Phase II Study of Capecitabine Plus Trastuzumab in Human
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Phase II Study of Capecitabine Plus Trastuzumab in Human
VOLUME 25 䡠 NUMBER 22 䡠 AUGUST 1 2007 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Phase II Study of Capecitabine Plus Trastuzumab in Human Epidermal Growth Factor Receptor 2–Overexpressing Metastatic Breast Cancer Pretreated With Anthracyclines or Taxanes Gerhard Schaller, Ilka Fuchs, Thomas Gonsch, Jan Weber, Anke Kleine-Tebbe, Peter Klare, Hans-Joachim Hindenburg, Volker Lakner, Axel Hinke, and Nikola Bangemann From the Breast Care Institute, Munich; WiSP Research Institute, Langenfeld; and the Department of Gynecology and Obstetrics, Charité, Berlin, Germany. Submitted December 1, 2006; accepted April 25, 2007; published online ahead of print at www.jco.org on June 18, 2007. Supported in part by Roche Pharma AG, Germany. G.S. and I.F. contributed equally to this work. Presented in part at the San Antonio Breast Cancer Symposium, December 8-11, 2005, San Antonio, TX. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Address reprint requests to Gerhard Schaller, MD, Romanstrae 93, 80639 München, Germany; e-mail: gerhard@ schaller-berlin.de. © 2007 by American Society of Clinical Oncology 0732-183X/07/2522-3246/$20.00 DOI: 10.1200/JCO.2006.09.6826 A B S T R A C T Purpose The oral fluoropyrimidine carbamate, capecitabine, is a highly active and well-tolerated treatment for metastatic breast cancer. In patients treated previously with anthracyclines and taxanes, capecitabine is an approved single-agent therapy. Trastuzumab, a monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER-2), is also highly active in HER-2– overexpressing breast cancer. We have conducted a phase II study to confirm activity and feasibility of capecitabine and trastuzumab in combination in HER-2– overexpressing advanced/metastatic breast cancer. Patients and Methods Twenty-seven patients with HER-2– overexpressing metastatic breast cancer previously treated with anthracyclines and/or taxanes received oral capecitabine 1,250 mg/m2 bid for 14 days followed by a 7-day rest period combined with intravenous trastuzumab 4 mg/kg body weight on day 1 (loading dose) followed by 2 mg/kg weekly. Results Capecitabine/trastuzumab treatment achieved objective responses in 12 patients (45%), including complete response in four patients (15%) and partial response in eight patients (30%). Disease was stabilized in an additional nine patients (33%). The median overall survival time was 28 months, and the median progression-free survival time was 6.7 months. The safety profile of the combination was favorable and predictable, with a low incidence of grade 3/4 adverse events. The most common adverse events were pain, hand-foot syndrome, and GI toxicities. Severe myelosuppression was rare and severe alopecia did not occur. Conclusion These data confirm that the combination of capecitabine and trastuzumab is highly active in patients with HER-2– overexpressing anthracycline- and/or taxane-pretreated breast cancer, with only slight restrictions regarding quality of life. J Clin Oncol 25:3246-3250. © 2007 by American Society of Clinical Oncology INTRODUCTION The treatment of intensively pretreated advanced metastatic breast cancer is essentially palliative, with the aim of providing antitumor activity and prolonging survival but without significant deterioration in quality of life. The novel, tumor-activated oral fluoropyrimidine capecitabine is highly active in this setting1-4 and is the best approved treatment for patients with anthracycline- and taxanepretreated disease. Based on the demonstration of significantly superior efficacy, including significantly improved overall survival, compared with single-agent docetaxel, capecitabine plus docetaxel has been approved recently in the United States and Europe for the treatment of patients with anthracycline-pretreated metastatic breast cancer.5 Capecitabine generates fluorouracil (FU) preferentially in tumor tissue, via exploitation of the enzyme thymidine phosphorylase, which is expressed significantly more strongly in tumor than in normal tissue.6 The humanized monoclonal antibody trastuzumab, which targets the human epidermal growth factor receptor 2 (HER-2), is also an effective treatment, but only for HER-2–positive metastatic breast cancer, comprising approximately 15% to 25% of all breast cancers.7,8 The combination of trastuzumab with chemotherapy (anthracyclines or paclitaxel) has proven particularly effective, and has achieved 3246 Downloaded from ascopubs.org by 78.47.27.170 on January 13, 2017 from 078.047.027.170 Copyright © 2017 American Society of Clinical Oncology. All rights reserved. Capecitabine and Trastuzumab in Breast Cancer superior response rates, time to disease progression (TTP), and overall survival compared with chemotherapy alone.9,10 As a biologic agent, trastuzumab is well tolerated and devoid of the toxicities typically associated with standard chemotherapy. The combination of two tumor-targeted agents, capecitabine and trastuzumab, might achieve improved efficacy in patients with HER-2–positive metastatic breast cancer without compromising tolerability. The efficacy of capecitabine is established clearly in metastatic breast cancer, both as a single agent and in combination with docetaxel.1,2,4,5,11,12 However, to date, no studies have investigated the impact of tumor HER-2 status on the antitumor activity of capecitabine. This is an important question. Preclinical study showed that, although trastuzumab shows synergy with a variety of chemotherapeutic agents in vitro, FU was seen to antagonize the antitumor activity of trastuzumab.13 These early studies suggested that combinations of trastuzumab and fluoropyrimidines may be ineffective. However, antagonism was not confirmed in tumor xenograft models. Capecitabine and trastuzumab were shown to have at least additive antitumor activity in vivo when administered in combination in a mouse breast tumor xenograft model,14 indicating that exploration of this two-agent combination in the clinical setting is warranted. Our study was undertaken to evaluate the activity of capecitabine plus trastuzumab in patients with heavily pretreated, HER-2–overexpressing, metastatic breast cancer. PATIENTS AND METHODS Study Design and Entry Criteria We conducted a multicenter, open-label, single-arm phase II study, which was planned to enroll up to 30 patients. The study was performed in eight centers in Germany. Patients were eligible if they had pathologically proven, measurable, unresectable, metastatic, HER-2– overexpressing breast cancer. A pretreatment with anthracyclines and/or taxanes (neoadjuvant, adjuvant, or palliative) was mandatory. Additional inclusion criteria included age ⱖ 18 years and progressive disease after at least one or a maximum of two chemotherapies in the metastatic situation. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, adequate contraception and negative pregnancy test for patients during the childbearing age, life expectancy of at least 3 months, and adequate organ functions (neutrophils 1.5 ⫻ 109/L, platelets 75 ⫻ 109/L, basal creatinine clearance ⬎ 30 mL/min [Cockroft and Gault], ALT 2.5⫻ upper limit of normal, and total bilirubin 5⫻ upper limit of normal). Exclusion criteria included pretreatment with trastuzumab (Herceptin; Hoffman-La Roche AG, Basel, Switzerland) and/or capecitabine (Xeloda; Hoffman-La Roche AG); hypersensitivity to fluoropyrimidines, trastuzumab, capecitabine, or any other substance of the drug preparation; simultaneous treatment with sorivudine; known lack of dihydropyrimidine dehydrogenase; local resection or irradiation of the marker lesion after study entry; additional systemic antitumor therapy after study entry, bisphosphonate therapy started less than 4 weeks before study entry; brain metastases before enrollment; pregnancy; or breastfeeding. Ethics Writteninformedconsentwasobtainedfromeachpatient.Theprotocoland the informed consent form were approved by the Research Ethics Review Board of the University-Clinic Benjamin Franklin (Berlin, Germany) and of each participating center. An assurance was taken out for every patient of the study. HER-2 Status Patients with HER-2–receptor overexpression at the 3⫹ level (HercepTest; DakoCytomation, Carpinteria, CA) were immediately eligible for inclusion. A HER-2 expression at the 2⫹ level required confirmation by the proof of a HER-2 gene amplification by fluorescent in situ hybridization (Ventana, Tucson, AZ). HER-2 testing was performed on a sample of the primary tumor or a biopsy of a metastatic site. Central testing was conducted at the Laboratory for Molecular Oncology at the Clinic for Gynecology, Medical Center Benjamin Franklin. Therapy Trastuzumab was administered at an initial dose of 4 mg/kg body weight during 90 minutes and was administered subsequently at weekly doses of 2 mg/kg body weight during 30 minutes. Capecitabine was administered during 14 days with a subsequent pause of 7 days. The daily dose was 2,500 mg/m2 administered in equal parts in the morning and in the evening. This cycle was repeated every 21 days. Trastuzumab and capecitabine were administered until disease progression or unacceptable toxicity. If capecitabine-associated toxicity occurred, dosage reduction and delays were permitted. If a grade 2 toxicity (eg, diarrhea or hand-foot syndrome) occurred, the therapy was interrupted immediately until the symptoms disappeared completely. At that time, the medication was continued at a 75% level. This process was allowed once more, at which point a 50% level was reached. The treatment was discontinued when the patient developed signs of toxicity for a third time. A dose modification of trastuzumab was not allowed. Assessment Tumor response was assessed using Response Evaluation Criteria in Solid Tumors criteria, with computed tomography scans at baseline and every three cycles or 9 weeks of treatment. The primary objective of the trial was the tumor overall response rate, with secondary end points including overall and progression-free survival, stable disease rate (⬎ 3 months), TTP, and safety and tolerability of this treatment. Summary statistics, such as the median, range, proportion, and frequency, were used to describe the patient sample. The Kaplan-Meier method was applied to estimate overall and progressionfree survival outcomes. No multivariate analyses were undertaken because of the limited sample size. Variables investigated were the patients’ baseline age, grading, hormone receptor status, HER-2 status, TNM classification, ECOG status, tumor type, metastatic extent, history of cardiac diseases, and history of pretreatments. All tests were two sided, and a P ⬍ .05 was considered statistically significant. RESULTS Patient Characteristics Twenty-seven patients with metastatic and HER-2– overexpressing breast cancer were enrolled between June 2001 and April 2004. Demographics and other baseline characteristics are listed in Table 1. Most patients had a good performance status at the start of the therapy (ECOG performance status of 0 to 1 in 79%). The median age was 54 years (range, 37 to 66 years). Twenty-three patients were assessable for efficacy, and 25 patients were assessable for toxicity analysis. Four patients dropped out before response analyses: one patient was treated off-protocol immediately after enrollment. In three additional patients, objective response evaluation was not performed and follow-up assessment sheets were missing. Nineteen (73%) of the patients had ductal cancers, two patients (8%) had lobular cancer, and five patients (19%) had cancers of other different types. All patients had progressive metastatic disease with a remarkably high proportion of visceral metastases (74%). A total of 214 cycles were delivered, with a median of eight cycles (range, two to 24 cycles) of treatment with the capecitabine/trastuzumab combination. Across all cycles, a dose reduction for capecitabine was necessary in 16% of patients. The main reasons for dose reductions (in 90% of patients) were nonhematologic toxicities (Table 2). Two patients requested a break, and one discontinuation was at the physician’s discretion because of other comorbidities. Dose reductions were rarely required for myelosuppression. Median 3247 www.jco.org Downloaded from ascopubs.org by 78.47.27.170 on January 13, 2017 from 078.047.027.170 Copyright © 2017 American Society of Clinical Oncology. All rights reserved. Schaller et al Table 1. Baseline Patient Characteristics Table 2. Toxicity Results of Capecitabine/Trastuzumab Combination Therapy 1-2† No. of Patients (n ⫽ 27) Characteristic Age, years Median Range Histology, WHO classification Ductal Lobular Other Estrogen receptor positive Progesterone receptor positive Localization of metastases Local Visceral metastases Liver Lung (visceral) Lung (pleural) Bone Skin Abdominal carcinomatosis Other No. of metastases localizations 1 2 ⱖ3 ECOG performance status 0 1 2 History of heart disease Hypertension Prior cardiac infarction, CHD Heart failure (NYHA I) Duration of disease until study entry, days Median Range Chemotherapeutic pretreatment Adjuvant or neoadjuvant chemotherapy Anthracyclines Taxanes Palliative chemotherapy 1 prior 2 prior Anthracyclines Taxanes % 54 37-66 19 2 5 14 13 73 8 19 54 50 8 20 13 8 3 8 2 2 2 30 74 48 30 11 30 7 7 7 Toxicity Gradeⴱ Hematologic toxicity Anemia Leukopenia Thrombocytopenia Nonhematologic toxicity Nausea Vomiting Diarrhea Mucositis Impaired sensibility Impaired motor function Pain Impaired vigilance Alopecia Hand-foot syndrome Chills Fever Bilirubin No. of Patients 3-4‡ % No. of Patients % 17 14 10 68 56 40 2 1 0 8 4 0 9 4 13 10 11 10 10 4 5 17 12 13 0 36 16 52 40 44 40 40 16 20 68 48 52 0 3 0 0 0 1 4 7 1 — 4 1 0 2 12 0 0 0 4 16 28 4 — 16 4 0 8 ⴱ 16 7 4 59 26 15 7 12 5 29 50 21 5 1 1 19 4 4 123 12-840 24 20 11 10 3 7 8 6 89 74 41 37 11 26 30 22 Abbreviations: ECOG, Eastern Cooperative Oncology Group; CHD, coronary heart disease; NYHA, New York Heart Association. follow-up time per patient was 19 months (range, 3.5 to 49.5 months). Objective responses were observed in 12 patients (45%), including complete response in four patients (15%) and partial response in eight patients (30%). Disease was stabilized in an additional nine patients (33%; Table 3). The median overall survival time was 28 months (Fig 1) and the median progression-free survival time was 6.7 months (Fig 2). Safety The combination of capecitabine with trastuzumab generally was well tolerated. There were no treatment-related deaths. The most common adverse event was pain, which was primarily related to dis- According to National Cancer Institute Common Toxicity Criteria. †Mild to moderate. ‡Severe to life-threatening. ease and not treatment. Hand-foot syndrome was the most frequent medication-related adverse effect in 21 patients (84%). However, only four of the patients (16%) developed grade 3 toxicity. Grade 4 toxicity was not observed. Alopecia was seldom and moderate. Severe hematologic adverse events (grade 3 and 4) were seen in only three patients (Table 2). Dose reduction of capecitabine was necessary in 30 of 189 cycles (16% of cycles, cycle 1 excluded). Mean dosage of capecitabine was 2,024 mg/m2 (range, 0 to 2,516 mg/m2). An extension of the medication interval was observed in 26 of 189 cycles (14% of cycles). Trastuzumab medication was administered as scheduled. Only one patient (4%) suffered from a trastuzumab-induced heart failure. After discontinuation and specific treatment, antitumor therapy could be continued with the study medication. Table 3. Efficacy Results of Capecitabine/Trastuzumab Combination Therapy Intent to Treat (n ⫽ 27ⴱ) Category No. of Patients % CR PR SD Benefit rate† PD ORR ⫹ SD disease control 4 8 9 17 2 21 15 30 33 63 7 78 Abbreviations: CR, complete response; PR, partial response; SD, stable disease for ⱖ 3 cycles; PD, progressive disease; ORR, objective response rate. ⴱ Four patients dropped out before response analyses: one patient dropped out immediately after enrollment because of off-protocol treatment; three additional patients dropped out because objective response evaluation was not performed and follow-up assessment sheets were missing. †Defined as CR ⫹ PR ⫹ SD ⱖ 6 months. 3248 JOURNAL OF CLINICAL ONCOLOGY Downloaded from ascopubs.org by 78.47.27.170 on January 13, 2017 from 078.047.027.170 Copyright © 2017 American Society of Clinical Oncology. All rights reserved. Capecitabine and Trastuzumab in Breast Cancer Proportion Alive 1.0 0.8 0.6 0.4 0.2 10 0 20 30 40 50 Time (months) Fig 1. Kaplan-Meier curve demonstrating the overall survival (OS) of the patients. The median OS was 122 weeks (28 months). DISCUSSION The selection of chemotherapeutic regimens is challenging for metastatic breast cancer patients whose disease has failed to respond to anthracyclines and/or taxanes. In particular, the treatment of patients experiencing severe myelosuppression with these cytotoxic therapies has been particularly problematic. The oral fluoropyrimidine capecitabine was approved for treatment of anthracycline- and taxane-pretreated metastatic breast cancer based on the demonstration of high efficacy and a favorable safety profile in a pivotal trial conducted in 135 patients with measurable disease.1 In that trial, capecitabine achieved a high disease control rate of 60%, including a 20% objective response rate, with median TTP of 3.1 months (93 days) and median overall survival of 12.8 months (384 days). The results of this study, together with those of three subsequent studies, show that single-agent capecitabine achieves consistently high efficacy in a large population (n ⫽ 500) of anthracycline- and taxanepretreated patients.2-4 Similarly, capecitabine has high single-agent activity when administered together with docetaxel. In this combination it also confers a significant survival advantage compared with single-agent docetaxel in patients with anthracycline-pretreated metastatic breast cancer.5 Proportion Alive and Progression Free 1.0 0.8 0.6 0.4 0.2 0 10 20 30 40 50 Time (months) Fig 2. Kaplan-Meier curve demonstrating the progression-free survival (PFS) of the patients. The median PFS was 29 weeks (6.7 months). In patients with HER-2– overexpressing tumors, the addition of trastuzumab to chemotherapy confers a significant survival advantage compared with chemotherapy alone. The rate of complete and partial responses increased significantly from 32% to 50%.9 Based on these data, we originally postulated that the combination of capecitabine and trastuzumab, two tumor-targeted therapies with distinct mechanisms of action, may be highly effective for patients with HER-2– overexpressing tumors previously treated with anthracyclines and taxanes. This hypothesis was supported by two pilot studies. One pilot study, conducted by Blum et al,1 investigated the antitumor activity of capecitabine in patients with anthracyclineand taxane-pretreated metastatic breast cancer. The second pilot trial, published by Bangemann et al,15 evaluated the feasibility of combination therapy with capecitabine plus trastuzumab in 16 patients with anthracycline- and taxanepretreated advanced metastatic breast cancer. The combination showed highly promising antitumor activity, with a disease control rate of 88% (overall response rate, 50%; stable disease, 38% of patients). Mean TTP was 7 months and 81% of patients were alive after a mean follow-up of 9 months. The combination demonstrated a favorable and predictable safety profile that was consistent with that of capecitabine monotherapy. The results of this capecitabine/trastuzumab trial confirm these results. We found a high effectiveness, with a disease control rate of 78% (intent to treat). TTP was 6.7 months for the capecitabine/ trastuzumab combination. This doubles the time seen previously after single-agent administration of capecitabine.1,2 The result is particularly important given that HER-2– expressing patients have a worse prognosis16 than the average breast cancer patient. The large increase of the average TTP is due to the four patients with complete remission. To date, the TTP for those patients is more than 3 years. Using the same drug design, Xu et al17 observed an overall response rate of 63% as first-line treatment in patients with HER-2–positive metastatic breast cancer. A complete remission was reported in five patients. To us it seems reassuring that our study was able to confirm the high efficacy of capecitabine/trastuzumab combination therapy documented in their study, especially because we applied the capecitabine/ trastuzumab combination therapy as second- or third-line treatment rather than first-line treatment for metastatic disease. The high response rates in this trial confirm the data of the phase II study by applying the regimen as first-line treatment. The same response rate was achieved in our study. Given that all of our patients had already received at least one systemic treatment for the metastatic disease, the efficacy results of this study seem reassuring. As expected, the tolerability of this combination was good. As in all other studies with capecitabine, the most common adverse events were hand-foot syndrome and GI toxicities. There was a low incidence of grade 3/4 adverse events, grade 3/4 myelosuppression was rare, and severe alopecia was not observed. The addition of trastuzumab did not add significant adverse effects and the rate of cardiac adverse effects was negligible. As has been shown in the trials evaluating capecitabine monotherapy, dose interruption and subsequent dose reductions were effective in managing adverse effects. However, these promising data are in obvious contrast with in vitro findings showing that trastuzumab and FU have antagonistic activity in cell culture experiments with human breast cancer cells.13 When the application of capecitabine is transferred into an in vivo model, the combination of capecitabine plus trastuzumab has at least additive antitumor activity in a human breast cancer 3249 www.jco.org Downloaded from ascopubs.org by 78.47.27.170 on January 13, 2017 from 078.047.027.170 Copyright © 2017 American Society of Clinical Oncology. All rights reserved. Schaller et al xenograft model.14 One possible explanation for the discrepancy between the in vitro and in vivo activity of the capecitabine/trastuzumab combination may be because oral capecitabine needs to be activated by carboxylesterase (located primarily in the liver) and deoxycytidine deaminase (located primarily in the liver and tumor), which cannot be mimicked by in vitro cell-line experiments. In addition to direct antitumor effects, an antiangiogenic effect may occur. The oral application bid provides constant low-dose levels of capecitabine. The regimen of a chronic low-dose chemotherapy without prolonged breaks has been described as metronomic chemotherapy, and is used to target tumor neoangiogenesis by inhibiting proliferating endothelial cells as well as precursors.18 The effectiveness of such a regimen has been proven in vitro for various chemotherapeutic agents19,20; therefore, one might speculate that similar antiangiogenic effects can be observed with capecitabine. Moreover, anti–HER-2 antibodies are also able to inhibit angiogenesis via downregulation of vascular endothelial growth factor.21 In conclusion, the results of this phase II trial confirm that capecitabine in combination with trastuzumab is highly effective in patients with anthracycline- and taxane-pretreated HER-2– overexpressing metastatic breast cancer, with an acceptable safety profile and manageable toxicities. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. REFERENCES 1. Blum JL, Jones SE, Buzdar AU, et al: Multicenter phase II study of capecitabine in paclitaxelrefractory metastatic breast cancer. J Clin Oncol 17: 485-493, 1999 2. Blum JL, Dieras V, Lo Russo PM, et al: Multicenter, phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer 92:1759-1768, 2001 3. Reichardt P, von Minckwitz G, Thuss-Patience PC, et al: Multicenter phase II study of oral capecitabine (Xeloda) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy. Ann Oncol 14:1227-1233, 2003 4. Fumoleau P, Largillier R, Clippe C, et al: Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Eur J Cancer 40:536-542, 2004 5. O’Shaughnessy J, Miles D, Vukelja S, et al: Superior survival with docetaxel/capecitabine combination therapy in anthracycline-pretreated patients with advanced/metastatic breast cancer: Phase III trial results. J Clin Oncol 20:2812-2823, 2002 6. Miwa M, Ura M, Nishida M, et al: Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34:1274-1281, 1998 No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: Anke Kleine-Tebbe, Roche Pharma AG; Peter Klare, Roche Pharma AG; Hans-Joachim Hindenburg, Roche Pharma AG; Volker Lakner, Roche Pharma AG; Axel Hinke, Roche Pharma AG Research Funds: Gerhard Schaller, Roche Pharma AG; Jan Weber, Roche Pharma AG; Anke Kleine-Tebbe, Roche Pharma AG; Peter Klare, Roche Pharma AG; Hans-Joachim Hindenburg, Roche Pharma AG; Volker Lakner, Roche Pharma AG; Axel Hinke, Roche Pharma AG Testimony: N/A Other: N/A AUTHOR CONTRIBUTIONS Conception and design: Gerhard Schaller Administrative support: Gerhard Schaller, Ilka Fuchs Provision of study materials or patients: Thomas Gonsch, Jan Weber, Anke Kleine-Tebbe, Peter Klare, Hans-Joachim Hindenburg, Volker Lakner, Nikola Bangemann Collection and assembly of data: Gerhard Schaller, Nikola Bangemann Data analysis and interpretation: Gerhard Schaller, Axel Hinke Manuscript writing: Gerhard Schaller, Ilka Fuchs, Axel Hinke, Nikola Bangemann Final approval of manuscript: Gerhard Schaller 7. Hynes NE, Stern DF: The biology of erbB-2/ neu/HER-2 and its role in cancer. Biochim Biophys Acta 1198:165-184, 1994 8. Révillion F, Bonneterre J, Peyrat JP: ERBB2 oncogene in human breast cancer and its clinical significance. Eur J Cancer 34:791-808, 1998 9. Slamon DJ, Leyland-Jones D, 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 10. Jones RL, Smith IE: Efficacy and safety of trastuzumab. Expert Opin Drug Saf 3:317-327, 2004 11. O’Shaughnessy JA, Blum J, Moiseyenko V, et al: Randomized, open-label, phase II trial of oral capecitabine (Xeloda) vs. a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer. Ann Oncol 12:1247-1254, 2001 12. Talbot D, Moiseyenko V, Van Belle S, et al: Randomised, phase II trial comparing oral capecitabine (Xeloda) with paclitaxel in patients with metastatic/advanced breast cancer pretreated with anthracyclines. Br J Cancer 86:1367-1372, 2002 13. Pegram M, Hsu S, Lewis G, et al: Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene 18:2241-2251, 1999 14. 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 49:211-216, 2002 15. Bangemann N, Kuhle A, Ebert A, et al: Capecitabine combined with trastuzumab in the therapy of intensively pretreated HER2-overexpressing metastatic breast cancer (MBC). Ann Oncol 11:143a, 2000 (suppl 4) 16. Carlson RW, Moench SJ, Hammond ME, et al: HER2 testing in breast cancer: NCCN Task Force report and recommendations. J Natl Compr Cancer Netw 3:S1-S22, 2006 (suppl 4) 17. Xu L, Song S, Zhu J, et al: A phase II trial of trastuzumab (H) ⫹ capecitabine (X) as first line treatment in patients (pts) with Her2 positive metastatic breast cancer. J Clin Oncol 24:577s, 2006 (suppl; abstr 10615) 18. Yap R, Veliceasa D, Emmenegger U, et al: Metronomic low-dose chemotherapy boosts CD95-dependent antiangiogenic effect of the thrombospondin peptide ABT-510: A complementation antiangiogenic strategy. Clin Cancer Res 15:6678-6685, 2005 19. Browder T, Butterfield CE, Kraling BM, et al: Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60:1878-1886, 2000 20. Hanahan D, Bergers G, Bergsland E: Less is more, regularly: Metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 105:1045-1107, 2000 21. Izumi Y, Xu L, di Tomaso E, et al: Tumour biology: Herceptin acts as an anti-angiogenic cocktail. 416:279-280, 2002 ■ ■ ■ Acknowledgment We thank Bettina Conrad and Birgit Ruhmland for their collaboration on this manuscript. 3250 JOURNAL OF CLINICAL ONCOLOGY Downloaded from ascopubs.org by 78.47.27.170 on January 13, 2017 from 078.047.027.170 Copyright © 2017 American Society of Clinical Oncology. All rights reserved.