment of women with HER2-positive advanced breast cancer that has progressed after treatment with trastuzumab.

Blackwell et al conducted a phase III study (EGF104900) of lapatinib and trastuzumab in patients with HER2-positive metastatic breast cancer who had been heavily pretreated for metastatic breast cancer, including with anthracyclines and taxanes (median of six prior chemotherapy regimens), and had progressed on prior trastuzumab. Patients were randomized to either lapatinib only (1,500 mg daily dose) or to trastuzumab (4 mg/kg loading dose then 2 mg/kg weekly) plus lapatinib (1,000 mg daily dose ). Previously reported outcomes from this study showed that dual targeting with lapatinib plus trastuzumab significantly improved progression-free survival and clinical benefit rate vs lapatinib monotherapy, offering a chemotherapy-free option for patients with heavily retreated HER2-positive disease. In the updated final analysis of this study, patients randomly assigned to lapatinib plus trastuzumab (n = 291) continued to show superiority compared with lapatinib monotherapy in progression-free survival (HR = 0.74; 95% CI, 0.58–0.94; P = .011) and offered significant overall survival benefit (HR = 0.74; 95% CI, 0.57–0.97; P = .026). Improvements in absolute overall survival rates were 10% at 6 months and 15% at 12 months in the combination arm compared with the monotherapy arm. Multiple baseline factors, including Eastern Cooperative Oncology Group (ECOG) performance status of 0, nonvisceral disease, fewer than three metastatic sites, and less time from initial diagnosis until random assignment, were associated with improved overall survival. The incidence of adverse events was consistent with previously reported rates. The majority of previously reported adverse events were grade 1 or 2, and the only grade 3 or 4 event with a 5% or greater incidence was diarrhea, seen in 8% of patients on the combination treatment and in 7% treated with the single agent. Investigation of the role of combined anti-HER2 therapy with chemotherapy in less heavily pretreated patients with early-stage disease was investigated in the recently closed ALTTO (Adjuvant L and/or T Treatment Optimization) study.

Preclinical studies demonstrated a synergistic interaction between lapatinib and trastuzumab, suggesting that dual blockade may be a more effective strategy than single-agent therapy in patients with HER2-positive tumors. A randomized, phase III trial investigated lapatinib alone or in combination with trastuzumab in patients with HER2-positive, trastuzumab-refractory metastatic breast cancer. The primary endpoint was progression-free survival. Secondary efficacy endpoints included ORR, clinical benefit rate (CBR; complete response, partial response, and stable disease for 24 weeks or longer), and overall survival. In the intent-to-treat population (N = 296) who received a median of three prior trastuzumab-containing regimens, the combination of lapatinib with trastuzumab was superior to lapatinib alone for progression-free survival (HR = 0.73; 95% CI, 0.57–0.93; P = .008) and CBR (24.7% in the combination arm vs 12.4% in the monotherapy arm; P = .01). A trend for improved overall survival in the combination arm was observed (HR = 0.75; 95% CI, 0.53–1.07; P = .106). There was no difference in ORR (10.3% in the combination arm vs 6.9% in the monotherapy arm; P = .46). The most frequent adverse events were diarrhea, rash, nausea, and fatigue; the incidence of diarrhea was higher in the combination arm (P = .03). The incidence of symptomatic and asymptomatic cardiac events was low (2% and 3.4%, respectively, for combination therapy; 0.7% and 1.4%, respectively, for monotherapy). Despite disease progression on prior trastuzumab-based therapy, lapatinib in combination with trastuzumab significantly improved progression-free survival and CBR vs lapatinib alone, thereby offering a chemotherapy-free option with an acceptable safety profile to patients with HER2-positive metastatic breast cancer.

Bevacizumab (Avastin). Bevacizumab(Drug information on bevacizumab) is a recombinant humanized monoclonal antibody that targets vascular endothelial growth factor receptor (VEGF) and is the first antiangiogenic agent to demonstrate benefit in women with HER2-negative advanced breast cancer.

The first large, open-label, randomized phase III trial evaluated the efficacy and safety of capecitabine alone vs capecitabine in combination with bevacizumab in 462 women with metastatic breast cancer. Bevacizumab in combination with capecitabine did not significantly improve progression-free survival (4.86 vs 4.17 months; HR = 0.98; 95% CI, 0.77–1.25; P = .857). There was also no difference in overall survival. However, the addition of bevacizumab to capecitabine improved the objective response rate from 9.1% to 19.8% for the independent reviewers (P = .001). The bevacizumab combination arm was well tolerated and did not worsen capecitabine-related toxicity such as diarrhea and hand-foot syndrome. Bevacizumab-related toxicities included hypertension (grade 3: 17.9% vs 0.5% for single-agent capecitabine), thromboembolic events (grades 2-4: 6.9% vs 5.6%), proteinuria (grades 1-4: 22.3% vs 7.4%), and minor bleeding (grade 1 or 2 epistaxis). Two patients treated with bevacizumab developed grade 3 proteinuria and, consequently, their therapy was discontinued. Nine patients developed grade 3/4 congestive heart failure or cardiomyopathy: seven in the combination arm (3.1%) and two in the single-agent capecitabine arm (0.9%). Serious hemorrhage and thromboembolic events were uncommon and did not differ between treatment arms. In this heavily pretreated patient population, the activity of bevacizumab was obscured. It was hypothesized that advanced stages of breast cancer may have redundant angiogenic pathways, making the inhibition of a single receptor pathway inadequate for significant clinical benefit.

In order to maximize antiangiogenic inhibition, ECOG performed a large, open-label phase III trial with weekly paclitaxel and bevacizumab. In ECOG 2100, a total of 722 patients were randomized to weekly paclitaxel, with or without bevacizumab as first-line therapy for locally advanced or metastatic breast cancer. The addition of bevacizumab to paclitaxel significantly improved the progression-free survival time to 11.8 months, compared with 5.9 months in the paclitaxel-only arm (P < .001). A higher overall response rate of 36.9% was seen in the combination arm, compared with 21.2% in the single-agent arm (P < .001). Despite the improved progression-free survival and overall response rate, there was no difference in median overall survival between the two treatment arms. Toxicities associated with the bevacizumab combination included hypertension, proteinuria, and neuropathy.

Two additional phase III studies investigated the role of bevacizumab in the first-line treatment of advanced breast cancer in combination with chemotherapy. The AVADO (Avastin and Docetaxel) trial tested docetaxel in combination with either placebo or bevacizumab at 7.5 or 15 mg/m² given every 21 days in patients with HER2-negative breast cancer. The RIBBON-1 (Regimens in Bevacizumab for Breast Oncology) trial investigated several chemotherapies (ie, anthracyclines, taxanes, and capecitabine) in combination with placebo vs bevacizumab at 15 mg/m² given every 3 weeks. Both trials demonstrated a modest but statistically significant improvement in progression-free survival with the addition of bevacizumab. However, no statistically significant improvement in overall survival was seen; neither study was powered for an overall survival endpoint. RIBBON-2 tested the role of bevacizumab in the second-line treatment of metastatic breast cancer and was very similar in design to RIBBON-1 except that additional chemotherapies (eg, gemcitabine, vinorelbine) were permissible. Similar to the first-line setting, the addition of bevacizumab to chemotherapy statistically improved progression-free survival (7.2 months vs 5.1 months) and response rates but not overall survival. Progression-free survival results were consistent across each chemotherapy cohort with the exception of the small vinorelbine subgroup of 76 patients. In summary, bevacizumab plus chemotherapy improves response rates and prolongs progression-free survival when used as first- and second-line therapy for advanced breast cancer but it has not yet been shown to improve overall survival.

The initial promising results of a 5-month improvement in progression-free survival from the ECOG 2100 trial provided the basis for the "accelerated approval" of bevacizumab in metastatic breast cancer by the FDA. However, given the only modest improverment in progression-free survival in subsequent trials of bevacizumab and the lack of improvement in overall survival, coupled with the severe to life-threatening side effects of bevacizumab, such as gastrointestinal perforation and severe bleeding, enthusiasm for this agent is waning. An advisory committee to the FDA has recently voted unanimously to withdraw the approval of bevacizumab for treatment of metastatic breast cancer.

Three randomized trials, E2100, AVADO, and RIBBON-1, have demonstrated significantly improved progression-free survival with bevacizumab in combination with other chemotherapy agents and administered as first-line treatment in patients with metastatic breast cancer. At the 2010 American Society of Clinical Oncology (ASCO) meeting, Dr. O'Shaughnessy presented findings of a pooled analysis of the overall survival data from these three trials. In the pooled analysis of demographic and disease-related characteristics, patients treated with bevacizumab were of an age (56 years) similar to those who were not (55 years), with approximately 25% in each arm having triple-negative disease, and a similar disease-free survival (37 months vs 39 months), and there were similar percentages with three or more metastatic sites (41% vs 38%, respectively). Progression-free survival was greater with bevacizumab-containing treatment in the pooled analysis (median of 9.2 months vs 6.7 months; HR = 0.64; 95% CI, 0.57–0.71; P < .001). Progression-free survival was greater regardless of age, hormone receptor status, or disease-free interval. Across the studies, the HRs ranged from 0.48 to 0.69, with P values of .0003 or less. In each of the three trials, overall survival was a secondary endpoint measure. In the individual studies, the median overall survival follow-up ranged from 23 to 35 months. In the pooled analysis of overall survival, bevacizumab-treated patients had a median overall survival of 26.7 months, compared with 26.4 months in those who did not receive bevacizumab (HR = 0.97; 95% CI, 0.86–1.08). One-year survival rates of 82% and 77% were seen in bevacizumab-treated vs non–bevacizumab-treated patients, respectively. There was a 17% increase in the objective response rate with bevacizumab-containing regimens. The investigators concluded that patients with adverse prognostic features do benefit from the addition of bevacizumab, as do those with more indolent disease. The RIBBON-2 trial, which evaluated the combination of bevacizumab with various chemotherapy agents in the treatment of metastatic breast cancer as second-line therapy, found that the combination consistently demonstrated improved progression-free survival. Brufsky and colleagues examined various subgroups of the RIBBON-2 participants to assess the consistency of the benefits on progression-free survival. The hazard ratios of progression-free survival consistently favored the bevacizumab-plus-chemotherapy arm over the placebo-plus-chemotherapy arm when data were pooled across all chemotherapy cohorts. Investigators concluded that bevacizumab combined with standard chemotherapies provides progression-free survival benefits to HER2-negative patients with metastatic breast cancer.

Adjunctive bisphosphonate therapy for bone metastasis

Zoledronic acid (Zometa). Zoledronic acid(Drug information on zoledronic acid) is an intravenously administered bisphosphonate that reduces skeletal-related events (SREs) including pain and risk of fracture in women with breast cancer metastatic to bone. In addition, zoledronic acid treats hypercalcemia of malignancy. Multiple published reports have now confirmed the benefit of bisphosphonates as an adjunct to treatment of patients with bone metastasis. Use of these agents results in a significant reduction in SREs, including pathologic fracture, bone pain, and the need for radiation therapy to bone. Zoledronic acid and pamidronate(Drug information on pamidronate) (Aredia) are both available in IV formulations in the United States. An oral bisphosphonate used for this indication, ibandronate (Boniva), is also available in the US.

Patients with breast carcinoma who had all types of bone metastases (osteolytic, mixed, or osteoblastic) were randomized to receive treatment with either 4 or 8 mg of zoledronic acid as a 15-minute infusion or 90 mg of pamidronate as a 2-hour infusion every 3 to 4 weeks for 12 months. The proportion of patients who had an SRE (defined as a pathologic fracture, spinal cord compression, radiotherapy, or surgery to bone) was comparable between treatment groups (approximately 45%). However, among patients who had breast carcinoma with at least one osteolytic lesion, treatment with 4 mg of zoledronic acid was more effective in reducing skeletal complications than was 90 mg of pamidronate.

The most commonly reported adverse events for both zoledronic acid and pamidronate, which are more common and dramatic at the time of the first infusion, can include fatigue, muscle aches, bone pain, nausea, vomiting, fever, and/or swelling in the feet or legs. Rarely, zoledronic acid has been associated with osteonecrosis of the jaw. The 4-mg dose of zoledronic acid results in elevated serum creatinine levels in about 7.7% of patients, vs 6% with pamidronate. A larger proportion of patients had elevated serum creatinine levels with 8-mg of zoledronic acid; therefore, this dose is not recommended. Symptomatic hypocalcemia, although relatively rare, requires frequent monitoring of calcium and phosphate levels during treatment.

Denosumab (Xgeva). Denosumab is a fully human monoclonal antibody against receptor activator of nuclear factor κ B ligand (RANKL), a key mediator of osteoclast activity. Results from a phase III pivotal study demonstrated that denosumab was superior to zoledronic acid in delaying or preventing SREs in breast cancer patients with bone metastases. Patients with breast cancer and bone metastases who had not been treated with IV bisphosphonates were randomized 1:1 to receive either subcutaneous (SC) denosumab at 120 mg and IV placebo (n = 1,026), or SC placebo and IV zoledronic acid at 4 mg adjusted for creatinine clearance every 4 weeks (n = 1,020). The primary endpoint was time to first on-study SREs. Denosumab was superior to zoledronic acid in significantly delaying the time to first on-study SRE (HR = 0.82; 95% CI, 0.71–0.95; P < .001 noninferiority; P = .01 superiority) and the time to first and subsequent on-study SRE (rate ratio 0.77; 95% CI, 0.66–0.89; P = .001). Denosumab also significantly delayed the time to first radiation to bone (HR = 0.74; 95% CI, 0.59–0.94; P = .01) and the time to first on-study SRE or hypercalcemia of malignancy (HR = 0.82; 95% CI, 0.70–0.95; P = .007) compared with zoledronic acid. Overall survival, disease progression, and rates of adverse events and serious adverse events were similar between groups. An excess of renal adverse events and acute-phase reactions occurred with zoledronic acid; hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw occurred infrequently (2%, denosumab; 1.4%, zoledronic acid; P = .39).

Radiation therapy

Irradiation remains an integral component of the management of metastatic breast carcinoma. Although bone metastases are the most commonly treated metastatic sites in patients with breast cancer, brain metastases, spinal cord compression, choroidal metastases, endobronchial lung metastases, and metastatic lesions in other visceral sites can be effectively palliated with irradiation.

Radiation dose and schedule. Depending on the disease site and volume of the radiation field, fractionation schedules ranging from 20 Gy in 5 fractions to 30 Gy in 10 fractions are used most commonly. In some situations, more protracted courses using lower daily doses may be indicated.

Bone metastasis. For patients with widespread bone metastasis, hemibody irradiation (6-7 Gy in one fraction to the upper body or 8 Gy to the lower body) has been shown to be effective. Strontium-89 chloride (Metastron) and other systemic radionuclides also provide effective palliation for widespread bone disease.

Brain metastasis. Patients who develop metastasis to the brain generally have poor outcomes. Nonetheless, radiation therapy can often be helpful in palliating their symptoms and may help control disease for some time. In one randomized trial, patients with one to three newly diagnosed brain metastases (breast as well as other sites) were randomly allocated to receive either whole-brain radiation therapy (WBRT, 164 patients) or WBRT followed by a stereotactic radiosurgery boost (167 patients). Univariate analysis showed that there was a survival advantage in the WBRT and surgery group for patients with a single brain metastasis (median survival: 6.5 months vs 4.9 months; P = .039).

Surgery

There are selected indications for surgical intervention in patients with metastatic breast cancer, and the role of surgery at this point is generally palliative. Most commonly, palliative surgery is offered to patients with brain metastases, spinal cord compression, fractures, or symptomatic pleural or pericardial effusions not controlled by other means. It is also used for gastrointestinal complications stemming from metastatic deposits. The curative benefit of surgery in the treatment of metastatic disease to the lungs or liver is not proven, but in highly selected cases surgery may be beneficial.

Locoregional therapy of the primary tumor with distant metasteses

Approximately 5% to 10% of patients with newly diagnosed breast cancer will have distant metastatic disease at the time of presentation. Recent data have shown that patients who have local and regional control, in the face of distant metastatic disease, have an improved survival. The treatment offered may be surgical resection, radiotherapy, or both.

Le Scodan and others retrospectively reviewed data on 581 patients who had synchronous metastases at diagnosis. In all, 320 patients received locoregional therapy (LRT), with 249 given exclusive locoregional radiotherapy (LRR), 41 treated with surgery of the primary tumor with adjunct LLR, and 31 undergoing surgery alone. No LRT was given to 262 patients. The 3-year survival rate was 43.3% in patients who were treated with LRT and 26.7% in patients who were not (P = .00002). A randomized, phase III trial is now underway by ECOG, to assess the value of early local therapy for the intact primary tumor in patients with oligometastases.

Spinal cord compression. Patients with spinal cord compression who have progressive symptoms during irradiation, disease recurrence after irradiation, spinal instability, or who require diagnosis are candidates for surgery.

Solitary brain metastasis. Patients with a long disease-free interval and solitary brain metastasis may be candidates for resection. Evidence suggests an improved disease-free survival, overall survival, and quality of life in this subset of patients when treated with surgery combined with postoperative cranial irradiation, as compared with radiation therapy alone.

Gamma- and cyber-knife radiosurgery is increasingly used to manage brain metastases. In some instances, these modalities have been used in patients who have multiple metastatic brain lesions or in patients who had previously received conventional treatment modalities for brain metastases, including whole-brain irradiation. No radiation-induced dementia and a remarkably low incidence of local failure were reported with these treatments. Although local control of brain metastasis was an issue in the past, these treatment modalities are shifting the question of survival to that of systemic control.

Chest wall resection. It is extremely rare for a patient with distant metastatic disease to be a candidate for chest wall resection; however, patients with symptomatic recurrence of disease in the chest wall who have limited distant disease and a life expectancy of > 12 months may be appropriate candidates.

Liver metastasis. Patients with metastatic disease to the liver often have a poor prognosis. Although rarely indicated, patients with single metastases or a prolonged disease-free or disease-stable interval may be candidates for resection or ablation to completely remove the metastatic lesion.

Follow-up of long-term survivors

For recommendations on the type and timing of follow-up evaluations, see the "Stage II Breast Cancer" chapter.