HER-2-Positive Metastatic Breast Cancer: Optimizing Trastuzumab-Based Therapy

Transcription

1 HER-2-Positive Metastatic Breast Cancer: Optimizing Trastuzumab-Based Therapy Christian Jackisch Department of Gynecology and Obstetrics, Klinikum Offenbach, Offenbach, Germany Key Words. Trastuzumab Metastatic breast cancer Combination therapy Treatment beyond disease progression Abstract Trastuzumab with a taxane as first-line therapy is now the standard of care for patients with human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer (MBC). The search for additional and more effective trastuzumab-based therapies continues. Novel combinations of trastuzumab with chemotherapeutic agents, including vinorelbine, gemcitabine, and capecitabine, and hormonal therapy agents, such as tamoxifen and aromatase inhibitors, are currently under investigation in clinical trials. Available data suggest these combinations will provide additional treatment options that may ultimately lead to better outcomes for patients with HER-2-positive MBC. Evidence is growing for the use of trastuzumab treatment beyond disease progression and retreatment after (neo)adjuvant relapse is being explored to assist in clinical decision making. Already, the use of trastuzumab in the metastatic setting has changed HER-2-positive status from a marker of poor prognosis to one of better overall outcome, and ongoing studies should expand further the treatment options for patients with HER-2-positive MBC. The Oncologist 2006;11(suppl 1):34 41 Introduction Human epidermal growth factor receptor 2 (HER-2) is a transmembrane receptor tyrosine kinase with a key role in normal cell growth and differentiation. Overexpression of HER-2, usually as a result of her-2 gene amplification, can result in malignant transformation of cells and is seen in tumor tissue in up to 30% of patients with metastatic breast cancer (MBC) [1 5]. HER-2 overexpression is usually associated with a more aggressive tumor phenotype, and women with HER-2-positive disease have a poor overall prognosis and faster relapse times at all stages of cancer development [1, 6, 7]. The advent of trastuzumab (Herceptin ; F. Hoffmann- La Roche, Basel, Switzerland), a humanized monoclonal antibody against the extracellular domain of HER-2, represented a major breakthrough in the treatment of women with HER-2-positive MBC. Pivotal trials of trastuzumab alone or in combination with taxanes have resulted in Correspondence: Christian Jackisch, M.D., Klinikum Offenbach GmbH, Department of Gynecology and Obstetrics, Starkenburgring 66, D Offenbach, Germany. Telephone: ; Fax: ; christian.jackisch@klinikumoffenbach.de Received June 12, 2006; accepted for publication June 21, AlphaMed Press /2006/$20.00/0 The Oncologist 2006;11(suppl 1): significant clinical benefit [8 11], and trastuzumab plus taxanes as first-line therapy is now the standard of care for patients with HER-2-positive disease. In order to further improve patient care, the search for even more effective trastuzumab-based therapies continues in preclinical research and within clinical trials. Pivotal Trastuzumab Trials in MBC The pivotal randomized combination trials of trastuzumab (H0648g and M77001) demonstrated that trastuzumab plus a taxane is associated with a clinical benefit that is superior to that of a taxane alone [9, 11]. Four hundred sixty-nine HER-2-positive MBC patients who had not received prior treatment for advanced disease were enrolled in the H0648g trial. Patients who had previously received anthracyclines in the adjuvant setting or who were not suitable to receive anthracyclines (n = 188) were randomized to receive paclitaxel with or without

2 Jackisch 35 trastuzumab. All other patients (n = 281) were randomized to receive an anthracycline plus cyclophosphamide with or without trastuzumab. The combination of trastuzumab with paclitaxel or with an anthracycline plus cyclophosphamide improved all clinical end points over paclitaxel or an anthracycline plus cyclophosphamide alone (median follow-up, 30 months). The overall survival duration was longer (22.1 vs months) with trastuzumab plus paclitaxel and with trastuzumab plus an anthracycline plus cyclophosphamide (26.8 vs months ) [9]. Despite these improvements in survival, the number of cardiac events reported in that trial was higher than anticipated from initial clinical data. A retrospective analysis revealed that trastuzumab-associated cardiac events mainly occurred with concomitant use of anthracyclines. Of patients receiving trastuzumab plus an anthracycline plus cyclophosphamide, 28% experienced a cardiac event, compared with only 9.6% receiving an anthracycline plus cyclophosphamide alone [12]. As a result of this finding, the combination of trastuzumab with an anthracycline plus cyclophosphamide is not currently indicated for clinical use. Of patients receiving trastuzumab plus paclitaxel, 13% experienced a cardiac event, compared with 1% receiving paclitaxel alone. This combination is now indicated for use in a number of countries worldwide. In the pivotal trial, trastuzumab plus paclitaxel resulted in a higher objective response rate, 49% versus 17%, and longer time to progression (TTP) and response duration (RD), 6.9 versus 3.0 months and 10.5 versus 4.5 months, respectively [9]. Notably, a subset analysis revealed that trastuzumab plus paclitaxel improved outcomes in patients with immunohistochemistry (IHC) 3+ disease relative to the overall patient population (IHC 2+ and 3+). The median survival time in patients with IHC 3+ disease was 18 months without trastuzumab and 25 months with trastuzumab [13]. The M77001 trial investigated the combination of standard weekly trastuzumab plus weekly or 3-weekly docetaxel in 188 patients with previously untreated MBC. At a 24-month follow-up, the median overall survival time was 22.7 months with docetaxel alone and 31.2 months with trastuzumab plus docetaxel (p =.0062), despite a 57% documented crossover. All clinical outcomes investigated, including the median RD (11.4 vs. 5.1 months) and median TTP (10.6 vs. 5.7 months), were superior for trastuzumab plus docetaxel versus docetaxel alone. Only one patient receiving trastuzumab plus docetaxel experienced symptomatic heart failure (1%). Another patient experienced symptomatic heart failure 5 months after discontinuation of trastuzumab because of disease progression and following treatment with an investigational anthracycline for 4 months [11]. Both pivotal trials demonstrated a favorable safety profile for the combination of trastuzumab with a taxane. The addition of trastuzumab did not significantly add to the toxicity profile of taxanes alone. Novel Trastuzumab Chemotherapy Combinations There is continuing interest in new trastuzumab chemotherapy combinations, arising from the ongoing aim of improving treatment efficacy. Also, taxanes are increasingly being used in the adjuvant setting, and trastuzumab-based treatment options are needed for patients with MBC who are not candidates for taxane-containing regimens. Combinations of trastuzumab (standard schedule, 4 mg/kg loading dose followed by 2 mg/kg weekly) with agents such as vinorelbine, gemcitabine, and capecitabine have been investigated with encouraging results. Trastuzumab has also been investigated with chemotherapy combinations, including capecitabine and docetaxel, and taxanes and platinum agents. Trastuzumab Plus Vinorelbine Phase II trials of trastuzumab plus vinorelbine as first- or subsequent-line therapy indicate that this combination is highly active in the treatment of MBC, with response rates in the range of 43% 85% (Fig. 1) [14 22]. In general, firstline therapy produced higher response rates. One singlecenter study allowed more direct comparison of first-line (84% response rate, 34 weeks TTP) and second- or thirdline therapy (67% and 16 weeks, respectively) [16], indicating that first-line therapy with this combination may be more effective than later treatment. The combination of trastuzumab with vinorelbine was well tolerated in all of these trials. There was no evidence that this combination resulted in more cardiac events compared with trastuzumab alone. For example, in the aforementioned single-center Figure 1. Summary of response rates in phase II trials of trastuzumab plus vinorelbine as first- or subsequent-line therapy in patients with metastatic breast cancer [14 22].

3 36 Trastuzumab in HER-2 + Metastatic Breast Cancer study, only three of 40 patients experienced grade 2 cardiac toxicity (>20% decline in left ventricular ejection fraction [LVEF] or to <50%) and no patients had symptomatic heart failure [16]. Trastuzumab Plus Gemcitabine The combination of trastuzumab with gemcitabine in patients with HER-2-positive MBC has also been reported as effective and well tolerated. In a study conducted by the Hellenic Cooperative Oncology Group (HeCOG) [23], 28 patients with HER-2-positive disease received trastuzumab plus gemcitabine (1,000 mg/m 2 on days 1, 8, and 15) as salvage treatment after failure of prior chemotherapy with at least one taxane- and/or anthracycline-containing regimen. The overall response rate was 36%, median TTP was 7.8 months, and median overall survival time was 18.7 months (median follow-up, 17.2 months). Similarly, in a phase II study of trastuzumab plus gemcitabine (1,200 mg/m 2 on days 1 and 8 every 3 weeks) in MBC patients who had previously received a taxane- and/or anthracycline-containing regimen, the overall response rate in evaluable patients (n = 61) was 38%. The median RD was 5.8 months, median overall survival time was 14.7 months, and median TTP was 5.8 months. These data support the suggestion of additive antitumor activity between gemcitabine and trastuzumab. Moreover, the combination of trastuzumab plus gemcitabine was well tolerated, with no cases of congestive heart failure [24]. Trastuzumab Plus Capecitabine Early experiments investigating the combination of trastuzumab with 5-fluorouracil found that this combination was less effective than either drug alone, suggesting an antagonism in vitro [25]. However, further studies indicated that trastuzumab and the 5-fluorouracil prodrug capecitabine had at least additive antitumor activity in human breast cancer models [26], and this has been supported by recent studies in the clinical setting. In a multicenter phase II study of weekly trastuzumab with capecitabine (1,250 mg/m 2 twice a day [bid] on days 1 14, 3-weekly) in patients with pretreated MBC (n = 27), the objective response rate was 60% (four complete responses, eight partial responses; n = 20), median progression-free survival time was 28 weeks, and median overall survival time was 90 weeks [27]. This high response rate was mirrored in a phase II study of firstline trastuzumab capecitabine therapy (capecitabine, 1,250 mg/m 2 bid on days 1 14, 3-weekly), in which an objective response rate of 76% (five complete responses, 14 partial responses; n = 19) was recorded [28]. In both phase II studies, the combination of trastuzumab plus capecitabine was generally well tolerated. There was no evidence of greater cardiotoxicity with this combination. As recent studies have shown a survival benefit for trastuzumab plus docetaxel [11], and also for docetaxel plus capecitabine [29], there is a clear rationale for exploring the combination of trastuzumab plus docetaxel and capecitabine. A randomized trial of trastuzumab plus docetaxel with or without capecitabine in patients with HER-2-positive metastatic or locally advanced breast cancer (Capecitabine, Herceptin, and Taxotere [CHAT]) is currently in progress. An interim safety analysis of CHAT (n = 110) reported a congestive heart failure incidence of 2% [30], which is the same as that reported in recent trials of trastuzumab plus docetaxel [11]. The rate of complicated neutropenia (26%) was also comparable with that seen in previous trials of trastuzumab docetaxel or docetaxel capecitabine combination therapy [11, 29]. As of November, 2005, recruitment to CHAT was complete, with 225 patients enrolled, and efficacy results are awaited. Triple-Combination Regimens CHAT is not the only study to investigate trastuzumab as part of a triple-combination regimen. Several studies have shown that triple combinations are effective and produce high response rates (Table 1) [31 37]. For example, in a large randomized trial of first-line trastuzumab plus paclitaxel with or without carboplatin in patients with HER-2-positive MBC (n = 196), patients who received the triple combination had better outcomes than those who received trastuzumab and paclitaxel only (objective response rate, 52% vs. 36%; median TTP, 10.7 vs. 7.0 months; median survival, 36 vs. 32 months, respectively) [33]. Studies have shown that triple combinations of chemotherapeutic agents are generally feasible if overlapping toxicity profiles are avoided. Trastuzumab Anthracycline Combinations Anthracyclines are a mainstay of therapy for patients with MBC; therefore, combination with trastuzumab is an area of active investigation. The significant benefit of adding trastuzumab to an anthracycline (mainly doxorubicin) and cyclophosphamide was clearly demonstrated in the pivotal trastuzumab combination trial (H0648g) [9, 13], despite a higher rate of cardiac events with this combination [12]. For this reason, several studies are examining the cardiac safety of trastuzumab combined with anthracyclines less cardiotoxic than doxorubicin, such as epirubicin or liposomal formulations of doxorubicin. Initial analyses of the Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) trial, a multicenter phase I II trial of trastuzumab plus epirubicin cyclophosphamide (EC) versus EC alone as first-line therapy for MBC, indicate that, because of its lower potential for cardiotoxic events compared with an anthracycline cyclophosphamide The Oncologist

4 Jackisch 37 Table 1. Trastuzumab-based triple combinations Study Regimen n ORR (%) Yardley et al. [36] Carboplatin/paclitaxel Perez et al. [32] Robert et al. [33] Carboplatin/paclitaxel weekly Carboplatin/paclitaxel 3-weekly Carboplatin/paclitaxel Paclitaxel Pegram et al. [31] Cisplatin/docetaxel Pegram et al. [31] Carboplatin/paclitaxel Venturini et al. [37] Epirubicin/docetaxel Miller et al. [34] Gemcitabine/paclitaxel Yardley et al. [35] Vinorelbine/docetaxel Abbreviation: ORR, objective response rate combination, it is feasible to combine trastuzumab with EC [38]. In phase I of this trial, patients with HER-2-positive disease initially received trastuzumab plus 60 mg/m 2 epirubicin (EC60; n = 26). Once it was established that this regimen was not associated with any dose-limiting toxicity, phase II of the trial was initiated. Patients with HER-2-positive disease were then enrolled into an arm of trastuzumab plus 90 mg/m 2 epirubicin (EC90; n = 25) and HER-2-negative patients received EC90 alone (n = 24). Both trastuzumab-containing arms met the criteria for acceptable tolerability, with only three patients experiencing a cardiac event: asymptomatic decline in LVEF to <50% in one patient receiving trastuzumab plus EC60 and congestive heart failure in two patients receiving trastuzumab plus EC90. One patient in the EC90-alone arm experienced arrhythmia/ tachycardia. Response rates were 62% for trastuzumab plus EC60 and 64% for trastuzumab plus EC90. This compared favorably with a response rate of 26% in patients with HER- 2-negative disease treated with EC90 alone [38]. In the M77035 trial, the efficacy and safety of combining trastuzumab with the liposomal doxorubicin TLC D-99 (Myocet ; Elan Pharmaceuticals, Princeton, NJ) was investigated [39]. By formulating doxorubicin within a liposome, exposure of normal cells to the cytotoxic agent is minimized, resulting in fewer cardiac events. The triple combination of trastuzumab plus paclitaxel (80 mg/m 2, weekly) plus TLC D-99 (50 mg/m 2, 3-weekly) was generally well tolerated. Two cases of cardiac insufficiency were reported but were not related to study treatment. The combination was also highly active, as evidenced by an objective response rate of 93% in 54 evaluable patients [39]. Trastuzumab in Combination with Hormonal Therapy In estrogen receptor (ER)-positive patient populations, the rate of HER-2 positivity is 11% 35% [40 42]. In the trastuzumab pivotal trials, approximately 50% of patients with HER-2-positive metastatic disease were also ER positive [43]. Together, these data show that ER/HER- 2-copositive disease is common, and it is of interest to explore specific treatment options for these patients. In the pivotal trials, hormone-receptor status did not affect the efficacy of trastuzumab given as a single agent or combined with chemotherapy [8 11, 44], indicating that trastuzumab is equally effective in ER-negative and ERpositive disease (Fig. 2). Resistance to hormonal therapy, particularly tamoxifen, appears to be a characteristic of ER-positive, HER-2- positive tumors [45], and it has been hypothesized that the addition of trastuzumab to hormonal therapy may overcome Figure 2. Objective response rates with trastuzumab in patients with human epidermal growth factor receptor 2- positive and estrogen receptor (ER)-positive or ER-negative disease [8 10]. Abbreviation: HR, hormone receptor. From Brufsky A, Lembersky B, Schiffman K et al. Hormone receptor status does not affect the clinical benefit of trastuzumab therapy for patients with metastatic breast cancer. Clin Breast Cancer 2005;6: , with permission from Cancer Information Group, copyright

5 38 Trastuzumab in HER-2 + Metastatic Breast Cancer this relative resistance. In preclinical studies, the combination of tamoxifen with anti-her-2 antibodies was shown to produce a greater inhibitory effect on cell growth than either agent alone [46, 47]. There is also some evidence that, compared with tamoxifen, aromatase inhibitors may elicit a greater response in HER-2-positive tumors [48]. Taken together, these findings provide a clear rationale for combining trastuzumab with hormonal agents in patients with HER-2/ER-copositive MBC. Several clinical trials of trastuzumab plus hormonal therapy as first- or subsequent-line therapy in patients with HER-2-positive, ER-positive, metastatic or locally advanced breast cancer are planned or ongoing. Two important phase III randomized trials are nearing completion: first-line trastuzumab with or without letrozole and first-line trastuzumab with or without anastrozole (TrAstuzumab in Dual HER2 ER-Positive Metastatic breast cancer [TAnDEM]). Recruitment to the TAnDEM trial was completed in May of 2004, and results are expected toward the end of It is anticipated that the results of these trials will help establish the role of trastuzumab in this specific population. Trastuzumab Use Beyond Disease Progression in MBC The potential benefit of continuing trastuzumab treatment beyond disease progression with a new chemotherapy partner is a topic of considerable interest in clinical practice. To date, no results from randomized trials have been published; however, preclinical observations and a range of clinical data provide some evidence to support the concept of treatment beyond progression. In preclinical studies using HER-2-positive human xenograft models, tumor regrowth was observed if levels of trastuzumab monotherapy were not sustained [49]. Also, continuous administration of trastuzumab in combination with a taxane after progression on trastuzumab monotherapy was shown to potentiate the antitumor activity of taxanes even after trastuzumab monotherapy was no longer effective (Fig. 3) [50]. Clinical evidence for trastuzumab treatment beyond progression was provided by the H0659g trial, an extension of the pivotal phase III H0648g trial, in which patients were given the opportunity to continue trastuzumab at the time of disease progression, either alone at a higher dose or with a new chemotherapy partner. Prolonged use of trastuzumab was safe and well tolerated and did not appear to increase the risk of cardiac dysfunction. The efficacy of trastuzumab treatment beyond progression was also encouraging, with an objective response rate of 11% and median RD of 6.7 months [51]. Follow-up of patients who progressed on trastuzumab plus docetaxel in a phase II MBC trial reported a median postprogression survival time of 20 months for six patients who continued trastuzumab treatment beyond progression [52], and results from several retrospective analyses of case series also indicate that patients continue to derive benefit from trastuzumab after disease progression [53 55]. In a retrospective analysis of patients with HER-2 positive MBC, objective response rates and TTP were maintained in patients receiving two or more trastuzumab-based regimens (Table 2) [53]. One large randomized trial investigating trastuzumab treatment beyond progression is currently under way: MO17038, a phase III study of trastuzumab plus capecitabine compared with capecitabine alone in women with HER-2-positive MBC progressing after trastuzumab in combination with a taxane or other chemotherapy. Retreatment with Trastuzumab After Relapse Following (Neo)adjuvant Trastuzumab Results from four large-scale global trials have demonstrated that adjuvant trastuzumab reduces the risk of disease recurrence by approximately 50% [56 58]. Further to this, the joint analysis of two of these trials demonstrated a signif- Figure 3. Addition of trastuzumab to paclitaxel in the human breast cancer xenograft model KPL-4 progressing on trastuzumab monotherapy [50]. Table 2. Response rates and time to progression in metastatic breast cancer patients who received one, two, or more than two trastuzumab-based regimens [53] Trastuzumab treatment Objective response (%) TTP (95% CI), mos First (n = 54) ( ) Second (n = 54) ( ) Beyond second (n = 33) 30 6 ( ) Abbreviations: TTP, time to progression; CI, confidence interval. The Oncologist

6 Jackisch 39 icant survival benefit when patients received a total of 1 year of trastuzumab [57]. Based on these groundbreaking results, the use of trastuzumab in the adjuvant setting is becoming standard clinical practice. There is, therefore, a need to determine the optimal treatment regimen for those patients who relapse after adjuvant trastuzumab. The Retreatment after HErceptin Adjuvant (RHEA) retreatment trial is a phase II study of trastuzumab with or without a taxane for the firstline treatment of HER-2-positive MBC in women who have relapsed after (neo)adjuvant treatment with trastuzumab. It is anticipated that data from that trial will provide guidance on how best to treat this important subgroup of patients. Conclusions The combination of trastuzumab with chemotherapy is now standard for the first-line treatment of women with HER- 2-positive MBC. The use of trastuzumab in the metastatic setting has changed HER-2-positive status from a marker of poor prognosis to one of better overall outcome. In a phase II trial of vinorelbine with or without trastuzumab according to HER-2 expression, women with HER-2-positive disease treated with vinorelbine plus trastuzumab had a better prognosis than patients with HER-2-negative disease treated with vinorelbine alone, thus suggesting that trastuzumab can change the natural history of HER-2 positive disease [22]. Novel trastuzumab-containing combinations with additive or even synergistic effects are of great interest, and several are being studied in ongoing clinical trials. Trastuzumab combined with cytotoxic agents such as taxanes, vinorelbine, gemcitabine, and capecitabine has been shown to produce superior response rates, TTP, and overall survival times in patients with MBC, and triplet combinations have the potential to offer additional benefit. Moreover, trastuzumab can be combined with a wide range of chemotherapy regimens while adding little to the toxicity profile of chemotherapy. Cardiac events can occur during trastuzumab treatment but are generally reversible and manageable. However, combinations with anthracyclines are not recommended outside clinical trials and combinations with less cardiotoxic anthracyclines are currently under investigation. HER-2/ER-copositive disease is common: up to 25% of ER-positive tumors are also HER-2 positive. In this population, the combination of trastuzumab with hormonal therapies such as tamoxifen, exemestane, anastrozole, and letrozole is under investigation, and the results from several large clinical trials are eagerly anticipated. Trials of trastuzumab treatment beyond disease progression and retreatment after (neo)adjuvant relapse are also under way, and it is hoped that data from those trials will provide further guidance for clinical practice. The number of trastuzumab-based treatment options in clinical practice is steadily increasing with each new clinical trial. Trastuzumab has become the foundation of care in HER-2-positive disease, and ongoing studies seek to provide further improvements in outcomes, broaden potential treatment approaches, and provide further information about the optimal use in clinical practice. Acknowledgment The author would like to thank Alan Russell for medical writing support during the preparation of this manuscript. Disclosure of Potential Conflicts of Interest C.J. has acted as a consultant and performed contract work for Roche within the past 2 years. References 1 Slamon DJ, Clark GM, Wong SG et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235: Slamon DJ, Godolphin W, Jones LA et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989;244: Owens MA, Horten BC, Da Silva MM. HER2 amplification ratios by fluorescence in situ hybridization and correlation with immunohistochemistry in a cohort of 6556 breast cancer tissues. Clin Breast Cancer 2004;5: Ross JS, Fletcher JA, Bloom KJ et al. Targeted therapy in breast cancer: The HER-2/neu gene and protein. Mol Cell Proteomics 2004;3: Penault-Llorca F, Vincent-Salomon A, Mathieu MC et al. Incidence and implications of HER2 and hormonal receptor overexpression in newly diagnosed metastatic breast cancer (MBC). J Clin Oncol (Meeting Abstracts) 2005;23:69s. 6 Menard S, Fortis S, Castiglioni F et al. HER2 as a prognostic factor in breast cancer. Oncology 2001;61(suppl 2): Press MF, Bernstein L, Thomas PA et al. HER-2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas. J Clin Oncol 1997;15: 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 1999;17: 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 2001;344: Vogel CL, Cobleigh MA, Tripathy D et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:

7 40 Trastuzumab in HER-2 + Metastatic Breast Cancer 11 Marty M, Cognetti F, Maraninchi D et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol 2005;23: Suter TM, Cook-Bruns N, Barton C. Cardiotoxicity associated with trastuzumab (Herceptin) therapy in the treatment of metastatic breast cancer. Breast 2004;13: Baselga J. Herceptin alone or in combination with chemotherapy in the treatment of HER2-positive metastatic breast cancer: pivotal trials. Oncology 2001;61(suppl 2): Bayo J, Mayordomo JI, Sanchez-Rovira P et al. Trastuzumab and vinorelbine combination in the treatment of Her2 positive metastatic breast cancer. Proc Am Soc Clin Oncol 2004;23: Bernardo G, Palumbo R, Bernardo A et al. Final results of phase II study of weekly trastuzumab and vinorelbine in chemonaive patients with HER2-overexpressing metastatic breast cancer. Proc Am Soc Clin Oncol 2004;23: Burstein HJ, Kuter I, Campos SM et al. Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol 2001;19: Burstein HJ, Harris LN, Marcom PK et al. Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol 2003;21: Chan A, Petruzelka L, Untch M et al. Long term survival of vinorelbine (N) and trastuzumab (H) as first line therapy for HER2-positive metastatic breast cancer patients (HER2+MBC) (pts). J Clin Oncol (Meeting Abstracts) 2005;23:25s. 19 de Wit M, Becker K, Thomssen C et al. Vinorelbine and trastuzumab as first line therapy in patients with HER2-positive metastatic breast cancer interim analysis of a prospective, open-label, multicentre phase II trial. Ann Oncol 2004;15(suppl 3): Glogowska I, Sienkiewicz-Kozlowska R, Bauer-Kosinska B et al. Trastuzumab (T) plus vinorelbine (VNR) as first combination in Her-2 overexpressing patients with metastatic breast cancer. Proc Am Soc Clin Oncol 2004;23: Jahanzeb M, Mortimer JE, Yunus F et al. Phase II trial of weekly vinorelbine and trastuzumab as first-line therapy in patients with HER2 + metastatic breast cancer. The Oncologist 2002;7: Papaldo P, Fabi A, Ferretti G et al. A phase II study on metastatic breast cancer patients treated with weekly vinorelbine with or without trastuzumab according to HER2 expression: changing the natural history of HER2-positive disease. Ann Oncol 2006;17: Christodoulou C, Fountzilas G, Razi E et al. Gemcitabine and trastuzumab combination as salvage treatment in patients with HER 2-positive metastatic breast cancer. Proc Am Soc Clin Oncol 2003;22: O Shaughnessy JA, Vukelja S, Marsland T et al. Phase II study of trastuzumab plus gemcitabine in chemotherapy-pretreated patients with metastatic breast cancer. Clin Breast Cancer 2004;5: Pegram MD, Lopez A, Konecny G et al. Trastuzumab and chemotherapeutics: drug interactions and synergies. Semin Oncol 2000;27(suppl 11):21 25; discussion Fujimoto-Ouchi K, Sekiguchi F, Tanaka Y. Antitumor activity of combinations of anti-her-2 antibody trastuzumab and oral fluoropyrimidines capecitabine/5 -dfurd in human breast cancer models. Cancer Chemother Pharmacol 2002;49: Schaller G, Bangemann N, Weber J et al. Efficacy and safety of trastuzumab plus capecitabine in a German multicentre phase II study of pre-treated metastatic breast cancer. J Clin Oncol (Meeting Abstracts) 2005;23:57s. 28 Xu L, Song S, Zhu J et al. Results of a phase II trial of Herceptin plus Xeloda in patients with previously untreated HER2-positive metastatic breast cancer. Breast Cancer Res Treat 2004;88(suppl 1):S O Shaughnessy J, Miles D, Vukelja S et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002;20: Wardley A, Antón-Torres A, Otero Reyes D et al. CHAT - an open-label, randomised, Phase II study of trastuzumab plus docetaxel with or without capecitabine in patients with advanced and/or metastatic HER2-positive breast cancer: second interim safety analysis. Poster 6094 presented at the 28th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8 11, Pegram MD, Pienkowski T, Northfelt DW et al. Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-positive advanced breast cancer. J Natl Cancer Inst 2004;96: Perez EA, Suman VJ, Rowland KM et al. Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study Clin Breast Cancer 2005;6: Robert NJ, Leyland-Jones B, Asmar L et al. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin versus trastuzumab and paclitaxel in women with HER-2 overexpressing metastatic breast cancer: An update including survival. Proc Am Soc Clin Oncol 2004;23: Miller KD, Sisk J, Gize G. Phase II study of gemcitabine, paclitaxel and trastuzumab in metastatic breast cancer: a Hoosier Oncology Group study. Breast Cancer Res Treat 2002;76(suppl 1):S Yardley DA, Greco FA, Porter LL et al. First line treatment with weekly docetaxel, vinorelbine, and trastuzumab in HER2 overexpressing metastatic breast cancer (HER2+ MBC): a Minnie Pearl Cancer Research Network phase II trial. Proc Am Soc Clin Oncol 2004;23: Yardley DA, Greco FA, Hainsworth JD et al. Final results of the Minnie Pearl Cancer Research Network first-line trial of weekly paclitaxel/carboplatin/trastuzumab in metastatic breast cancer. Breast Cancer Res Treat 2002;76:S Venturini M, Bighin C, Monfardini S et al. Multicenter phase II study of trastuzumab in combination with epirubicin and docetaxel as first-line treatment for HER2-overexpressing metastatic breast cancer. Breast Cancer Res Treat 2006;95: Untch M, Eidtmann H, du Bois A et al. Cardiac safety of trastuzumab in combination with epirubicin and cyclophosphamide in women with metastatic breast cancer: results of a phase I trial. Eur J Cancer 2004;40: Baselga J, Climent MA, Lluch A et al. Results of a phase II study of liposomal doxorubicin (Myocet ) in combination with weekly paclitaxel and trastuzumab (Herceptin ) in patients with HER2-positive locally advanced or metastatic breast cancer (LA/MBC). EJC Suppl 2004;2: Arpino G, Green SJ, Allred DC et al. HER-2 amplification, HER-1 expression, and tamoxifen response in estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group study. Clin Cancer Res 2004;10: Fornier MN, Seidman AD, Panageas KS et al. Correlation of ER/PR [immunohistochemistry (IHC)] status to HER2 status by IHC and gene amplification (GA) [fluorescent in-situ hybridization (FISH)], and The Oncologist

8 Jackisch 41 response rate (RR) for weekly (W) trastuzumab (H) and paclitaxel (T) in metastatic breast cancer (MBC) patients (pts). Proc Am Soc Clin Oncol 2002;21:56a. 42 Pinto AE, Andre S, Pereira T et al. C-erbB-2 oncoprotein overexpression identifies a subgroup of estrogen receptor positive (ER+) breast cancer patients with poor prognosis. Ann Oncol 2001;12: Mass RD, Vogel C, Murphy M et al. Relationship of estrogen receptor (ER) status to clinical benefit in clinical trials of Herceptin. Eur J Cancer 2001;37(suppl 6):S Brufsky A, Lembersky B, Schiffman K et al. Hormone receptor status does not affect the clinical benefit of trastuzumab therapy for patients with metastatic breast cancer. Clin Breast Cancer 2005;6: Lipton A, Ali SM, Leitzel K et al. Elevated serum Her-2/neu level predicts decreased response to hormone therapy in metastatic breast cancer. J Clin Oncol 2002;20: Benz CC, Scott GK, Sarup JC et al. Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat 1993;24: Witters LM, Kumar R, Chinchilli VM et al. Enhanced anti-proliferative activity of the combination of tamoxifen plus HER-2-neu antibody. Breast Cancer Res Treat 1997;42: Ellis MJ, Coop A, Singh B et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1 and/or ErbB-2 positive, estrogen receptor positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol 2001;19: Pietras RJ, Pegram MD, Finn RS et al. Remission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER-2 receptor and DNA-reactive drugs. Oncogene 1998;17: Tripathy D, Slamon DJ, Cobleigh M et al. Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J Clin Oncol 2004;22: Montemurro F, Faggiuolo R, Redana S et al. Continuation of trastuzumab beyond disease progression [letter]. J Clin Oncol 2005;23: ; discussion Bartsch R, Wenzel C, Hussian D et al. Analysis of trastuzumab and chemotherapy in advanced breast cancer after the failure of at least one earlier combination: an observational study. BMC Cancer 2006;6: García-Sáenz JA, Martín M, Puente J et al. Trastuzumab associated with successive cytotoxic therapies beyond disease progression in metastatic breast cancer. Clin Breast Cancer 2005;6: Stemmler HJ, Kahlert S, Siekiera W et al. Prolonged survival of patients receiving trastuzumab beyond disease progression for HER2 overexpressing metastatic breast cancer (MBC). Onkologie 2005;28: 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: Romond EH, Perez EA, Bryant J et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353: Slamon D, Eiermann W, Robert N et al. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. Breast Cancer Res Treat 2005;94(suppl 1):S5. 50 Fujimoto-Ouchi K, Sekiguchi F, Kazushige M. Preclinical study of continuous administration of trastuzumab as combination therapy after disease progression with trastuzumab monotherapy. Proc Am Assoc Cancer Res 2005;46:5062a.