Targeted Therapy For Metastatic Breast Cancer
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editorials
Dr. Wenzel reports serving on advisory boards for Pfizer and Replidyne and receiving research support from Pfizer. No other potential conflict of interest relevant to this article was reported. From the Department of Internal Medicine, Virginia Commonwealth University, Richmond. 1. National Hospital Discharge Survey: 2002 annual summary with detailed diagnosis and procedure data. Series 13. No. 158. Hyattsville, MD: National Center for Health Statistics, 2005. (DHHS publication no. (PHS) 2005-1729.) 2. National Nosocomial Infections Surveillance System. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control 2004;32:470-85. 3. Pittet D, Tarara D, Wenzel RP. Nosocomial bloodstream infection in critically ill patients: excess length of stay, extra costs, and attributable mortality. JAMA 1994;271:1598-601.
4. Donabedian A. Evaluating the quality of medical care. Mil-
bank Mem Fund Q 1966;44:Suppl:166-206. 5. Haley RW, Culver DH, White JW, et al. The efficacy of infec-
tion surveillance and control programs in preventing nosocomial infections in US hospitals. Am J Epidemiol 1985;121:182-205. 6. Cochrane AL. Effectiveness and efficiency: random reflections on health services. London: Nuffield Provincial Hospitals Trust, 1972. 7. Guidelines for the prevention of intravascular catheter-related infections. MMWR Recomm Rep 2002;51(RR10):1-29. 8. Pronovost P, Needham D, Berenholtz S, et al. An intervention to decrease catheter-related bloodstream infections in the ICU. N Engl J Med 2006;355:2725-32. 9. Roethlisberger FJ, Dickson WJ. Management and the worker: an account of a research program conducted by the Western Electric Company, Hawthorne Works, Chicago. Cambridge, MA: Harvard University Press, 1939. Copyright © 2006 Massachusetts Medical Society.
Targeted Therapy for Metastatic Breast Cancer Hyman B. Muss, M.D. Metastatic breast cancer is incurable, so most oncologists favor sequential chemotherapy with one agent at a time over concurrent therapy with multiple agents.1 The use of single agents on a sequential basis can control the growth of metastases and improve the quality of life without a detrimental effect on survival. This conventional practice is about to change as a result of the development of new targeted agents for cancer.2 These targeted therapies — drugs that are specifically designed to block one or more critical pathways involved in cancer-cell growth and metastases — have led to major advances in the treatment of breast cancer and other malignant conditions. The development of these therapies stems from advances in molecular biology that have permitted the identification of qualitative and quantitative differences in gene expression between cancer cells and normal cells.3 The new agents range from antibodies that form complexes with antigens on the surface of the cancer cell to small molecules that have been engineered to block key enzymatic reactions. The interaction of the antibody or drug with its target inhibits pathways that are essential for cell proliferation or metastasis or activates pathways that culminate in cell death (apoptosis). Since these targets are usually specific for or overexpressed in cancer cells, the new agents generally have fewer side effects than most conventional chemotherapeutic agents, and when the targeted agents are combined with single-agent chemotherapy, toxicity is only minimally increased. Thus, combinations of targeted and conventional chemotherapeutic n engl j med 355;26
agents may improve the response to treatment without a major increase in side effects. The epidermal growth factor receptor stands at the origin of a major signaling pathway involved in the growth of breast cancer.4 Two of the four transmembrane glycoprotein receptors in this pathway, epidermal growth factor receptor type 1 (HER1) and epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu or ErbB2), are promising targets for new treatments. In about 20% of patients with breast cancer, the tumor overexpresses HER2. Trastuzumab, a humanized monoclonal antibody that targets the extracellular domain of HER2, is effective as adjuvant therapy and as treatment for metastatic disease in patients with HER2-positive breast cancer. Lapatinib, an orally administered smallmolecule inhibitor of the tyrosine kinase domains of HER1 and HER2, has antitumor activity when used as a single agent in patients with HER2positive inflammatory breast cancer or HER2-positive breast cancer with central nervous system (CNS) metastases that are refractory to trastuzumab. This finding is important because HER2positive tumors frequently spread to the CNS, where the tumor is sheltered from trastuzumab and most chemotherapeutic agents. In this issue of the Journal, Geyer and colleagues report on a study that expands the indications for lapatinib.5 In their trial, 324 patients with locally advanced or metastatic breast cancer that had progressed after initial chemotherapy plus trastuzumab were randomly assigned to receive treatment with the oral fluorouracil prodrug
www.nejm.org
december 28, 2006
Downloaded from www.nejm.org on November 19, 2009 . Copyright © 2006 Massachusetts Medical Society. All rights reserved.
2783
The
n e w e ng l a n d j o u r na l
capecitabine, either alone or in combination with lapatinib. The primary end point of the trial was the time to progression, defined as the time from randomization to disease progression or death due to breast cancer. The median time to progression was 4.4 months for the group that received capecitabine alone and 8.4 months for the combination-therapy group (hazard ratio for the independently assessed time to progression with combination therapy, 0.49; P<0.001). The combination-therapy group also had a higher tumor response rate (22% vs. 14%, P = 0.09), and fewer patients in this group had CNS metastases (4 vs. 11 patients, P = 0.10). There was no difference in survival between the two groups: 22% of patients had died by the end of the reported study. Side effects were similar in the two groups except for diarrhea, dyspepsia, and rash, which were more common in the combination-therapy group. Adverse events led to the discontinuation of therapy in less than 15% of patients in both groups. Cardiac toxicity, a major side effect of trastuzumab, was minimal in both groups. Other targeted therapies also show great promise in the treatment of breast cancer. Bevacizumab is a monoclonal antibody against the vascular endothelial growth factor. In one study, the combination of bevacizumab and paclitaxel for the treatment of metastatic breast cancer, as compared with paclitaxel alone, significantly improved progression-free survival (11.0 vs. 6.1 months, P<0.001; hazard ratio for disease progression with combination therapy, 0.50) and tumor response (28% vs. 14%, P<0.001).6 Survival data are incomplete. Hypertension, proteinuria, and neuropathy were more frequent in the combination-therapy group. When administered as second-line treatment in patients with metastatic breast cancer, the combination of bevacizumab and capecitabine was associated with a significantly higher tumor response rate than capecitabine alone (20% vs. 9%, P = 0.001), but there was no difference in progression-free or overall survival.7 As compared with most combination-therapy regimens, the combination of lapatinib or bevacizumab with a standard chemotherapeutic agent has been associated with only modest increases in toxicity. Minimizing toxicity while improving response rates and the time to tumor progression will be important if these new combinations of targeted agents and chemotherapeutic agents can prolong survival and convert metastatic breast
2784
n engl j med 355;26
of
m e dic i n e
cancer to a chronic, manageable disease. Currently, the greatest potential for these agents lies in their use as adjuvant therapy, before metastatic disease is evident and when their addition to chemotherapeutic agents may improve the chance for a cure. In two studies, the addition of trastuzumab to adjuvant chemotherapy, as compared with adjuvant chemotherapy alone, reduced the recurrence rate by almost 50%8,9 and reduced breast cancer–specific mortality by 33%.8 Randomized trials now in progress and several in the planning stage will explore the role of lapatinib and bevacizumab as adjuvant therapy. Almost all currently approved targeted agents are used in conjunction with conventional chemotherapy regimens, thereby adding costs to the health care system.10 When the goal is to improve the chance for a cure, these new treatments seem well worth the expenditure. However, when the goal is to improve the quality of life or delay the time to disease progression by several months, as it is with many treatments for metastatic breast cancer, it is less clear whether the health care system can and should bear these expenses. In the current health care environment, not all patients who are likely to benefit from the new treatments have access to them. Government leaders and the public, with guidance from health care professionals, now face hard decisions regarding the use of innovative and expensive treatments for metastatic disease. Before we celebrate the advent of new ways of treating cancer, we must ensure that all who might benefit from these treatments have a chance to receive them. No potential conflict of interest relevant to this article was reported. From the Vermont Cancer Center, University of Vermont College of Medicine, and Fletcher Allen Health Care — all in Burlington, VT. 1. Wood WC, Muss HB, Solin LJ, Olopade OI. Malignant tumors of the breast. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles & practice of oncology. 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2005:1415-77. 2. Sawyers C. Targeted cancer therapy. Nature 2004;432:294-7. 3. Ramaswamy S, Perou CM. DNA microarrays in breast cancer: the promise of personalised medicine. Lancet 2003;361:1576-7. 4. Shtiegman K, Kochupurakkal BS, Ben-Basat Y, Yarden Y. Epidermal growth factor receptor. In: Perry MC, ed. Cancer: genetic aberrations and underlying signal pathways. Alexandria, VA: American Society of Clinical Oncology, 2005:689-707. 5. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:2733-43. 6. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line
www.nejm.org
december 28, 2006
Downloaded from www.nejm.org on November 19, 2009 . Copyright © 2006 Massachusetts Medical Society. All rights reserved.
editorials
therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:Suppl 1:S6. abstract. 7. Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792-9. 8. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus ad-
n engl j med 355;26
juvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673-84. 9. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659-72. 10. Schrag D. The price tag on progress — chemotherapy for colorectal cancer. N Engl J Med 2004;351:317-9. Copyright © 2006 Massachusetts Medical Society.
www.nejm.org
december 28, 2006
Downloaded from www.nejm.org on November 19, 2009 . Copyright © 2006 Massachusetts Medical Society. All rights reserved.
2785
Dr. Wenzel reports serving on advisory boards for Pfizer and Replidyne and receiving research support from Pfizer. No other potential conflict of interest relevant to this article was reported. From the Department of Internal Medicine, Virginia Commonwealth University, Richmond. 1. National Hospital Discharge Survey: 2002 annual summary with detailed diagnosis and procedure data. Series 13. No. 158. Hyattsville, MD: National Center for Health Statistics, 2005. (DHHS publication no. (PHS) 2005-1729.) 2. National Nosocomial Infections Surveillance System. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control 2004;32:470-85. 3. Pittet D, Tarara D, Wenzel RP. Nosocomial bloodstream infection in critically ill patients: excess length of stay, extra costs, and attributable mortality. JAMA 1994;271:1598-601.
4. Donabedian A. Evaluating the quality of medical care. Mil-
bank Mem Fund Q 1966;44:Suppl:166-206. 5. Haley RW, Culver DH, White JW, et al. The efficacy of infec-
tion surveillance and control programs in preventing nosocomial infections in US hospitals. Am J Epidemiol 1985;121:182-205. 6. Cochrane AL. Effectiveness and efficiency: random reflections on health services. London: Nuffield Provincial Hospitals Trust, 1972. 7. Guidelines for the prevention of intravascular catheter-related infections. MMWR Recomm Rep 2002;51(RR10):1-29. 8. Pronovost P, Needham D, Berenholtz S, et al. An intervention to decrease catheter-related bloodstream infections in the ICU. N Engl J Med 2006;355:2725-32. 9. Roethlisberger FJ, Dickson WJ. Management and the worker: an account of a research program conducted by the Western Electric Company, Hawthorne Works, Chicago. Cambridge, MA: Harvard University Press, 1939. Copyright © 2006 Massachusetts Medical Society.
Targeted Therapy for Metastatic Breast Cancer Hyman B. Muss, M.D. Metastatic breast cancer is incurable, so most oncologists favor sequential chemotherapy with one agent at a time over concurrent therapy with multiple agents.1 The use of single agents on a sequential basis can control the growth of metastases and improve the quality of life without a detrimental effect on survival. This conventional practice is about to change as a result of the development of new targeted agents for cancer.2 These targeted therapies — drugs that are specifically designed to block one or more critical pathways involved in cancer-cell growth and metastases — have led to major advances in the treatment of breast cancer and other malignant conditions. The development of these therapies stems from advances in molecular biology that have permitted the identification of qualitative and quantitative differences in gene expression between cancer cells and normal cells.3 The new agents range from antibodies that form complexes with antigens on the surface of the cancer cell to small molecules that have been engineered to block key enzymatic reactions. The interaction of the antibody or drug with its target inhibits pathways that are essential for cell proliferation or metastasis or activates pathways that culminate in cell death (apoptosis). Since these targets are usually specific for or overexpressed in cancer cells, the new agents generally have fewer side effects than most conventional chemotherapeutic agents, and when the targeted agents are combined with single-agent chemotherapy, toxicity is only minimally increased. Thus, combinations of targeted and conventional chemotherapeutic n engl j med 355;26
agents may improve the response to treatment without a major increase in side effects. The epidermal growth factor receptor stands at the origin of a major signaling pathway involved in the growth of breast cancer.4 Two of the four transmembrane glycoprotein receptors in this pathway, epidermal growth factor receptor type 1 (HER1) and epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu or ErbB2), are promising targets for new treatments. In about 20% of patients with breast cancer, the tumor overexpresses HER2. Trastuzumab, a humanized monoclonal antibody that targets the extracellular domain of HER2, is effective as adjuvant therapy and as treatment for metastatic disease in patients with HER2-positive breast cancer. Lapatinib, an orally administered smallmolecule inhibitor of the tyrosine kinase domains of HER1 and HER2, has antitumor activity when used as a single agent in patients with HER2positive inflammatory breast cancer or HER2-positive breast cancer with central nervous system (CNS) metastases that are refractory to trastuzumab. This finding is important because HER2positive tumors frequently spread to the CNS, where the tumor is sheltered from trastuzumab and most chemotherapeutic agents. In this issue of the Journal, Geyer and colleagues report on a study that expands the indications for lapatinib.5 In their trial, 324 patients with locally advanced or metastatic breast cancer that had progressed after initial chemotherapy plus trastuzumab were randomly assigned to receive treatment with the oral fluorouracil prodrug
www.nejm.org
december 28, 2006
Downloaded from www.nejm.org on November 19, 2009 . Copyright © 2006 Massachusetts Medical Society. All rights reserved.
2783
The
n e w e ng l a n d j o u r na l
capecitabine, either alone or in combination with lapatinib. The primary end point of the trial was the time to progression, defined as the time from randomization to disease progression or death due to breast cancer. The median time to progression was 4.4 months for the group that received capecitabine alone and 8.4 months for the combination-therapy group (hazard ratio for the independently assessed time to progression with combination therapy, 0.49; P<0.001). The combination-therapy group also had a higher tumor response rate (22% vs. 14%, P = 0.09), and fewer patients in this group had CNS metastases (4 vs. 11 patients, P = 0.10). There was no difference in survival between the two groups: 22% of patients had died by the end of the reported study. Side effects were similar in the two groups except for diarrhea, dyspepsia, and rash, which were more common in the combination-therapy group. Adverse events led to the discontinuation of therapy in less than 15% of patients in both groups. Cardiac toxicity, a major side effect of trastuzumab, was minimal in both groups. Other targeted therapies also show great promise in the treatment of breast cancer. Bevacizumab is a monoclonal antibody against the vascular endothelial growth factor. In one study, the combination of bevacizumab and paclitaxel for the treatment of metastatic breast cancer, as compared with paclitaxel alone, significantly improved progression-free survival (11.0 vs. 6.1 months, P<0.001; hazard ratio for disease progression with combination therapy, 0.50) and tumor response (28% vs. 14%, P<0.001).6 Survival data are incomplete. Hypertension, proteinuria, and neuropathy were more frequent in the combination-therapy group. When administered as second-line treatment in patients with metastatic breast cancer, the combination of bevacizumab and capecitabine was associated with a significantly higher tumor response rate than capecitabine alone (20% vs. 9%, P = 0.001), but there was no difference in progression-free or overall survival.7 As compared with most combination-therapy regimens, the combination of lapatinib or bevacizumab with a standard chemotherapeutic agent has been associated with only modest increases in toxicity. Minimizing toxicity while improving response rates and the time to tumor progression will be important if these new combinations of targeted agents and chemotherapeutic agents can prolong survival and convert metastatic breast
2784
n engl j med 355;26
of
m e dic i n e
cancer to a chronic, manageable disease. Currently, the greatest potential for these agents lies in their use as adjuvant therapy, before metastatic disease is evident and when their addition to chemotherapeutic agents may improve the chance for a cure. In two studies, the addition of trastuzumab to adjuvant chemotherapy, as compared with adjuvant chemotherapy alone, reduced the recurrence rate by almost 50%8,9 and reduced breast cancer–specific mortality by 33%.8 Randomized trials now in progress and several in the planning stage will explore the role of lapatinib and bevacizumab as adjuvant therapy. Almost all currently approved targeted agents are used in conjunction with conventional chemotherapy regimens, thereby adding costs to the health care system.10 When the goal is to improve the chance for a cure, these new treatments seem well worth the expenditure. However, when the goal is to improve the quality of life or delay the time to disease progression by several months, as it is with many treatments for metastatic breast cancer, it is less clear whether the health care system can and should bear these expenses. In the current health care environment, not all patients who are likely to benefit from the new treatments have access to them. Government leaders and the public, with guidance from health care professionals, now face hard decisions regarding the use of innovative and expensive treatments for metastatic disease. Before we celebrate the advent of new ways of treating cancer, we must ensure that all who might benefit from these treatments have a chance to receive them. No potential conflict of interest relevant to this article was reported. From the Vermont Cancer Center, University of Vermont College of Medicine, and Fletcher Allen Health Care — all in Burlington, VT. 1. Wood WC, Muss HB, Solin LJ, Olopade OI. Malignant tumors of the breast. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles & practice of oncology. 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2005:1415-77. 2. Sawyers C. Targeted cancer therapy. Nature 2004;432:294-7. 3. Ramaswamy S, Perou CM. DNA microarrays in breast cancer: the promise of personalised medicine. Lancet 2003;361:1576-7. 4. Shtiegman K, Kochupurakkal BS, Ben-Basat Y, Yarden Y. Epidermal growth factor receptor. In: Perry MC, ed. Cancer: genetic aberrations and underlying signal pathways. Alexandria, VA: American Society of Clinical Oncology, 2005:689-707. 5. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:2733-43. 6. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line
www.nejm.org
december 28, 2006
Downloaded from www.nejm.org on November 19, 2009 . Copyright © 2006 Massachusetts Medical Society. All rights reserved.
editorials
therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:Suppl 1:S6. abstract. 7. Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792-9. 8. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus ad-
n engl j med 355;26
juvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673-84. 9. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659-72. 10. Schrag D. The price tag on progress — chemotherapy for colorectal cancer. N Engl J Med 2004;351:317-9. Copyright © 2006 Massachusetts Medical Society.
www.nejm.org
december 28, 2006
Downloaded from www.nejm.org on November 19, 2009 . Copyright © 2006 Massachusetts Medical Society. All rights reserved.
2785
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