Treatment of Metastatic Breast Cancer
On a worldwide scale, more than a million new cases of breast cancer occur each year, accompanied by an annual mortality of 370 000.1 Although adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) increases the 10-year survival in early breast cancer by approximately 7% to 11% over that with surgery alone, radiotherapy alone, or both modalities in combination among women under 50 years of age at the time of diagnosis, and by about 2% to 3% for those aged 50 to 69 years,2,3 25% to 40% of patients with breast cancer develop distant metastases,1 which signal incurable disease in which the median survival commonly ranges from 18 to 36 months from the time of diagnosis.2,4 Because of this, the chief goals of treating metastatic breast cancer are control of the disease, relieving its symptoms, improving the patient's quality of life, and prolonging survival.2,4
The past 3 decades have witnessed notable improvement in the management of metastatic breast cancer, with the addition of anthracyclines, cyclophosphamide, taxanes, platinum-containing drugs, and antiestrogenic agents to 5-FU-based regimens. Yet despite gains in the duration of survival after a first recurrence of metastatic breast cancer through the introduction of new hormonal and cytotoxic agents,5 the goal of substantively improving survival in such advanced disease remains elusive. In recent studies, trastuzumab, a humanized monoclonal antibody (MAb) directed at the epidermal growth factor receptor (EGFR) designated human epidermal growth factor receptor 2 (HER2), has produced dramatic improvements in disease-free and overall survival when added to established regimens of adjuvant chemotherapy.6-8 Encouraging effects of the use of trastuzumab in conjunction with established cytotoxic agents including taxanes, vinorelbine, and platinum-containing compounds have supported its promise for improving outcomes in late-stage HER2-positive breast cancer.1,6-10 In metastatic breast cancer that overexpresses HER2, the combination of trastuzumab with chemotherapy has increased response rates and extended survival in comparison with chemotherapy alone.11
One of 4 members of the ErbB family of EGFRs,9 HER2 was identified in 1983. Like the other members of the EGFR family, HER2 initiates its growth-promoting, differentiate, and survival-promoting effects on HER2-bearing cells through autophosphorylation of the receptor's protein tyrosine kinase domain.6 The overexpression of HER2, and the amplification of the gene that encodes the receptor, , have been found in up to 25% of patients with breast cancer and are linked to an increased invasiveness and metastatic behavior of such cancers.6
Directed specifically at the extracellular domain of HER2, trastuzumab was approved in 1998 by the US Food and Drug Administration for use in combination with paclitaxel in the first-line treatment of metastatic breast cancer,8 and became the first targeted agent to be approved for routine use in treating advanced breast cancer.10 It has since proven effective both alone and in combination with other chemotherapeutic agents in the 25% to 30% of breast carcinomas that overexpress protein as detected by fluorescence in situ hybridization, or exhibit amplification of as shown by immunohistochemistry, or show both of these effects.6,10,12
In the decade following its approval in 1993, various clinical studies found a response rate of 11% to 26% with trastuzumab alone in treating metastatic breast cancer in which there was overexpression or amplification of HER2.6 Key phase 2 and 3 trials found trastuzumab effective and safe when used as a single agent in the second-or third-line treatment of breast cancer,13 and combination regimens of trastuzumab with taxanes have been widely examined. These latter combination regimens have been generally effective in improving various clinical outcomes in breast cancer, and the combination of trastuzumab, docetaxel, and platinum-containing drugs has shown a high-level synergistic effect even at low doses.14
In a pivotal phase 3 trial in which anthracycline-naÃ¯ve patients with metastattic HER2-overexpressing breast cancers were treated with the combination of doxorubicin or epirubicin and cyclophosphamide, with or without trastuzumab, and in which patients who had undergone prior anthracycline-based therapy were given paclitaxel with or without trastuzumab, the trastuzumab-treated groups collectively experienced a 7.4-month time to disease progression, as compared with a corresponding 4.6-month period in the chemotherapy-only arms of the study, as well as a 9.1-versus 6.1-month duration of response and a longer median survival of 25.1 versus 20.3 months, respectively, with all of these differences being highly statistically significant.12
Other studies both preceding and following this pivotal phase 3 study have provided compelling evidence that a weekly regimen in which trastuzumab combined with docetaxel is highly active against metastatic breast cancer, yielding response rates of 55% to 75% even among patients with disease that has progressed despite prior treatment, leading to the suggested use of trastuzumab as first-line therapy for this patient population.4 In a recently reported study of 6 cycles of treatment with docetaxel given every 3 weeks, given alone or with trastuzumab administered on a once-weekly schedule, and in which 186 patients received at least 1 dose of trastuzumab, the 2-drug combination produced a response rate of 61% versus 34% for docetaxel alone, with a respective median duration of overall survival of 31.2 versus 22.7 months and median duration of response of 11.7 versus 5.7 months.5,15
Collectively, the combination of trastuzumab with paclitaxel has also proven highly active in HER2-positive metastatic breast cancer, with the ability to reduce tumor size by percentages ranging from 56% to 86% and the capacity to provide 8 to 12 months of survival without disease progression.16
A phase 2 trial compared a regimen of paclitaxel and carboplatin given for 3 weeks of a 4-week cycle, accompanied by trastuzumab given once every 4 weeks, to a regimen of paclitaxel, carboplatin, and trastuzumab given every 21 days to women with metastatic breast cancer showing either grade 3+ overexpression of HER2 or amplification of the gene. Both regimens were highly active, with respective overall response rates of 81% and 65% and median times to survival of more than 39.9 months and more than 23.5 months. However, differences in toxicity, including a 59% versus 88% frequency of grade 3 or 4 neutropenia and 2% versus 19% incidence of neurosensory toxicity, favored the former, 3- per 4-week regimen.16 Other studies of trastuzumab in metastatic breast cancer have also provided promising results for its use in combination regimens involving docetaxel and carboplatin,5 including a high-level synergistic effect in such regimens.13
The efficacy of trastuzumab with docetaxel and carboplatin will be more fully known with completion of phase 3 of the ongoing Breast Cancer International Research Group protocol 007.17 Concurrently, phase 2 studies have reported significant clinical activity of trastuzumab in combination with other drugs.18 Novel targeted agents, including the monoclonal antibody pertuzumab, which binds to another epitope of than does trastuzumab, are now also being evaluated in clinical studies.10
Trastuzumab has been generally well tolerated, with cardiotoxicity its most marked adverse effect. This has been observed in 1.4% of women given trastuzumab as a single agent for metastatic breast cancer,6 but has particularly been observed in combination regimens of trastuzumab with doxorubicin and other anthracyclines.10 Cardiotoxicity of New York Heart Association (NYHA) grades III or IV was found in 27% of patients treated with the combination of an anthracycline, cyclophosphamide, and trastuzumab, as opposed to 8% of patients given only an anthracycline and cyclophosphamide.12 This has led to extensive monitoring of cardiac function in patients treated with trastuzumab10 and to the recommendation that it not be used in conjunction with anthracyclines other than under closely monitored conditions, such as those of clinical trials.5 However, a 65% rate of complete response without cardiotoxicity in a study of trastuzumab given in conjunction with paclitaxel and an epirubicin-based regimen as neoadjuvant therapy for breast cancer has prompted re-examination of the issue of cardiotoxicity with the use of trastuzumab, and this is being examined in a number of studies of its combined use with epirubicin and liposomal doxorubicin.5 Related to this is the question of whether patients susceptible to trastuzumab-associated cardiotoxicity can be identified before being treated.2
Although trastuzumab in combination with chemotherapy now provides significantly better response rates and durations of survival than does chemotherapy alone for metastatic breast cancer, a number of important questions remain to be answered with regard to its use in this setting. One of these, relating to combinations of trastuzumab with docetaxel or paclitaxel, and important because of the taxanes' wide use in metastatic disease, is whether 1 of these 2 taxanes is superior to the other. A further question is whether greater efficacy can be achieved with a weekly or a 3-weekly dosing schedule of these 2 taxanes. It has been suggested that paclitaxel is more efficient on a weekly than on a 3-weekly schedule, whereas docetaxel on a weekly schedule produces unacceptable toxicity.2,5,16 A further question has to do with the comparative benefit achieved with trastuzumab given concurrently with as opposed to sequentially after taxane-based and other chemotherapeutic regimens.5 Two other issues, important both clinically and from the fiscal standpoint, are whether to continue trastuzumab in the face of breast cancer that progresses despite its use, and if so, for how long.2
With progress in the endocrine therapy of estrogen- and progesterone-positive breast cancer, including progress made with tamoxifen and the more recent advent of the aromatase inhibitors, treatment-induced resistance to these agents has become an important question.1
As new and increasingly sensitive imaging techniques promise major improvements in the detection and staging of breast cancer, and as microarray techniques for profiling gene expression herald further improvements, selecting the optimal treatment regimens for specific patients with breast cancer will become critical. Further study will be needed to clarify all of these findings. As matters now stand, trastuzumab represents a major contribution to the treatment of metastatic breast cancer and is likely to remain a model for new treatment agents.
While endocrine manipulation is the preferred technique for managing hormone-receptor-positive breast cancer that has not invaded the viscera,1 chemotherapy is the treatment of choice for steroid-receptor-negative breast cancer, and regimens combining different chemotherapeutic agents have proven more effective than treatment with a single agent.1 Primary chemotherapy is increasingly used in treating operable or locally advanced breast cancer, with growing rates of breast-conserving surgery and significantly better long-term outcomes among patients who achieve a histopathologically confirmed complete response to therapy.1
Adjuvant chemotherapeutic regimens based on cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) were introduced to the management of breast cancer in the 1960s and 1970s.19 Data reported in 1998 by the Early Breast Cancer Trialists Collaborative Group indicated that combination chemotherapy containing an anthracycline was more effective as adjuvant therapy than the CMF regimen alone, yielding a 5-year survival of 72% versus 69% for the older regimen, 2 and regimens containing anthracyclines have proven superior to the original CMF combination.19
Originally used to treat lymph node-positive breast cancer in younger women, adjuvant combination chemotherapy is increasingly used in node-negative disease, particularly for steroid hormone-receptor-negative tumors and for older women, and has been shown to improve cure rates among women at risk of disease recurrence, with improvements in both disease-free and overall survival.3 Adjuvant regimens currently in use call for 5-FU with doxorubicin and cyclophosphamide, 5-FU with epirubicin and cyclophosphamide, or an anthracycline followed by CMF.1 In early breast cancer, adjuvant chemotherapy with anthracycline- or CMF-based combination regimens yields a gain of about 7% to 11% in 10-year survival for women younger than 50 years of age, and of about 2% to 3% for those aged 50 to 69.2,3 The introduction of taxanes has made a further contribution to adjuvant chemotherapy, with the addition of 4 cycles of paclitaxel following 4 cycles of doxorubicin and cyclophosphamide found to reduce the risk of disease recurrence by 17% with manageable toxicity.20,21
Among the phenotypes of breast carcinoma are tumors that show overexpression or amplification of HER2, 1 of the 4 members of the ErbB family of EGFRs.22
Representing as many as a quarter of carcinomas of the breast, tumors that overexpress HER2 and show amplification of the gene that encodes this protein, , tend to be poorly differentiated and to show other features associated with a greater probability of disease recurrence and death, including a high rate of cell proliferation, increased invasiveness and metastatic behavior, and a lower likelihood of expressing estrogen or progesterone receptors.6
In recent studies, trastuzumab has produced dramatic improvements in disease-free and overall survival when added to established regimens of adjuvant chemotherapy for breast cancer.6-8 In 4 major recent studies of its use in such therapy, it has produced highly positive results, with significant reductions in disease recurrence reported after follow-up periods ranging to 3 years.6 Exemplifying this were the findings in one of these 4 major studies, the Herceptin Adjuvant trial. In this phase 3 study, in which 1694 women were randomly assigned to 4 courses of adjuvant or neoadjuvant therapy with trastuzumab and 1693 women were allocated to observation alone, treatment with trastuzumab reduced the hazard ratio for disease recurrence to 0.54 and produced an 8.4% gain in disease-free survival at 2 years versus observation alone. These gains compare highly favorably with the 2% to 6% gains in disease-free survival and other treatment end points seen at 3 years of follow-up in recent phase 3 trials of other adjuvant chemotherapeutic regimens for breast cancer.6,9 A cumulative analysis of the data from 2 more of the 4 major trials of trastuzumab in adjuvant therapy, National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 and North Central Treatment Group (NCTG) trial N9831, found that adding it to chemotherapy produced an absolute gain of 12% in disease-free survival and 33% lower risk of death at 3 years, and suggested that its use directly after surgery may be highly effective in preventing disease recurrence.6,8 The projected absolute benefit from the addition of trastuzumab in both of these trials is projected to be 18% at 4 years of follow-up, surpassing all of the benefits reported with other regimens.8
Perhaps most remarkably, the NSABP B-31 and NCTG N9831 trials failed to find, in their trastuzumab-containing treatment arms, the peak in breast cancer recurrence that is typically seen during the first 3 years after adjuvant therapy, and which was seen in the control arms of these 2 trials.6 These findings suggest that trastuzumab may intrinsically affect the behavior of HER2- positive breast cancers, and may even be able to cure such disease.6 On the basis of the findings in studies so far conducted, the combination of trastuzumab with chemotherapy has been called significantly superior to chemotherapy alone in the adjuvant treatment of HER2-positive tumors, both in terms of response rates and survival.1
Clinically, the greatest level of synergy in combination regimens involving trastuzumab has been found for its use in conjunction with docetaxel and platinum-containing drugs.14 Trastuzumab has also been successfully used in combination with gemcitabine and capecitabine.22 An in vitro study reported synergistic interactions of trastuzumab with docetaxel, carboplatin, 4-hydroxycyclophosphamide, and vinorelbine in 4 HER2-overexpresssing lines of breast cancer cells, and found additive effects for trastuzumab with doxorubicin, epirubicin, and paclitaxel.23
Despite the positive findings with trastuzumab in adjuvant therapy, several important issues in its adjuvant use remain to be resolved. Although trastuzumab has been reported to be generally well tolerated, with hypersensitivity typically occurring soon after its administration22 and rare instances of interstitial pneumonitis,8 cardiotoxicity, which was an unexpected finding in the phase 2 trials of trastuzumab,22 has continued to be reported as a troublesome effect of its use. This was seen in 0.5% of the women treated with trastuzumab in the Herceptin Adjuvant Breast Cancer Trial (HERA),9 while the combined analysis of data from the NSABP B-31 and NCTG N9831 trials found a cumulative incidence of congestive heart failure of NYHA grades III or IV and death of cardiac origin in 4.1% of trastuzumab-treated patients as opposed to 0.8% of patients in the control arms of these studies.8 This has led to a call for careful patient selection and cardiac monitoring of patients chosen for adjuvant therapy with trastuzumab.8 In response to reports of increased toxicity with the use of trastuzumab in conjunction with anthracyclines,2,18 studies have continued to examine its effects in such regimens.22 Interim data from a recent German study of its use in metastatic breast cancer have indicated that trastuzumab can be combined with epirubicin and cyclophosphamide with a low risk of cardiac toxicity.24
Another issue in the use of trastuzumab has been the occurrence of disease metastatic to the central nervous system in conjunction with its use. A study published in 2003 reported such disease in a third of patients treated with trastuzumab for breast cancer that had spread systemically.25 Longer follow-up and greater study will be needed to determine whether this is due to the aggressiveness of particular cancers or possibly inadequate penetration of trastuzumab into the central nervous system.22
An added issue in the adjuvant use of trastuzumab has been the scheduling of its administration. In NSABP B-31, paclitaxel was given in a 3-weekly schedule, with trastuzumab begun concurrently with the first dose of paclitaxel. In NCTG N9831, treatment was given in a weekly cycle and trastuzumab was begun after paclitaxel in one arm of the study and concurrently with paclitaxel in another.8 These differences in treatment regimen and scheduling, and differences in lymph node involvement and other patient variables, complicate the question of whether the simultaneous or sequential use of trastuzumab is preferable in adjuvant regimens involving its combination with other drugs, and will require further study.6
Ongoing studies of trastuzumab in the adjuvant treatment of breast cancer are largely investigating its effects when given over a period of 1 year. However, its use in a 2-year regimen is being examined in an arm of the HERA study. This has raised the question of whether an even longer period of adjuvant treatment with trastuzumab should be investigated because of the gains in outcome found with 5 years as opposed to 1 year of treatment of hormone-receptor-positive breast cancer with tamoxifen.3,22 Examining the relationship between disease recurrence and 1 year versus 2 years of adjuvant therapy with trastuzumab-containing regimens in more than 5000 patients in 39 nations, investigators in the HERA trial have found a 46% lower risk of recurrence with 1 year of such therapy as compared with observation alone, and are expected to report the results for 2 years of treatment by 2008.9
Eur J Nucl Med
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