Stages III and IV Breast Cancer

June 1, 2015
Lori Jardines, MD

Sharad Goyal, MD

Melanie Royce, MD, PhD

Ishmael Jaiyesimi, DO

Shari B. Goldfarb, MD

This chapter addresses the diagnosis and management of locally advanced, locally recurrent, and metastatic breast cancer, that is, stages III and IV disease.


This chapter addresses the diagnosis and management of locally advanced, locally recurrent, and metastatic breast cancer, that is, stages III and IV disease. Approximately 20% to 25% of patients present with locally advanced breast cancer. Inflammatory breast cancer is a particularly aggressive form of breast cancer that falls under the heading of locally advanced disease and accounts for 1% to 3% of all breast cancers.

Locoregional recurrence of breast cancer remains a major oncologic problem. Rates of locoregional recurrence may vary from < 10% to > 50%, depending on initial disease stage and treatment.

Metastatic disease is found at presentation in 5% to 10% of patients with breast cancer. The most common sites of distant metastasis are the lungs, liver, lymph nodes, and bone.

The optimal therapy for stage III breast cancer continues to change. Neoadjuvant chemotherapy has been effective in downstaging locally advanced breast cancer prior to surgical intervention. The optimal neoadjuvant chemotherapeutic regimens continue to evolve, and studies are currently being performed to evaluate new agents and delivery methods.


Locally Advanced Disease

Patients with locally advanced breast cancer do not have distant metastatic disease; they are categorized in this group based on tumor size and/or nodal status. Such patients often present with a large breast mass or axillary nodal disease that is easily palpable on physical examination. In some instances, the breast is diffusely infiltrated with disease, and no dominant mass is evident.

Patients with inflammatory breast cancer often present with erythema and edema of the skin of the breast (peau d’orange); they may not have a discrete mass within the breast. These patients often are treated with antibiotics unsuccessfully for presumed mastitis before they are diagnosed with breast cancer.


Mammography is beneficial in determining the local extent of disease in the ipsilateral breast, and in studying the contralateral breast.

Fine-needle aspiration or core biopsy

In the locally advanced setting, although breast cancer can be confirmed by either fine-needle aspiration (FNA) cytology or core biopsy, the latter is preferred. Core biopsy provides sufficient tissue to perform the wide variety of marker analyses. When there is suspicion of inflammatory breast carcinoma, a skin biopsy is also recommended to ascertain the presence of dermal lymphatic invasion. Because the diagnosis of inflammatory breast cancer is based on clinical findings, a negative skin biopsy does not preclude the diagnosis.

Search for metastasis

The presence of distant metastatic disease should be ruled out by physical examination, chest x-ray, bone scan, and contrast enhanced CT scans of the chest, abdomen, and pelvis. 18Fluorodeoxyglucose positron emission tomography (FDG-PET) has moderate accuracy for detecting axillary metastasis. It is highly predictive of nodal involvement when multiple intense foci of tracer uptake are identified, but it fails to detect small nodal metastasis. However, addition of FDG-PET to the standard workup of patients with locally advanced breast cancer may lead to the detection of unexpected distant metastases. Abnormal PET findings should be confirmed to prevent patients from being denied appropriate treatment.

Locoregional Recurrence

Biopsy or FNA

Locoregional recurrence of breast cancer can be diagnosed by surgical biopsy or FNA cytology. The biopsy specimen should be sent for hormone-receptor studies, and testing for human epidermal growth factor type 2 (HER2/neu) overexpression, since these biomarkers are not always concordant between the primary tumor and recurrence. Discrepancy rates ranging from 17% to 55% have been reported. When the suspected recurrent disease is not extensive, the biopsy procedure of choice is a negative margin excisional biopsy. For an extensive recurrence, an incisional biopsy can be used if a core biopsy is not possible.

Search for distant metastasis

Prior to beginning a treatment regimen for a patient with locoregional recurrence, an evaluation for distant metastasis should be performed, since the findings may alter the treatment plan.

Distant Metastasis From the Breasts

Metastatic breast cancer may be manifested by bone pain, shortness of breath secondary to a pleural effusion or lymphangitic spread, pleural or pulmonary nodules, or neurologic deficits secondary to spinal cord compression or brain metastases. In some instances, metastatic disease is identified after abnormalities are found on routine laboratory or radiologic studies.

Assessment of disease extent

It is important to assess the extent of disease using radiography, CT, and radionuclide scanning. Organ functional impairment may be determined by blood tests (liver/renal/hematologic) or may require cardiac and pulmonary function testing. A biopsy should be highly encouraged to confirm the diagnosis of metastatic disease; this is especially important when only a single distant lesion is identified.

Metastasis to the breasts

The most common source of metastatic disease to the breasts is a contralateral breast primary. Metastasis from a nonbreast primary is rare, representing less than 1.5% of all breast malignancies. Some malignancies that can metastasize to the breast include non-Hodgkin lymphoma, leukemias, melanoma, lung cancer (particularly small-cell lung cancer), gynecologic cancers, soft-tissue sarcomas, and gastrointestinal (GI) adenocarcinomas. Metastasis to the breasts from a nonbreast primary is more common in younger women. The average age at diagnosis ranges from the late 30s to 40s. Treatment depends on the status and location of the primary site.

Mammographic findings

Mammography in patients with metastatic disease to the breasts most commonly reveals a single lesion or multiple masses with distinct or semidiscrete borders. Less common mammographic findings include skin thickening or axillary adenopathy.

FNA or biopsy

FNA cytology has been extremely usesful in establishing the diagnosis when the metastatic disease has cytologic features that are not consistent with a breast primary. When cytology is not helpful, core biopsy or even open biopsy may be necessary to distinguish primary breast cancer from metastatic disease.


Locally Advanced Disease

The optimal treatment for patients with locally advanced breast cancer has yet to be defined, due to the heterogeneity of this group. There are approximately 40 different substage possibilities with the different combinations of tumor size and nodal status. Between 66% and 90% of patients with stage III breast cancer will have positive lymph nodes at the time of axillary dissection, and approximately 50% of patients will have four or more positive nodes.

Patients with locally advanced breast cancer have disease-free survival rates ranging from 0% to 60%, depending on tumor characteristics and nodal status. In general, the most frequent type of treatment failure is caused by distant metastases, and the majority of them appear within 2 years of diagnosis. With the increased utilization of multimodality therapy, including chemotherapy, radiation therapy, and surgery, survival of this patient population has improved significantly.

Neoadjuvant systemic therapy

Neoadjuvant chemotherapy is administered prior to surgery and has the same impact on disease-free and overall survival as adjuvant chemotherapy. Neoadjuvant therapy with cytotoxic drugs permits in vivo chemosensitivity testing, can downstage locally advanced disease and render it operable, and may allow breast-conservation surgery to be performed. Preoperative chemotherapy requires a coordinated multidisciplinary approach to plan for surgical and radiation therapy. A multimodality treatment approach can provide improved control of locoregional and systemic disease. When neoadjuvant therapy is used, accurate pathologic staging is not possible. The majority of patients receiving neoadjuvant chemotherapy and either breast-conservation treatment (BCT) or mastectomy will require radiation therapy following surgery.

TABLE 1: Doses and schedules of chemotherapy agents commonly used in patients with metastatic breast cancer

Active regimens. Preoperative chemotherapy regimens reported to result in high clinical response rates include anthracycline-containing regimens followed by a taxane (or vice versa). The most common anthracycline-containing regimens used are CAF (cyclophosphamide, Adriamycin [doxorubicin], and fluorouracil [5-FU]), FAC (5-FU, Adriamycin, and cyclophosphamide), or FEC (5-FU, epirubicin [Ellence], cyclophosphamide). The most common taxane regimens used are either weekly paclitaxel or every-3-week docetaxel (Taxotere) (Table 1). Administration of TAC (Taxotere [docetaxel], Adriamycin [doxorubicin] and cyclophosphamide) or AT or may produce equivalently high response rates. Although not yet definitive, recent data indicate that enhancing dose density may increase the pathologic complete response (pCR) rate for women with locally advanced disease. (The dosages of these combination chemotherapy regimens are provided in Table 1, “Stage II Breast Cancer” chapter.)

There seems to be no difference in survival in women with locally advanced disease who receive chemotherapy before or after surgery. Neoadjuvant chemotherapy results in complete clinical response rates ranging from 20% to 53% and partial response rates (≥ 50% reduction in bidimensionally measurable disease) ranging from 37% to 50%, with total response rates ranging from 80% to 90%. Patients with large lesions are more likely to have partial responses. However, pCRs do occur and are more likely to be seen in patients with smaller tumors that are triple-negative or which overexpress HER2. A pCR in the primary tumor is often predictive of a complete axillary lymph node response. Patients with locally advanced breast cancer who have a pCR in the breast and axillary nodes have a significantly improved disease-free survival compared with those who have less than a pCR. However, a pCR does not eliminate the risk of recurrence.

The phase II NeoSphere (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) and TRYPHAENA (Tolerability of Pertuzumab, Herceptin and Anthracyclines in Neoadjuvant breast cancer) studies invesigated whether pertuzumab (Perjeta) was beneficial and safe as neoadjuvant therapy administered to women with locally advanced and early-stage HER2-positive or inflammatory breast cancers. A significant number of women who received pertuzumab in combination with trastuzumab (Herceptin), an anthracycline, and docetaxel achieved a higher pCR or no evidence of cancer detected at the time of surgery. Approximately 40% of patients in NeoSphere-including women with locally advanced and inflammatory breast cancer and with HER2-positive disease treated with pertuzumab, trastuzumab, and docetaxel-have no evidence of cancer detected at the time of surgery compared with 21.5% of those taking trastuzumab and docetaxel,11.2% of those taking pertuzumab and trastuzumab, and 17.7% of women taking pertuzumab and docetaxel. The pertuzumab regimens in NeoSphere and TRYPHAENA were not associated with a significant increase in severe side effects. No new or unexpected cardiac toxicities were observed in the TRYPHAENA study. There are no data yet to document improved survival despite demonstrated clinical benefit and safety of the combination in the neoadjuvant settings.

In order to improve the prognostic information that can be obtained from evaluating pathologic response after neoadjuvant chemotherapy, Symmans et al developed the residual cancer burden (RCB) method of measuring residual disease. Pathologic slides and reports from 382 patients were reviewed in two different treatment cohorts: paclitaxel followed by FAC (n = 241) and FAC alone (n = 141). RCB was calculated as a continuous index combining pathologic measurements of primary tumor (size and cellularity) and nodal metastases (number and size) for prediction of distant relapse–free survival (DRFS) in multivariate Cox regression analyses. RCB was independently prognostic in a multivariate model that included age, pretreatment clinical stage, hormone receptor status, hormone therapy, and pathologic response (pCR vs residual disease [RD]; hazard ratio [HR] = 2.50; 95% confidence interval [CI], 1.70–3.69; P < .001). Minimal RD (RCB-I) in 17% of patients carried the same prognosis as pCR (RCB-0). Extensive RD (RCB-III) in 13% of patients was associated with poor prognosis, regardless of hormone receptor status, adjuvant hormone therapy, or pathologic stage of residual disease. The generalizability of RCB for prognosis of distant relapse was confirmed in the FAC-treated validation cohort. The investigators concluded that RCB determined from routine pathologic materials represented the distribution of RD, was a significant predictor of DRFS, and can be used to define categories of near-complete response and chemotherapy resistance.

Patients should be followed carefully while receiving neoadjuvant systemic therapy to determine treatment response. In addition to clinical examination, it may also be helpful to document photographically the response of ulcerated, erythematous, indurated skin lesions. Physical examination, mammography, and breast ultrasonography are best for assessing primary tumor response, whereas physical examination and ultrasonography are used to evaluate regional nodal involvement.

The role of magnetic resonance imaging (MRI) in evaluating response to preoperative chemotherapy is still evolving. Dynamic contrast-enhanced MRI performed at baseline, during chemotherapy, and before surgery has yielded more than 90% diagnostic accuracy in identifying tumors achieving a pCR and can potentially provide functional parameters that may help to optimize neoadjuvant chemotherapy strategies. Despite the high sensitivity of MRI, however, a large number of patients still may have either false-negative or false-positive results of MRI scanning.

Multimodality approach

A multimodality treatment plan for locally advanced breast cancer is shown schematically in Figure 1. This approach has been shown to result in a 5-year survival rate of 84% in patients with stage IIIA disease and a 44% rate in those with stage IIIB disease. The most striking benefit has been seen in patients with inflammatory breast cancer, with 5-year survival rates of 35% to 50% reported for a multimodality treatment approach including primary chemotherapy followed by surgery and radiation therapy and additional adjuvant systemic therapy. The same chemotherapy drugs, doses, and schedules used for single-modality therapy are employed in the multimodality approach.

FIGURE 1: Multimodality approach to locally advanced breast cancer

Surgery. Traditionally, mastectomy has been the surgical procedure of choice for patients with locally advanced breast cancer. In recently published studies, some patients with locally advanced breast cancer who responded to treatment with neoadjuvant chemotherapy became candidates for BCT and were treated with limited breast surgery and adjuvant breast irradiation. Patients who have been downstaged using neoadjuvant chemotherapy should be evaluated carefully before proceeding with conservative treatment. It may be helpful to mark the site of the primary tumor with the placement of a clip during the course of percutaneous biopsy prior to beginning adjuvant therapy. There can sometimes be a complete clinical and/or radiographic response after neoadjuvant chemotherapy or hormonal therapy, and this may facilitate a wide local incision.

The role of sentinel node biopsy in the treatment of breast cancer after neoadjuvant chemotherapy has yet to be defined. Pathologically positive axillary lymph nodes can be sterilized when neoadjuvant chemotherapy is utilized. There are other biologic concerns with sentinel node biopsy after neoadjuvant chemotherapy. The lymphatics may undergo fibrosis or may become obstructed by cellular debris, making the mapping procedure unreliable, with false-negative rates of up to 25%. The rate of conversion from positive to negative nodes can be enhanced when 4 cycles of a doxorubicin-based regimen are followed by 4 cycles of paclitaxel or docetaxel. Sentinel lymph node biopsy will only be accurate if all the metastatic deposits within the axilla respond in a similar fashion to chemotherapy. Preliminary data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-27 trial demonstrated an 11% false-negative rate in women who underwent sentinel node biopsy after receiving 4 cycles of doxorubicin and cyclophosphamide followed by 4 cycles of docetaxel. However, patients with clinically positive nodes prior to neoadjuvant chemotherapy should have a full lymph node dissection.

Radiation therapy. Radiotherapy remains an integral component of the management of patients with locally advanced breast cancer. For patients with operable breast cancer undergoing mastectomy, radiation therapy to the chest wall and/or regional lymph nodes (to a total dose of 50 to 60 Gy) is usually employed, as discussed in the “Stage II Breast Cancer” chapter. Randomized trials suggest that postmastectomy patients with any number of positive nodes derive a disease-free survival and/or overall survival benefit from postmastectomy irradiation.

In a retrospective review, more than 500 patients in six prospective trials who were treated with neoadjuvant chemotherapy, mastectomy, and radiation were compared with 134 patients treated with the same chemotherapy and mastectomy, but no radiation. Despite the more unfavorable characteristics, the irradiated patients had a lower rate of local-regional relapse than did the unirradiated group (11% vs 22%). Patients who presented with clinically advanced stage III or IV disease but subsequently achieved a pCR to neoadjuvant chemotherapy still had a high rate of locoregional response, which was significantly reduced with radiation (10-year rates: 33% vs 3%; P = .006). Radiation improved cause-specific survival in the subsets of patients with stage IIIB disease, clinical T4 tumors, and ≥ 4 positive nodes. The authors concluded that radiation should be considered for these patients regardless of their response to initial chemotherapy.

Available data do not suggest a problem in delaying radiation therapy until the completion of systemic chemotherapy. Even in patients undergoing high-dose chemotherapy with autologous bone marrow or stem-cell transplantation, irradiation is generally indicated following mastectomy for patients with locally advanced disease (primary tumors ≥ 5 cm and/or ≥ four positive axillary nodes).

For patients whose disease is considered to be inoperable, radiation therapy may be integrated into the management plan prior to surgery. Formenti et al achieved a promising 20% pCR rate with concomitant 5-FU and RT in patients who presented with T3/T4 tumors that could not be resected with primary wound closure. The patients were treated with preoperative continuous infusion 5-FU at 200 mg/m2/day with radiotherapy of 50 Gy in 2 Gy fractions to the breast and regional nodes, followed by mastectomy. A total of 35 women completed the protocol; 5-FU was interrupted during radiation in 10 of 35 patients because of oral mucositis in 8 patients, cellulitis in 1 patient, and patient choice in 1 patient. No grade 3/4 skin toxicities were seen. Objective clinical response rate before mastectomy was 71% (25 of 35 patients; 4 complete responses [CRs], 21 partial responses [PRs]). In all 35 patients, however, tumor response was sufficient to make them resectable with primary wound closure.

High-dose chemotherapy. To date, available clinical trials investigating the role of adjuvant high-dose chemotherapy (HDC) with autologous stem cell transplant in breast cancer have not shown superiority over conventional adjuvant chemotherapy, in terms of disease-free or overall survival. Furthermore, in some HDC trials, study design, power, and strategy have been questioned. Thus, currently HDC cannot be recommended for patients with primary or metastatic breast cancer outside the context of a clinical trial.

Locoregional Recurrence After Early-Stage or Early Invasive Breast Cancer

When a patient develops a local failure after BCT for early invasive cancer or ductal carcinoma in situ (DCIS), it is generally in the region of the initial primary tumor. The risk of ipsilateral breast tumor recurrence (IBTR) after conservative treatment in patients with early invasive cancer ranges from 0.5% to 2% per year, with long-term local failure rates that plateau at 15% to 20%. Local failure rates after wide excision alone for DCIS vary from 10% to 63%, as compared with rates between 7% and 21% after wide excision plus radiation therapy. Most patients whose disease recurs after conservative treatment for DCIS can be treated with salvage mastectomy. In one study, 14% of patients who developed local recurrence had synchronous distant metastatic disease.

The optimal treatment of a local or regional recurrence after mastectomy has yet to be defined. Locoregional recurrences are associated with initial nodal status and primary tumor size. Appropriate treatment may result in long-term control of locoregional disease. In many instances, these patients develop simultaneous distant metastasis, or distant disease develops some time after the locoregional recurrence manifests itself.

A retrospective study by Meyers et al investigated the impact of subtypes on locoregional recurrence (LRR) after neoadjuvant chemotherapy for locally advanced breast cancer. The impact of subtypes on LRR after neoadjuvant chemotherapy for locally advanced breast cancer is unknown. A total of 149 patients with stage II and III breast cancer with known ER, PR, and HER2 status who underwent neoadjuvant chemotherapy from 1991 to 2005 were analyzed. Clinical assays to distinguish luminal A (ER/PR+, HER2−, n = 55), luminal B (ER/PR+, HER2+, n = 25), HER2 (ER/PR−, HER2+, n = 20), and basal-like (ER/PR/HER2−, n = 49) subtypes were performed. With a median follow-up of 55 months, 49 (33%) patients had BCT with radiation, 82 (55%) had a mastectomy with radiation, and 18 (12%) had a mastectomy alone. A total of 88 (59%) were clinically node positive. A pCR was seen in 39 (26%) patients. LRR was identified in 11 (7%) patients: 2 after BCT (4%) and 9 after mastectomy (9%). LRR rates by subtype are as follows: luminal A, 2 of 55 (4%); luminal B, 1 of 25 (4%); HER2, 1 of 20 (5%); and basal-like, 7 of 49 (14%). Compared with all other subtypes, basal-like patients were more likely to have a LRR (7/49 (14%) vs 4/100 (4%), P = .03).

Recurrence of invasive cancer after breast conservation

After wide excision and breast irradiation. Some studies with limited follow-up have reported acceptable results with repeated wide local excision for IBTR following conservative surgery and radiation therapy. Selection criteria for this approach are unclear, however, and use of this salvage procedure remains controversial. Although the use of limited-field reirradiation has been reported, selection criteria for this management option and long-term follow-up data are lacking. The Radiation Therapy Oncology Group is currently investigating re-irradiation with accelerated partial breast irradiation (APBI) in patients with a recurrence after whole breast irradiation and breast-conserving surgery.

After wide excision alone. In patients initially treated with wide local excision alone who sustain an IBTR, small series with limited follow-up suggest that wide local excision followed by radiation therapy to the intact breast at the time of local recurrence may be a reasonable treatment alternative. In this situation, standard radiation doses would be employed.

Recurrent disease in the chest wall after mastectomy or breast-conserving surgery

When possible, disease recurring in the chest wall or axillary nodes should be resected and radiation therapy should be considered to aid in local control. Patients should be also evaluated for possible treatment with adjuvant chemotherapy.

Radiation treatment techniques are generally similar to those employed for patients treated with standard postmastectomy irradiation and consist of photon- and/or electron-beam arrangements directed at the chest wall and adjacent lymph node regions. Treatment planning should strive for homogeneous dose distributions to the target areas while minimizing the dose to the underlying cardiac and pulmonary structures.

Radiation dose and protocol. Conventional fractionation of 18 to 20 Gy/d to the area of locoregional recurrence and immediately adjacent areas at risk, to a total dose of 45 to 50 Gy, is indicated. A boost to the area of recurrence or gross residual disease, to a dose of approximately 60 Gy, results in acceptable long-term locoregional control.

Radical chest wall resection. A select group of patients with local chest wall recurrence secondary to breast cancer may be candidates for a radical chest wall resection, which may include resection of skin, soft tissue, and bone. Flap coverage or prosthetic chest wall reconstruction is required. Appropriate candidates would include patients who do not have distant metastases and who have persistent or recurrent chest wall disease after chest wall irradiation and those who present with a chest wall recurrence after a long disease-free interval.

Adjuvant systemic therapy

Ipsilateral breast tumor recurrence. The data suggest that women whose tumors recur in the ipsilateral breast within the first few years following the original diagnosis may be considered for adjuvant systemic therapy. Given the lack of prospective, randomized data, specific treatment recommendations for these women remain highly individualized.

Regional nodal recurrence and postmastectomy recurrence in the chest wall. Although there are limited data addressing the use of adjuvant systemic therapy at the time of locoregional relapse following mastectomy, given the high rate of systemic metastasis in this population, these patients may be considered for adjuvant systemic therapy. A randomized trial demonstrated a disease-free survival benefit with the use of adjuvant tamoxifen following radiation therapy at the time of postmastectomy recurrence in the chest wall in patients with ER-positive tumors. The 5-year disease-free survival rate was increased from 36% to 59%, and the median disease-free survival was prolonged by > 4.5 years.

Patients with ER-negative tumors and aggressive locoregional recurrences may also be considered for systemic cytotoxic chemotherapy, given their relatively poor prognosis and the high rate of metastasis.

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), 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, 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 (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 vs 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 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. A very similar study by SWOG (S0226), reported by Mehta et al, showed conflicting data in that the combination of anastrozole plus fulvestrant was superior to anastrozole alone or sequential anastrozole and fulvestrant for the treatment of HR-positive metastatic breast cancer. This was despite the use of a dose of fulvestrant that was below the current standard. However, over 59% of patients in this study were not exposed to tamoxifen in the adjuvant setting.

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 = 0.8; 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).

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 = 0.8; 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 (Femara) and 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. Recent randomized trials have indicated that fulvestrant or the aromatase inhibitors, such as anastrozole, letrozole, and exemestane, 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).

At the time of progression, patients in BOLERO-2 received additional treatments in roughly the same proportion (84% of patients in the everolimus plus exemestane arm vs 90% of patients in the placebo plus exemestane arm). Types of poststudy therapies were balanced across the two arms, except for chemotherapy (53% of patients randomized to everolimus plus exemestane vs 63% of those randomized to placebo plus exemestane). Despite the significant improvement seen in progression-free survival, the addition of everolimus to exemestane did not confer a statistically significant improvement in overall survvial. Median overall survival in patients receiving everolimus plus exemestane was 31.0 months compared to 26.6 months in patients receiving placebo plus exemestane (HR = 0.89; 95% CI, 0.73–1.10; log-rank P = .14). The study authors concluded that additional translational research is needed to further assess the benefit of mTOR inhibition and related pathways in this treatment setting.

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%). The combination of everolimus with aromatase inhibitor therapy (letrozole) in the front-line treatment of ER-positive metastatic breast cancer is being investigated in the BOLERO-4 trial (Open-label, Phase II Study of Everolimus Plus Letrozole in Postmenopausal Women With ER+, HER2− Metastatic or Locally Advanced Breast Cancer; National Cancer Institute ID number NCT01698918).

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 patients with metastatic breast cancer before the start of a new treatment. Patients with CTC levels greater than five per 7.5 mL of whole blood had a shorter median progression-free survival time (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, 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 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, ixabepilone (Ixempra), capecitabine (Xeloda), vinorelbine, and gemcitabine (see Table 1), as well as vinblastine, mitomycin, and 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 infused over a period of 3 hours) has not been shown to be superior to 175 mg/m2 infused 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 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 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 on 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 and paclitaxel; and gemcitabine and 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.

Palbociclib (PD-0332991) is an orally active, potent and highly selective inhibitor of CDK4/6 that prohibits progression of the cell cycle from G1 into S phase. It has very promising activity in ER-positive breast cancer. Given the preclinical evidence for the relevance of Cyclin D-CDK4/6-E2F signaling in the development of acquired resistance to hormonal therapy, CDK4-6 inhibition might be a strategy to overcome resistance in patients whose tumors have progressed after hormonal therapy for metastatic disease. In one phase II study of heavily pretreated patients with ER-positive advanced breast cancer, single-agent palbociclib showed a clinical benefit rate (partial response [PR] + stable disease ≥ 6 months) of 17%. In another phase II study, Finn et al found palbociclib in combination with letrozole as first-line hormonal treatment for advanced breast cancer extended progression-free survival. Several phase III studies are now investigating this agent in breast cancer, both in the advanced and earlier-stage settings.

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, 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 population with metastatic triple-negative breast cancer, failed to demostrate a significant improvement in overall survival or progression-free survival. The median overall survival time 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 time 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 triple-negative breast cancer.

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, 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.

Pertuzumab. The FDA approved pertuzumab (Perjeta) in late 2013 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 time 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 final survival analysis of the international phase III CLEOPATRA trial was reported at the 2014 European Society of Medical Oncology (EMSO) meeting in Madrid, Spain. Performed after 385 deaths and at a median follow-up of 50 months, it revealed a revealed median overall survival time of 56.5 months in the pertuzumab group vs 40.8 months in the placebo arm (HR = .68; P = .0002). A 6.3-month increase in progression-free survival time was sustained (HR = 0.68; P < .0001). Rarely, symptomatic left ventricular dysfunction and declines in left ventricular ejection fraction were seen and occurred at the same rate between the study arms.

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.

Eribulin. 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 vs sh389]). 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. 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 now-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.

Until the approval of pertuzumab, the only approved combination for trastuzumab-refractory HER2+ metastatic breast cancer was 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 q3wk + 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. Blackwell et al reported a significant improvement in progression-free survival favoring T-DM1 (9.6 vs 6.4 months; hazard ratio [HR] = 0.65; 95% confidence interval [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.

Bevacizumab. Bevacizumab is a recombinant humanized monoclonal antibody that targets vascular endothelial growth factor receptor (VEGF)

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 ORR 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 ORR, there was no difference in median overall survival between the two treatment arms. Toxicities associated with the bevacizumab combination included hypertension, proteinuria, and neuropathy.

The initial promising results of a 5-month improvement in progression-free survival time 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 waned, and in November 2011 the FDA revoked its accelerated approval of the breast cancer indication for bevacizumab.

Adjunctive bisphosphonate therapy for bone metastasis

Zoledronic acid. 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 (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. 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).


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 Knife and CyberKnife 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.

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