- Email: [email protected]
Challenges in the Management of Metastatic Breast Cancer
Challenges in the Management of Metastatic Breast Cancer Homayoon Sanati, MD, MS Breast cancer is the most common cancer in women in the United States. About 6% of newly diagnosed breast cancer cases present with metastatic disease, and one-third of women diagnosed with earlier stage breast cancer develop metastatic disease. Management of metastatic breast cancer (MBC) continues to be challenging, and MBC remains essentially an incurable disease. Treatment of MBC is individualized for each patient, and it is often based on patient’s preferences, comorbidities, performance status, prognostic factors, menopausal status, and prior history of treatments. Risk assessment is the first step in the management of MBC. Factors that can affect the prognosis (hormone receptor status, HER-2 expression status, disease-free interval, tumor burden, site of metastasis, and vital organ involvement) are considered before start of the treatments. Women with hormone responsive disease and stable bony metastasis are often treated with hormonal therapies and bisphosphonates. Women with hormone-unresponsive disease or fast-growing tumors are treated with systemic chemotherapy with or without a targeted therapy agent. Metastasis to the brain, spinal cord compression, pleural effusion, hypercalcemia, and pancytopenia secondary to bone marrow infiltration are common complications of MBC, and the management of each complication will be briefly discussed. Future research to identify molecular prognostic markers and to evaluate various strategies for optimal management of MBC is needed. Semin Breast Dis 10:128-133 © 2007 Elsevier Inc. All rights reserved. KEYWORDS metastatic breast cancer, endocrine therapy, chemotherapy, targeted therapy
B
reast cancer is the most commonly diagnosed cancer in women in the United States. An estimated 178,480 new cases of breast cancer in women are expected in the year 2007, and it is estimated that 40,460 women in the U.S. will die of this disease in 2007.1 About 6% of newly diagnosed breast cancer cases present with metastatic disease, and approximately 30% of women diagnosed with earlier stage breast cancer develop metastatic disease.2 Despite recent advances in formulating novel treatments, management of metastatic breast cancer (MBC) continues to be challenging, and MBC remains essentially an incurable disease. Treatment of MBC is individualized for each patient, and it is often based on patient’s preferences, comorbidities, performance status, prognostic factors, menopausal status, and prior history of treatments (including neoadjuvant or adjuDivision of Hematology/Oncology, Department of Medicine, Chao Comprehensive Cancer Center, University of California, Irvine, Orange, CA. Address reprint requests to Homayoon Sanati, Department of Medicine, Division of Hematology/Oncology, Chao Comprehensive Cancer Center, University of California, Irvine, 101 City Drive South, Orange, CA 92868-4061. E-mail: [email protected]
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vant treatments).3 The goals of treatment of MBC include disease control, palliation of symptoms, improving or maintaining quality of life, and prolonging overall survival.4 In this paper, we will review various strategies and challenges of the management of MBC.
Risk Assessment The first step in the management of MBC is risk evaluation according to the factors that affect prognosis. These prognostic factors include hormone receptor status, HER-2 expression status, disease-free interval, tumor burden, site of metastasis, and vital organ involvement. Patients with positive estrogen receptor (ER) status are considered to have better prognosis.5 HER-2 receptor overexpression, on the other hand, has been linked to worsen survival.6 Disease-free survival of more than 2 years is considered a good prognostic factor. Patients with limited tumor burden, bone metastasis only, and no vital organ involvement have good prognosis,7 whereas patients with extensive disease, visceral metastasis, or vital organ involvement are considered to have intermedi-
Management of metastatic breast cancer
129
Table 1 Risk Evaluation Based on Prognostic Indicators in Metastatic Breast Cancer Prognostic Factor
Low Risk
Hormone receptor status Her-2 receptor status Disease-free interval Vital organ involvement Viceral Metastasis Only bone metastasis Disease burden
Intermediate/ High Risk
Positive
Negative
Negative More than 2 years No No Yes Limited
Positive Less than 2 years Yes Yes No Extensive
ate or poor prognosis.8 Table 1 summarizes the prognostic characteristics of MBC.
Endocrine Therapy Front-line hormonal treatments are generally offered to patients whose tumors express hormone receptors and have a low risk of developing complications related to the disease. Endocrine treatments are best suited for women with ERpositive tumors who have mostly bone metastasis. Hormonal treatments are sometimes offered to patients with intermediate/high-risk disease who have comorbid conditions and/or poor performance status. These patients are not likely to tolerate cytotoxic chemotherapy treatments. Hormonal treatment approaches depends on the patient’s menopausal status. Historically, premenopausal women with MBC underwent surgical interventions like oophorectemy or radiation treatments to the ovaries to ablate the ovarian function, but over the past 35 years, tamoxifen has become the treatment of choice for hormone-responsive MBC.9,10 Widespread use of tamoxifen in adjuvant setting has created a need for novel strategies. Patients are often diagnosed with metastatic disease while they are taking tamoxifen. Recent development of new agents has shifted the endocrine treatment strategies for MBC. Table 2 summarizes some of the key studies on the endocrine treatment of MBC. Luteinizing hormone-releasing hormone (LHRH) agonists have been used alone or in combination with other endocrine agents in premenopausal women with MBC. LHRH agonists
result in ovarian suppression by interfering with gonadotrophin release, which subsequently lowers estrogen. LHRH agonists have been shown to be as effective as oophorectemy in premenopausal women with MBC.11 Tamoxifen has been used in combination with LHRH agonists, and the combination was found to be more effective than LHRH monotherapy treatments.12 Currently, goserelin given monthly is the only LHRH agonist approved for use in the United States for the treatment of MBC in premenopausal women. Complete estrogen depletion in postmenopausal women can be achieved by blocking aromatase enzyme. A new class of drugs that block aromatase has been developed over the past three decades. Aromatase inhibitors have been found to be effective for front-line treatment of MBC in postmenopausal women.13-17 In a meta-analysis, third-generation aromatase inhibitors (anastrazole, letrozole, and exemestane) have shown to improve survival when compared with tamoxifen in front-line treatment of MBC in postmenopausal women.18 Aromatase inhibitors are not commonly used in premenopausal women because reduced estrogen causes feedback stimulation of hypothalamus and pituitary gland, resulting in increased gonadotriphin secretion. Combination of LHRH agonists and aromatase inhibitors in premenopausal women are currently being studied in premenopausal women with MBC.19 Fulvestrant is another agent which has recently been developed for use in breast cancer. Fulvestrant is an antiestrogen that binds to estrogen receptors, blocks the receptor dimerization, and increases its turnover. Fulvestrant has been found to be effective for the treatment of MBC in tamoxifenresistant patients.20,21 It also has been shown to be effective in patients who had disease progression while they were on an aromatase inhibitor.22,23 Fluvestrant is commonly used as a second- or third-line treatment of hormone-responsive MBC.
Chemotherapy for MBC Systemic chemotherapy remains the most effective treatment for hormone unresponsive MBC.8 Patients with intermediate or high-risk prognostic factors are often treated with systemic chemotherapy. There are a number of chemotherapy agents that are active against breast tumors. These agents include antracyclines, taxanes, alkylating agents, antimetabolites, and vinorelbine.24-31 Using combination versus sequential single-
Table 2 Selected Studies on Front-Line Hormonal Treatment of Metastatic Breast Cancer Study Description
Study Drug
Response Rate (%)
TTP (months)
Reference
Tamoxifen treatments; 156 patients Tamoxifen versus DES; 143 postmenopausal women Letrozole versus Tamoxifen; 916 postmenopausal women Exemestane versus Tamoxifen; 120 postmenopausal women Anastrazole versus Tamoxifen; 668 postmenopausal women
Tamoxifen Tamoxifen DES Letrozole Tamoxifen Exemestane Tamoxifen Anastrazole Tamoxifen
20 33 41 32* 21* 41* 17* 21 17
6.7 5.7 4.7 9.4* 6.0* NR NR 11.1* 5.6*
10 9
*P < 0.05; RR, response rate; TTP, time to progression; NR, not reported; DES, diethylstilbesterol.
13 17 16
H. Sanati
130 agent treatments remains a controversial topic in the management of MBC. Combination treatments result in better response rate and better progression-free survival at a cost of increased toxicity.8,32 Combination chemotherapy, however, has not shown a significant improvement in overall survival when compared with single-agent treatments. Women with fast-growing tumors and visceral metastasis are often treated with combination chemotherapy because it is important to achieve disease remission rapidly in this group of patients. Currently there is no “standard” chemotherapy regimen for MBC, and the choice of chemotherapy is individualized based on goals of treatment, prior chemotherapy treatments (including neoadjuvant and adjuvant treatments), patient’s functional status, comorbid conditions, and preferences. Anthracycline-based chemotherapy has been the cornerstone of treatment of MBC.33-40 Doxorubicin and epirubicin are two commonly used antracyline chemotherapy agents for breast cancer. The use of anthracyclines is associated with increased risk of cardiotoxicity, especially with higher cumulative doses. Widespread use of this class of drugs in the adjuvant setting has limited their full potential use in patients with relapsed breast cancer who were previously treated with these agents as a part of neoadjuvant or adjuvant treatments. Use of taxane drugs has emerged as another front-line option for the treatment of MBC.24,25,31,33,41-43 Taxanes are commonly used in patients who have previously received antracycline-based adjuvant chemotherapy. Paclitaxel, docetaxel, and albumin-bound paclitaxel are the taxane drugs that are currently available for the treatment of MBC. All three agents can be given based on a weekly or every 3 week regimen. Paclitaxcel and docetaxel have been compared in an industry-sponsored study.43 In this study, docetaxel was found to have significantly prolonged the time to tumor progression (TTP) and overall survival, but it was associated with increased toxicities. In another phase III study, albuminbound paclitaxel was compared with paclitaxel. Both drugs were given on an every 3 week fashion. Albumin-bound paclitaxel was found to have significantly better response rates and prolonged TTP with less toxicities as compared with paclitaxel.41 Patients who have been pretreated with antracyclines and taxanes are commonly treated other active agents. These active chemotherapy agents include capecitabine, gemcitabine, and vinorelbine. Table 3 summarizes the response rates of these treatments of the use of these agents in the management of MBC.
Targeted Treatments for MBC New agents have been developed over the past two decades that target specific proteins that are responsible for increased tumor growth and proliferation. Her-2 receptor is one of these proteins that belong to the epidermal growth factor (EGFR) family. Presence of Her-2 overexpression has been associated with poor outcome in patients with breast cancer.6 Currently there are two drugs available that target Her-2 receptor: trastuzumab and lapatinib. Trastuzumab is a humanized monoclonal antibody that binds to Her-2, thus in-
Table 3 Response Rates of Single-Agent Chemotherapy for Metastatic Breast Cancer
Drug Doxorubicin Epirubicin Paclitaxel Albumin-bound paclitaxel Docetaxel Vinorelbine Gemcitabine Capecitabine
First- or SecondLine
Treatment After Antracyclines or Taxanes
32–50% 25–68% 19–63% 33–48%
— — — —
39–65% 17–44% 13–41% 20–30%
17% 25–36% 22% 20%
References 33–38 35,37,39,40 31,41,43 41,42 25,29,33,34,43 28,64 26,65 27,66
hibiting activation of the receptor. Trastuzumab has been found to be effective as a single agent44 or combined with chemotherapy for the treatment of MBC in women whose tumors overexpress Her-2.45-48 Trastuzumab is not being used in combination with antracyline agents because of increased risk of cardiotoxicity. Lapatinib is a small-molecule tyrosine kinase inhibitor that binds to Her-2 receptor intercellular domain and deactivated the receptor. Laptinib in combination with capecitabine has been found to be effective in a large phase III trial involving women with Her-2-positive MBC who had been previously treated with an antracycline, a taxane, and trastuzumab.49 Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF). Bevacizumab has shown modest activity as a single agent in MBC.50 Addition of bevacizumab to paclitaxel for front-line treatment of MBC has improved the response rate and progression-free survival in one randomized study.51 Combination of paclitaxel and bevacizumab can be considered in selected patients with MBC. Bevacizumab is not currently FDA-approved to use for breast cancer in the United States.
Management of Bony Metastasis Patients with bone metastasis are often treated with bisphosphonates. Bisphosphonates have been shown to induce apoptosis in breast cancer cell lines in vitro.52,53 There is evidence that treatment with this class of drugs prevents skeletal complications in women with breast cancer who have osteolytic bone involvement.54-58 In addition, bisphosphonate treatments improve pain control related to bone metastasis. Pamidronate and zolendronic acid are the two FDA-approved bisphosphonate drugs that are used in the United States for the management of bony metastatic disease. Treatment with bisphosphonates is associated with osteonecrosis of the jaw, buts its prevalence is considered to be very low.59
Management of Complications of MBC Metastasis to the brain, spinal cord compression, pleural effusion, hypercalcemia, and pancytopenia secondary to bone
Management of metastatic breast cancer marrow infiltration are common complications of MBC. The brain is a common failure site for MBC, especially for patients with Her-2-positive disease.60,61 Radiation treatments to the whole brain are indicated for patients with MBC who develop brain metastasis. Neurosurgical interventions or gamma knife surgery need be considered in patients who have a solitary brain metastasis. Currently, no additional treatments are available for patients who have progression of disease in the brain after radiation treatments, and prognosis for this group of patients remains poor. Preliminary data suggest that lapatinib is effective in reducing the size of the brain lesions in women with Her-2-positive disease who have been previously treated with trastuzumab and cranial radiation.62 Spinal cord compression is another complication of MBC that requires emergent attention. Prompt initiation of steroids and neurosurgical evaluation to decompress and stabilize the spinal cord is necessary. Patients will need radiation treatments to the involved area after surgical interventions. Patients who have extensive metastatic disease in the bone can present with hypercalcemia and/or pancytopenia. Hypercalcemia can occur in more than 10% of patients with MBC.63 Adequate fluid resuscitation followed by intravenous furosemide infusion, bisphosphonates, and calcitonin treatments are initial steps of the managment. Pancytopenia can occur with extensive bone marrow involvement with the metastatic disease. Other causes of pancytopenia need to be evaluated, and often a bone marrow biopsy is needed. Treating the underlaying MBC plays an important role in the management of both hypercalcemia and pancytopena related to MBC. Breast cancer is the second leading cause of malignant pleural effusion. This condition can be very debilitating and affect patient’s performance status or quality of life. Pleural effusion that causes symptoms should be drained promptly. Cytology review of the pleural fluid must be performed to confirm the presence of malignant breast cancer cells. Additional treatments, like placement of drainage catheter or pleudodeisis, should be considered if the fluid accumulates rapidly within 1 to 2 weeks.
Future Directions Optimal management of MBC remains a challenging task. Over the past four decades, significant improvements have been achieved in the treatment of MBC; however, MBC remains an incurable disease. Using combination chemotherapy versus single-agent sequential chemotherapy remains a controversial issue, and future studies are needed to adequately evaluate this topic. New prognostic indicators based on tumor molecular biology are also needed. These prognostic indicators can serve as future targets for treatments. A significant amount of work in this field has been initiated by clinical scientists, and new techniques are being developed to identify molecular markers of response to treatments or poor prognosis. One example is measurement of circulating tumor cells, which has provided promising results to predict response to the treatments. Optimal use of novel targeted agents alone or in combination with current treatments needs to be fully evaluated in the management of MBC. Addition-
131 ally, significant work is needed in the areas of symptom management to further maintain or improve patients’ quality of life.
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40. Mross K, Bohn C, Edler L, et al: Randomized phase II study of singleagent epirubicin ⫹/⫺ verapamil in patients with advanced metastatic breast cancer. An AIO clinical trial. Arbeitsgemeinschaft Internistische Onkologie of the German Cancer Society. Ann Oncol 4:45-50, 1993 41. Gradishar WJ, Tjulandin S, Davidson N, et al: Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 23: 7794-7803, 2005 42. Ibrahim NK, Samuels B, Page R, et al: Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer. J Clin Oncol 23:6019-6026, 2005 43. Jones SE, Erban J, Overmoyer B, et al: Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol 23:5542-5551, 2005 44. Cobleigh MA, Vogel CL, Tripathy D, et al: Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639-2648, 1999 45. Seidman AD, Fornier MN, Esteva FJ, et al: Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 19: 2587-2595, 2001 46. Schaller G, Fuchs I, Gonsch T, et al: Phase II study of capecitabine plus trastuzumab in human epidermal growth factor receptor 2 overexpressing metastatic breast cancer pretreated with anthracyclines or taxanes. J Clin Oncol 25:3246-3250, 2007 47. Pegram MD, Pienkowski T, Northfelt DW, et al: Results of two openlabel, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-positive advanced breast cancer. J Natl Cancer Inst 96:759-769, 2004 48. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001 49. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733-2743, 2006 50. Cobleigh MA, Langmuir VK, Sledge GW, et al: A phase I/II doseescalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol 30:117-124, 2003 (suppl 16) 51. Miller KD, Gralow J, Dickler M, et al: A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100), in 28th Annual San Antonio Breast Cancer Symposium, 2005, Abstract 3 52. Senaratne SG, Pirianov G, Mansi JL, et al: Bisphosphonates induce apoptosis in human breast cancer cell lines. Br J Cancer 82:1459-1468, 2000 53. Fromigue O, Lagneaux L, Body JJ: Bisphosphonates induce breast cancer cell death in vitro. J Bone Miner Res 15:2211-2221, 2000 54. Rosen LS, Gordon D, Kaminski M, et al: Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, doubleblind, comparative trial. Cancer J 7:377-387, 2001 55. Berenson JR, Rosen LS, Howell A, et al: Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer 91: 1191-1200, 2001 56. Lipton A, Small E, Saad F, et al: The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to pamidronate. Cancer Invest 20:45-54, 2002 (suppl 2) 57. Kohno N, Aogi K, Minami H, et al: Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol 23:3314-3321, 2005 58. Pavlakis N, Schmidt R, Stockler M: Bisphosphonates for breast cancer. Cochrane Database Syst Rev 3:CD003474, 2005 59. Murad OM, Arora S, Farag AF, et al: Bisphosphonates and osteonecrosis of the jaw: a retrospective study. Endocr Pract 13:232-238, 2007
Management of metastatic breast cancer 60. Clayton AJ, Danson S, Jolly S, et al: Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer. Br J Cancer 91:639-643, 2004 61. Bendell JC, Domchek SM, Burstein HJ, et al: Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 97:2972-2977, 2003 62. Lin NU, Lin VD, Paul D, et al: EGF105084, a phase II study of lapatinib for brain metastases in patients (pts) with HER2⫹ breast cancer following trastuzumab (H) based systemic therapy and cranial radiotherapy (RT). J Clin Oncol, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 1012
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B
reast cancer is the most commonly diagnosed cancer in women in the United States. An estimated 178,480 new cases of breast cancer in women are expected in the year 2007, and it is estimated that 40,460 women in the U.S. will die of this disease in 2007.1 About 6% of newly diagnosed breast cancer cases present with metastatic disease, and approximately 30% of women diagnosed with earlier stage breast cancer develop metastatic disease.2 Despite recent advances in formulating novel treatments, management of metastatic breast cancer (MBC) continues to be challenging, and MBC remains essentially an incurable disease. Treatment of MBC is individualized for each patient, and it is often based on patient’s preferences, comorbidities, performance status, prognostic factors, menopausal status, and prior history of treatments (including neoadjuvant or adjuDivision of Hematology/Oncology, Department of Medicine, Chao Comprehensive Cancer Center, University of California, Irvine, Orange, CA. Address reprint requests to Homayoon Sanati, Department of Medicine, Division of Hematology/Oncology, Chao Comprehensive Cancer Center, University of California, Irvine, 101 City Drive South, Orange, CA 92868-4061. E-mail: [email protected]
128
1092-4450/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.sembd.2007.10.009
vant treatments).3 The goals of treatment of MBC include disease control, palliation of symptoms, improving or maintaining quality of life, and prolonging overall survival.4 In this paper, we will review various strategies and challenges of the management of MBC.
Risk Assessment The first step in the management of MBC is risk evaluation according to the factors that affect prognosis. These prognostic factors include hormone receptor status, HER-2 expression status, disease-free interval, tumor burden, site of metastasis, and vital organ involvement. Patients with positive estrogen receptor (ER) status are considered to have better prognosis.5 HER-2 receptor overexpression, on the other hand, has been linked to worsen survival.6 Disease-free survival of more than 2 years is considered a good prognostic factor. Patients with limited tumor burden, bone metastasis only, and no vital organ involvement have good prognosis,7 whereas patients with extensive disease, visceral metastasis, or vital organ involvement are considered to have intermedi-
Management of metastatic breast cancer
129
Table 1 Risk Evaluation Based on Prognostic Indicators in Metastatic Breast Cancer Prognostic Factor
Low Risk
Hormone receptor status Her-2 receptor status Disease-free interval Vital organ involvement Viceral Metastasis Only bone metastasis Disease burden
Intermediate/ High Risk
Positive
Negative
Negative More than 2 years No No Yes Limited
Positive Less than 2 years Yes Yes No Extensive
ate or poor prognosis.8 Table 1 summarizes the prognostic characteristics of MBC.
Endocrine Therapy Front-line hormonal treatments are generally offered to patients whose tumors express hormone receptors and have a low risk of developing complications related to the disease. Endocrine treatments are best suited for women with ERpositive tumors who have mostly bone metastasis. Hormonal treatments are sometimes offered to patients with intermediate/high-risk disease who have comorbid conditions and/or poor performance status. These patients are not likely to tolerate cytotoxic chemotherapy treatments. Hormonal treatment approaches depends on the patient’s menopausal status. Historically, premenopausal women with MBC underwent surgical interventions like oophorectemy or radiation treatments to the ovaries to ablate the ovarian function, but over the past 35 years, tamoxifen has become the treatment of choice for hormone-responsive MBC.9,10 Widespread use of tamoxifen in adjuvant setting has created a need for novel strategies. Patients are often diagnosed with metastatic disease while they are taking tamoxifen. Recent development of new agents has shifted the endocrine treatment strategies for MBC. Table 2 summarizes some of the key studies on the endocrine treatment of MBC. Luteinizing hormone-releasing hormone (LHRH) agonists have been used alone or in combination with other endocrine agents in premenopausal women with MBC. LHRH agonists
result in ovarian suppression by interfering with gonadotrophin release, which subsequently lowers estrogen. LHRH agonists have been shown to be as effective as oophorectemy in premenopausal women with MBC.11 Tamoxifen has been used in combination with LHRH agonists, and the combination was found to be more effective than LHRH monotherapy treatments.12 Currently, goserelin given monthly is the only LHRH agonist approved for use in the United States for the treatment of MBC in premenopausal women. Complete estrogen depletion in postmenopausal women can be achieved by blocking aromatase enzyme. A new class of drugs that block aromatase has been developed over the past three decades. Aromatase inhibitors have been found to be effective for front-line treatment of MBC in postmenopausal women.13-17 In a meta-analysis, third-generation aromatase inhibitors (anastrazole, letrozole, and exemestane) have shown to improve survival when compared with tamoxifen in front-line treatment of MBC in postmenopausal women.18 Aromatase inhibitors are not commonly used in premenopausal women because reduced estrogen causes feedback stimulation of hypothalamus and pituitary gland, resulting in increased gonadotriphin secretion. Combination of LHRH agonists and aromatase inhibitors in premenopausal women are currently being studied in premenopausal women with MBC.19 Fulvestrant is another agent which has recently been developed for use in breast cancer. Fulvestrant is an antiestrogen that binds to estrogen receptors, blocks the receptor dimerization, and increases its turnover. Fulvestrant has been found to be effective for the treatment of MBC in tamoxifenresistant patients.20,21 It also has been shown to be effective in patients who had disease progression while they were on an aromatase inhibitor.22,23 Fluvestrant is commonly used as a second- or third-line treatment of hormone-responsive MBC.
Chemotherapy for MBC Systemic chemotherapy remains the most effective treatment for hormone unresponsive MBC.8 Patients with intermediate or high-risk prognostic factors are often treated with systemic chemotherapy. There are a number of chemotherapy agents that are active against breast tumors. These agents include antracyclines, taxanes, alkylating agents, antimetabolites, and vinorelbine.24-31 Using combination versus sequential single-
Table 2 Selected Studies on Front-Line Hormonal Treatment of Metastatic Breast Cancer Study Description
Study Drug
Response Rate (%)
TTP (months)
Reference
Tamoxifen treatments; 156 patients Tamoxifen versus DES; 143 postmenopausal women Letrozole versus Tamoxifen; 916 postmenopausal women Exemestane versus Tamoxifen; 120 postmenopausal women Anastrazole versus Tamoxifen; 668 postmenopausal women
Tamoxifen Tamoxifen DES Letrozole Tamoxifen Exemestane Tamoxifen Anastrazole Tamoxifen
20 33 41 32* 21* 41* 17* 21 17
6.7 5.7 4.7 9.4* 6.0* NR NR 11.1* 5.6*
10 9
*P < 0.05; RR, response rate; TTP, time to progression; NR, not reported; DES, diethylstilbesterol.
13 17 16
H. Sanati
130 agent treatments remains a controversial topic in the management of MBC. Combination treatments result in better response rate and better progression-free survival at a cost of increased toxicity.8,32 Combination chemotherapy, however, has not shown a significant improvement in overall survival when compared with single-agent treatments. Women with fast-growing tumors and visceral metastasis are often treated with combination chemotherapy because it is important to achieve disease remission rapidly in this group of patients. Currently there is no “standard” chemotherapy regimen for MBC, and the choice of chemotherapy is individualized based on goals of treatment, prior chemotherapy treatments (including neoadjuvant and adjuvant treatments), patient’s functional status, comorbid conditions, and preferences. Anthracycline-based chemotherapy has been the cornerstone of treatment of MBC.33-40 Doxorubicin and epirubicin are two commonly used antracyline chemotherapy agents for breast cancer. The use of anthracyclines is associated with increased risk of cardiotoxicity, especially with higher cumulative doses. Widespread use of this class of drugs in the adjuvant setting has limited their full potential use in patients with relapsed breast cancer who were previously treated with these agents as a part of neoadjuvant or adjuvant treatments. Use of taxane drugs has emerged as another front-line option for the treatment of MBC.24,25,31,33,41-43 Taxanes are commonly used in patients who have previously received antracycline-based adjuvant chemotherapy. Paclitaxel, docetaxel, and albumin-bound paclitaxel are the taxane drugs that are currently available for the treatment of MBC. All three agents can be given based on a weekly or every 3 week regimen. Paclitaxcel and docetaxel have been compared in an industry-sponsored study.43 In this study, docetaxel was found to have significantly prolonged the time to tumor progression (TTP) and overall survival, but it was associated with increased toxicities. In another phase III study, albuminbound paclitaxel was compared with paclitaxel. Both drugs were given on an every 3 week fashion. Albumin-bound paclitaxel was found to have significantly better response rates and prolonged TTP with less toxicities as compared with paclitaxel.41 Patients who have been pretreated with antracyclines and taxanes are commonly treated other active agents. These active chemotherapy agents include capecitabine, gemcitabine, and vinorelbine. Table 3 summarizes the response rates of these treatments of the use of these agents in the management of MBC.
Targeted Treatments for MBC New agents have been developed over the past two decades that target specific proteins that are responsible for increased tumor growth and proliferation. Her-2 receptor is one of these proteins that belong to the epidermal growth factor (EGFR) family. Presence of Her-2 overexpression has been associated with poor outcome in patients with breast cancer.6 Currently there are two drugs available that target Her-2 receptor: trastuzumab and lapatinib. Trastuzumab is a humanized monoclonal antibody that binds to Her-2, thus in-
Table 3 Response Rates of Single-Agent Chemotherapy for Metastatic Breast Cancer
Drug Doxorubicin Epirubicin Paclitaxel Albumin-bound paclitaxel Docetaxel Vinorelbine Gemcitabine Capecitabine
First- or SecondLine
Treatment After Antracyclines or Taxanes
32–50% 25–68% 19–63% 33–48%
— — — —
39–65% 17–44% 13–41% 20–30%
17% 25–36% 22% 20%
References 33–38 35,37,39,40 31,41,43 41,42 25,29,33,34,43 28,64 26,65 27,66
hibiting activation of the receptor. Trastuzumab has been found to be effective as a single agent44 or combined with chemotherapy for the treatment of MBC in women whose tumors overexpress Her-2.45-48 Trastuzumab is not being used in combination with antracyline agents because of increased risk of cardiotoxicity. Lapatinib is a small-molecule tyrosine kinase inhibitor that binds to Her-2 receptor intercellular domain and deactivated the receptor. Laptinib in combination with capecitabine has been found to be effective in a large phase III trial involving women with Her-2-positive MBC who had been previously treated with an antracycline, a taxane, and trastuzumab.49 Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF). Bevacizumab has shown modest activity as a single agent in MBC.50 Addition of bevacizumab to paclitaxel for front-line treatment of MBC has improved the response rate and progression-free survival in one randomized study.51 Combination of paclitaxel and bevacizumab can be considered in selected patients with MBC. Bevacizumab is not currently FDA-approved to use for breast cancer in the United States.
Management of Bony Metastasis Patients with bone metastasis are often treated with bisphosphonates. Bisphosphonates have been shown to induce apoptosis in breast cancer cell lines in vitro.52,53 There is evidence that treatment with this class of drugs prevents skeletal complications in women with breast cancer who have osteolytic bone involvement.54-58 In addition, bisphosphonate treatments improve pain control related to bone metastasis. Pamidronate and zolendronic acid are the two FDA-approved bisphosphonate drugs that are used in the United States for the management of bony metastatic disease. Treatment with bisphosphonates is associated with osteonecrosis of the jaw, buts its prevalence is considered to be very low.59
Management of Complications of MBC Metastasis to the brain, spinal cord compression, pleural effusion, hypercalcemia, and pancytopenia secondary to bone
Management of metastatic breast cancer marrow infiltration are common complications of MBC. The brain is a common failure site for MBC, especially for patients with Her-2-positive disease.60,61 Radiation treatments to the whole brain are indicated for patients with MBC who develop brain metastasis. Neurosurgical interventions or gamma knife surgery need be considered in patients who have a solitary brain metastasis. Currently, no additional treatments are available for patients who have progression of disease in the brain after radiation treatments, and prognosis for this group of patients remains poor. Preliminary data suggest that lapatinib is effective in reducing the size of the brain lesions in women with Her-2-positive disease who have been previously treated with trastuzumab and cranial radiation.62 Spinal cord compression is another complication of MBC that requires emergent attention. Prompt initiation of steroids and neurosurgical evaluation to decompress and stabilize the spinal cord is necessary. Patients will need radiation treatments to the involved area after surgical interventions. Patients who have extensive metastatic disease in the bone can present with hypercalcemia and/or pancytopenia. Hypercalcemia can occur in more than 10% of patients with MBC.63 Adequate fluid resuscitation followed by intravenous furosemide infusion, bisphosphonates, and calcitonin treatments are initial steps of the managment. Pancytopenia can occur with extensive bone marrow involvement with the metastatic disease. Other causes of pancytopenia need to be evaluated, and often a bone marrow biopsy is needed. Treating the underlaying MBC plays an important role in the management of both hypercalcemia and pancytopena related to MBC. Breast cancer is the second leading cause of malignant pleural effusion. This condition can be very debilitating and affect patient’s performance status or quality of life. Pleural effusion that causes symptoms should be drained promptly. Cytology review of the pleural fluid must be performed to confirm the presence of malignant breast cancer cells. Additional treatments, like placement of drainage catheter or pleudodeisis, should be considered if the fluid accumulates rapidly within 1 to 2 weeks.
Future Directions Optimal management of MBC remains a challenging task. Over the past four decades, significant improvements have been achieved in the treatment of MBC; however, MBC remains an incurable disease. Using combination chemotherapy versus single-agent sequential chemotherapy remains a controversial issue, and future studies are needed to adequately evaluate this topic. New prognostic indicators based on tumor molecular biology are also needed. These prognostic indicators can serve as future targets for treatments. A significant amount of work in this field has been initiated by clinical scientists, and new techniques are being developed to identify molecular markers of response to treatments or poor prognosis. One example is measurement of circulating tumor cells, which has provided promising results to predict response to the treatments. Optimal use of novel targeted agents alone or in combination with current treatments needs to be fully evaluated in the management of MBC. Addition-
131 ally, significant work is needed in the areas of symptom management to further maintain or improve patients’ quality of life.
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