Stage IIIB, Inoperable IIIC, IV, Recurrent, and Metastatic Breast Cancer

Inoperable Stage IIIB or IIIC or Inflammatory Breast Cancer
        Current Clinical Trials
Stage IV, Recurrent, and Metastatic Breast Cancer
        Recurrent local-regional breast cancer
        Stage IV and metastatic disease
        Current Clinical Trials
Systemic Therapy
        Bisphosphonates
        Hormone therapy
        mTOR Inhibitors
        Trastuzumab
        Lapatinib
        Pertuzumab
        Cytotoxic chemotherapy
        Bevacizumab
Current Clinical Trials

Multimodality therapy delivered with curative intent is the standard of care for patients with clinical stage IIIB disease. In a retrospective series, approximately 32% of patients with ipsilateral supraclavicular node involvement and no evidence of distant metastases (pN3c) had prolonged disease-free survival (DFS) at 10 years with combined modality therapy.[1] Although these results have not been replicated in another series, this result suggests such patients should be treated with the same intent.

Initial surgery is generally limited to biopsy to permit the determination of histology, estrogen-receptor (ER) and progesterone-receptor (PR) levels, and human epidermal growth factor receptor 2 (HER2/neu) overexpression. Initial treatment with anthracycline-based chemotherapy and/or taxane-based therapy is standard.[2,3] In one series of 178 patients with inflammatory breast cancer, DFS was 28% at 15 years with a combined-modality approach.[2][Level of evidence: 3iiiDii] For patients who respond to neoadjuvant chemotherapy, local therapy may consist of total mastectomy with axillary lymph node dissection followed by postoperative radiation therapy to the chest wall and regional lymphatics. Breast-conserving therapy can be considered in patients with a good partial or complete response to neoadjuvant chemotherapy.[3] Subsequent systemic therapy may consist of further chemotherapy. Hormone therapy should be administered to patients whose tumors are ER-positive or unknown. All patients should be considered candidates for clinical trials to evaluate the most appropriate fashion in which to administer the various components of multimodality regimens.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIIB breast cancer, stage IIIC breast cancer and inflammatory breast cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Recurrent breast cancer is often responsive to therapy, though treatment is rarely curative at this stage of disease. Patients with localized breast or chest wall recurrences, however, may be long-term survivors with appropriate therapy. Prior to treatment for recurrent or metastatic cancer, restaging to evaluate extent of disease is indicated. Cytologic or histologic documentation of recurrent or metastatic disease should be obtained whenever possible. The ER levels and PR levels, HER2/neu positivity at the time of recurrence, and previous treatment should be considered, if known, when selecting therapy. ER status may change at the time of recurrence. In a single small study by the Cancer and Leukemia Group B (MDA-MBDT-8081), 36% of hormone receptor–positive tumors were found to be receptor negative in biopsy specimens isolated at the time of recurrence.[4] Patients in this study had no interval treatment. If ER and PR status is unknown, then the site(s) of recurrence, disease-free interval, response to previous treatment, and menopausal status are useful in selecting chemotherapy or hormone therapy.[5]

Patients with local-regional breast cancer recurrence may become long-term survivors with appropriate therapy. A clinical trial indicated that between 10% and 20% of patients will have locally recurrent disease in the breast between 1 and 9 years after breast-conservation surgery plus radiation therapy.[6] Nine percent to 25% of these patients will have distant metastases or locally extensive disease at the time of recurrence.[7-9] Patients with local-regional recurrence should be considered for further local treatment (e.g., mastectomy). In one series, the 5-year actuarial rate of relapse for patients treated for invasive recurrence after initial breast conservation and radiation therapy was 52%.[8] A phase III randomized study showed that local control of cutaneous metastases could be achieved with the application of topical miltefosine; however, the drug is not currently available in the United States.[10][Level of evidence: 1iiDiii]

Local chest wall recurrence following mastectomy is usually the harbinger of widespread disease, but, in a subset of patients, it may be the only site of recurrence. For patients in this subset, surgery and/or radiation therapy may be curative.[11,12] Patients with chest wall recurrences of less than 3 cm, axillary and internal mammary node recurrence (not supraclavicular, which has a poorer survival), and a greater than 2-year disease-free interval prior to recurrence have the best chance for prolonged survival.[12] The 5-year DFS rate in one series of such patients was 25%, with a 10-year rate of 15%.[13] The local-regional control rate was 57% at 10 years. Systemic therapy should be considered in patients with local regional recurrence caused by the high risk of subsequent metastases.[14] No randomized controlled studies are available to guide patient care in this situation.

Treatment for systemic disease is palliative in intent. Goals of treatment include improving quality of life and prolongation of life. Although median survival has been reported to be 18 to 24 months,[15] some patients experience long-term survival. Among patients treated with systemic chemotherapy at a single institution between 1973 and 1982, 263 patients (16.6%) achieved complete responses. Of those, 49 patients (3.1% of the total group) remained in complete remission for more than 5 years, and 26 patients (1.5%) were still in complete remission at 16 years.[16][Level of evidence: 3iiDiii]

Treatment of metastatic breast cancer will usually involve hormone therapy and/or chemotherapy with or without trastuzumab. Radiation therapy and/or surgery may be indicated for patients with limited symptomatic metastases. All patients with metastatic or recurrent breast cancer should be considered candidates for ongoing clinical trials.

Surgery may be indicated for selected patients. Examples include patients who need mastectomies for fungating/painful breast lesions, parenchymal brain or vertebral metastases with spinal cord compression, isolated lung metastases, pathologic (or impending) fractures, or pleural or pericardial effusions. (Refer to the PDQ summary on Pain for more information and for information on pleural and pericardial effusions, refer to the PDQ summary on Cardiopulmonary Syndromes.)

Radiation therapy has a major role in the palliation of localized symptomatic metastases. Indications include painful bony metastases, unresectable central nervous system metastases (i.e., brain, meningeal, and spinal cord), bronchial obstruction, and fungating/painful breast or chest wall lesions. Radiation therapy should also be given following surgery for decompression of intracranial or spinal cord metastases and following fixation of pathologic fractures. Clinical trials (including the completed Radiation Therapy Oncology Group's trial [RTOG-9714]) are exploring the optimal radiation fractionation schedule. Strontium 89, a systemically administered radionuclide, can be administered for palliation of diffuse bony metastases.[17,18] (Refer to the PDQ summary on Pain for more information.)

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV breast cancer and recurrent breast cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

The use of bisphosphonates to reduce skeletal morbidity in patients with bone metastases should be considered.[19] Results of randomized trials of pamidronate and clodronate in patients with bony metastatic disease show decreased skeletal morbidity.[20-22][Level of evidence: 1iC] Zoledronate has been at least as effective as pamidronate.[23] (Refer to the PDQ summary on Pain for more information on bisphosphonates.)

Hormone therapy should generally be considered as initial treatment for a postmenopausal patient with newly diagnosed metastatic disease if the patient’s tumor is ER-positive, PR-positive, or ER/PR-unknown. Hormone therapy is especially indicated if the patient’s disease involves only bone and soft tissue and the patient has either not received adjuvant antiestrogen therapy or has been off such therapy for more than 1 year. While tamoxifen has been used in this setting for many years, several randomized trials suggest equivalent or superior response rates and progression-free survival (PFS) for the aromatase inhibitors compared to tamoxifen.[24-26][Level of evidence: 1iiDiii] In a meta-analysis that included randomized trials in patients who were receiving an aromatase inhibitor as either their first or second hormonal therapy for metastatic disease, those who were randomly assigned to a third-generation drug (anastrozole, letrozole, exemestane, or vorozole) lived longer (hazard ratio [HR] for death, 0.87; 95% confidence interval [CI], 0.82–0.93) than those who received standard therapy (tamoxifen or a progestational agent).[27][Level of evidence: 1iA]

Several randomized but underpowered trials have tried to determine if combined hormone therapy (luteinizing hormone-releasing hormone [LHRH] agonists + tamoxifen) is superior to either approach alone in premenopausal women. Results have been inconsistent.[28-30] The best study design compared buserelin (an LHRH agonist) versus tamoxifen versus the combination in 161 premenopausal women with hormone receptor–positive tumors.[31] Patients receiving buserelin and tamoxifen had a significantly improved median survival of 3.7 years compared with those receiving tamoxifen or buserelin who survived 2.9 and 2.5 years, respectively (P = .01).[31][Level of evidence: 1iiA] Very few women in this trial received adjuvant tamoxifen, which makes it difficult to assess whether these results are applicable to women who relapse after adjuvant tamoxifen.

Women whose tumors are ER-positive or unknown, with bone or soft tissue metastases only, who have received an antiestrogen within the past year, should be given second-line hormone therapy. Examples of second-line hormone therapy in postmenopausal women include selective aromatase inhibitors, such as anastrozole, letrozole, or exemestane; megestrol acetate; estrogens; androgens;[32-40] and the ER down-regulator, fulvestrant.[41,42] In comparison to megestrol acetate, all three currently available aromatase inhibitors have demonstrated, in prospective randomized trials, at least equal efficacy and better tolerability.[32-38,43] In a meta-analysis that included randomized trials of patients who were receiving an aromatase inhibitor as either their first or second hormonal therapy for metastatic disease, those who were randomly assigned to a third-generation drug (e.g., anastrozole, letrozole, exemestane, or vorozole) lived longer (HR for death 0.87; 95% CI, 0.82–0.93) than those who received standard therapy (tamoxifen or a progestational agent).[27][Level of evidence: 1iA] Two randomized trials that enrolled 400 and 451 patients who had progressed after receiving tamoxifen demonstrated that fulvestrant yielded similar results to anastrozole in terms of its impact on PFS.[44,45] The proper sequence of these therapies is currently not known.[43,46]

Premenopausal women should undergo oophorectomy (surgically, with external-beam radiation therapy or with an LHRH agonist).[47] Patients with lymphangitic pulmonary metastases, major liver involvement, and/or central nervous system involvement should not receive hormone therapy as a single modality. Patients with structural compromise of weight-bearing bones should be considered for surgical intervention and/or radiation in addition to systemic therapy. Patients with vertebral body involvement should be evaluated for impending cord compression even in the absence of neurologic symptoms. Increasing bone pain and increasing alkaline phosphatase within the first several weeks of hormone therapy does not necessarily imply disease progression.[48] Patients with extensive bony disease are at risk for the development of symptomatic hypercalcemia early in the course of hormone therapy.[48] Early failure (e.g., <6 months) on hormone therapy suggests that cytotoxic chemotherapy should be the next modality employed.

Endocrine therapy is recommended for patients with metastatic hormone receptor-positive (HR+) disease. However, patients inevitably develop resistance to endocrine therapy. Preclinical models and clinical studies suggest that mTOR inhibitors might enhance the efficacy of endocrine therapies.

BOLERO-2 [NCT00863655], a randomized, phase III, placebo-controlled trial, of randomly assigned patients with HR+ metastatic breast cancer resistant to nonsteroidal aromatase inhibition received the mTOR inhibitor everolimus plus exemestane versus placebo plus exemestane.[49][Level of Evidence: 1iDiii]. At the interim analysis, median PFS was 6.9 months for everolimus plus exemestane and 2.8 months for placebo plus exemestane (HR, 0.43; 95% CI, 0.35–0.54; P< .001). The addition of everolimus to exemestane was more toxic with the most common grade 3 or 4 adverse events being stomatitis (8% vs. 1%), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%). The results of this study report a benefit in PFS with the addition of an mTOR inhibitor to endocrine therapy but there were more side effects. Final OS outcomes on this trial are awaited.

Approximately 25% of patients with breast cancer have tumors that overexpress HER2/neu.[50] Trastuzumab is a humanized monoclonal antibody that binds to the HER2/neu receptor.[50] In patients previously treated with cytotoxic chemotherapy whose tumors overexpress HER2/neu, administration of trastuzumab as a single agent resulted in a response rate of 21%.[51][Level of evidence: 3iiiDiv] In a prospective trial, patients with metastatic disease were randomly assigned to receive either chemotherapy alone (doxorubicin and cyclophosphamide or paclitaxel) or the same chemotherapy and trastuzumab. Patients treated with chemotherapy plus trastuzumab had an OS advantage as compared with those receiving chemotherapy alone (25.1 months vs. 20.3 months, P = .05).[52][Level of evidence: 1iiA] When combined with doxorubicin, trastuzumab is associated with significant cardiac toxicity.[53] Consequently, patients with metastatic breast cancer with substantial overexpression of HER2/neu are candidates for treatment with the combination of trastuzumab and paclitaxel or for clinical studies of trastuzumab combined with taxanes and other chemotherapeutic agents.[54]

Clinical trials comparing multiagent chemotherapy plus trastuzumab versus single-agent chemotherapy have yielded conflicting results. In one randomized study of patients with metastatic breast cancer treated with trastuzumab, paclitaxel, and carboplatin, patients tolerated the combination well and had a longer time-to-progression, compared to trastuzumab and paclitaxel alone.[55][Level of evidence: 1iDiii] However, a phase III trial (BCIRG-007 [NCT00047255]) comparing carboplatin and docetaxel plus trastuzumab versus docetaxel plus trastuzumab as first-line chemotherapy for metastatic HER2-overexpressing breast cancer showed no difference in OS, time to progression, or response rate.[56][Level of evidence: 1iiA] Outside of a clinical trial, standard first-line treatment for metastatic HER2-overexpressing breast cancer should consist of single-agent chemotherapy plus trastuzumab.

Lapatinib is an orally administered tyrosine kinase inhibitor of both HER2/neu and the epidermal growth factor receptor. Lapatinib has shown activity in combination with capecitabine in patients who have HER2-positive metastatic breast cancer that progressed after treatment with trastuzumab. A nonblinded, randomized trial (GSK-EGF100151) compared the combination of capecitabine and lapatinib in 324 patients with locally advanced or metastatic disease that progressed after therapies that included anthracyclines, taxanes, and trastuzumab.[57] At the first planned interim analysis of the trial, a highly significant difference was found that favored the combination arm with respect to the primary study endpoint and time to progression (median time to progression 8.4 months vs. 4.4 months; HR, 0.49; 95% CI, 0.34–0.71; P < .001). There was no difference in OS (HR, 0.92; 95% CI, 0.58–1.46; P = .72).[57][Level of evidence: 1iiA] Patients on combination therapy were more likely to develop diarrhea, rash, and dyspepsia. No data on quality of life or treatment after progression are available. (Refer to the PDQ summary on Gastrointestinal Complications for more information on diarrhea.)

A double-blind, randomized phase III study compared paclitaxel and lapatinib for first-line therapy in patients with metastatic breast cancer.[58] There was no benefit for patients with HER2/neu metastatic breast cancer. Specimens were evaluated retrospectively to determine HER2/neu status. When used with HER2/neu-positive patients, treatment with paclitaxel and lapatinib showed improvement in time to progression, event-free survival, response rate, and clinical benefit rate; OS did not increase. Toxicities, specifically alopecia, diarrhea, and rash were higher in the HER2/neu-positive lapatinib group. A series of adverse events were low and existed in both arms.[58][Level of evidence: 1iDiii]

Pertuzumab is a humanized, monoclonal antibody that binds to a different epitope at the HER2 extracellular domain than trastuzumab. The binding of pertuzumab to HER2 prevents dimerization with other ligand-activated HER receptors, most notably HER3. Given their potentially complementary mechanisms of action, the phase III CLEOPATRA [NCT00567190] trial assessed the efficacy and safety of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel, in the first-line HER2+ metastatic setting.[59][Level of evidence: 1iA]. The median PFS was 12.4 months in the control group versus 18.5 months in the pertuzumab group (HR, 0.62; 95% CI, 0.51–0.75; P < .001). Final OS results are pending. The toxicity profile was similar in both treatment groups with no increase in cardiac toxic effects seen in the pertuzumab combination arm.

Patients whose tumors have progressed on hormone therapy are candidates for cytotoxic chemotherapy. Patients with hormone receptor–negative tumors and those with visceral metastases are also candidates for cytotoxic agents.[60]

Single agents that have shown activity in metastatic breast cancer include the following:

• Anthracyclines.
  • Doxorubicin.
  • Epirubicin.
  • Liposomal doxorubicin.[61-64]
  • Mitoxantrone.

• Taxanes.
  • Paclitaxel.[65,66]
  • Docetaxel.
  • Albumin-bound nanoparticle paclitaxel (ABI-007 or Abraxane).[67,68]

• Alkylating agents.
  • Cyclophosphamide.

• Fluoropyrimidines.
  • Capecitabine.[69-71]
  • 5-FU.

• Antimetabolites.
  • Methotrexate.

• Vinca alkaloids.
  • Vinorelbine.[72]
  • Vinblastine.
  • Vincristine.

• Platinum.
  • Carboplatin.
  • Cisplatin.

• Other.
  • Gemcitabine.[73]
  • Mitomycin C.
  • Eribulin mesylate.[74,75]

Combination regimens that have shown activity in metastatic breast cancer:

• CA: cyclophosphamide and doxorubicin.[76]
• Docetaxel and doxorubicin.[77]
• CAF: cyclophosphamide, doxorubicin, 5-fluorouracil.[78]
• CMF: cyclophosphamide, methotrexate, 5-fluorouracil.[79]
• Doxorubicin and paclitaxel.[80,81]
• Docetaxel and capecitabine.[82]
• Vinorelbine and epirubicin.[83]
• Capecitabine and ixabepilone.[84]

Whether single-agent chemotherapy or combination chemotherapy is preferable for first-line treatment is unclear. An Eastern Cooperative Oncology Intergroup study (E-1193) randomly assigned patients to receive paclitaxel and doxorubicin given both as a combination and sequentially.[85] Although response rate and time-to-progression were both better for the combination, survival was the same in both groups.[85][Level of evidence: 1iiA][86,87] The rate of disease progression, the presence or absence of comorbid medical conditions, and physician/patient preference will influence the choice of therapy in individual patients. At this time, no data support the superiority of any particular regimen. Sequential use of single agents or combinations can be used for patients who relapse. Combinations of chemotherapy and hormone therapy have not shown an OS advantage over the sequential use of these agents.[15,88] A systematic review of 17 randomized trials found that the addition of one or more chemotherapy drugs to a chemotherapy regimen in the attempt to intensify the treatment improved tumor response but had no effect on OS.[89][Level of evidence: 1iiA]

The optimal treatment duration for patients with responsive or stable disease has been studied by several groups. For patients who attain a complete response to initial therapy, two randomized trials have shown a prolonged DFS from immediate treatment with a different chemotherapy regimen compared to observation with treatment upon relapse.[90,91][Level of evidence: 1iiA] Neither of these studies, however, showed an improvement in OS for patients who received immediate treatment, and in one of these studies,[91] survival was actually worse in the immediately treated group. Similarly, no difference in survival was noted when patients with partial response or stable disease after initial therapy were randomized to receive either a different chemotherapy versus observation [92] or a different chemotherapy regimen given at higher versus lower doses.[93][Level of evidence: 1iiA] These four studies indicate that different combination regimens of additional chemotherapy immediately following a patient’s best response to an induction chemotherapy regimen does not improve OS. In view of the lack of a standard approach, patients requiring second-line regimens are good candidates for clinical trials.

The potential for doxorubicin-induced cardiotoxicity should be considered in the selection of chemotherapeutic regimens for an individual patient. Recognized risk factors for cardiac toxicity include advanced age, prior chest-wall radiation therapy, prior anthracycline exposure, hypertension, diabetes, and known underlying heart disease. The cardioprotective drug dexrazoxane has been shown to decrease the risk of doxorubicin-induced cardiac toxicity in patients in controlled studies. The use of this agent has permitted patients to receive greater cumulative doses of doxorubicin and allowed patients with cardiac risk factors to receive doxorubicin.[94-97] Dexrazoxane has a similar protective effect in patients receiving epirubicin.[98] The risks of cardiac toxicity may also be reduced by administering doxorubicin as a continuous intravenous infusion.[99]

Studies comparing high-dose chemotherapy with stem cell support to conventional chemotherapy in patients with metastatic disease indicate no OS or relapse-free survival benefit for patients receiving high-dose chemotherapy with stem cell support.[100,101][Level of evidence: 1iiA] In the absence of data suggesting a benefit from high-dose chemotherapy with stem cell support, this remains an area of clinical evaluation.[102,103]

Bevacizumab is a humanized monoclonal antibody directed against all isoforms of vascular endothelial growth factor-A. Its role in the treatment of metastatic breast cancer remains controversial. The efficacy and safety of bevacizumab as a second- and third-line treatment for patients with metastatic breast cancer were studied in a single, open-label, randomized trial.[104] The study enrolled 462 patients who had received prior anthracycline and taxane therapy and were randomly assigned to receive capecitabine with or without bevacizumab. The study failed to demonstrate a statistically significant effect on PFS (4.86 months vs. 4.17 months; HR, 0.98) or OS (15.1 months vs. 14.5 months).[104][Level of Evidence: 1iiA]

ECOG-2100 (NCT00028990), a completed, open-label, randomized, phase III trial, demonstrated that the addition of bevacizumab to paclitaxel significantly prolonged median PFS compared with paclitaxel alone as the initial treatment for patients with metastatic breast cancer (11.8 months vs. 5.9 months; HR, 0.60; P <.001).[105][Level of Evidence: 1iiA] However, the addition of bevacizumab did not improve OS (26.7 months vs. 25.2 months, P = .16). Notably, patients treated on the bevacizumab-containing arm had significantly higher rates of severe hypertension, proteinuria, cerebrovascular ischemia, and infection.

The AVADO (NCT00333775) trial randomly assigned 736 patients to docetaxel plus either placebo or bevacizumab at 7.5 mg/kg or 15 mg/kg every 3 weeks as the initial treatment for patients with metastatic breast cancer. The combination of bevacizumab at 15 mg/kg, but not 7.5 mg/kg, with docetaxel modestly improved median PFS compared with placebo (10.1 months vs. 8.1 months) but did not improve OS (30.2 months vs. 31.9 months; P = .85).[106][Level of Evidence: 1iiA] Again, more toxicity was seen in patients in the bevacizumab-containing arms with significantly higher rates of bleeding and hypertension compared with the placebo arms.

Similarly, the RIBBON 1 (NCT00262067) trial randomly assigned 1,237 patients in a 2:1 fashion to standard chemotherapy plus bevacizumab or standard chemotherapy plus placebo.[107] Median PFS was longer for each bevacizumab-containing combination (Cape cohort: increased from 5.7 mo. to 8.6 mo.; HR, 0.69; 95% CI, 0.56–0.84; log-rank, P < .001; and Taxane/Anthracycline cohort: increased from 8.0 mo. to 9.2 mo.; HR, 0.64; 95% CI, 0.52–0.80; log-rank, P < .001).[107][Level of Evidence: 1iiA] However, no statistically significant differences in OS between the placebo- and bevacizumab-containing arms were observed. Toxicities associated with bevacizumab were similar to those seen in prior bevacizumab clinical trials.

In November 2011, based on the consistent finding that bevacizumab only modestly improved PFS but not OS, and given bevacizumab’s considerable toxicity profile, the Food and Drug Administration revoked approval of bevacizumab for the treatment of metastatic breast cancer.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIIB breast cancer, stage IIIC breast cancer, stage IV breast cancer, recurrent breast cancer and metastatic cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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