Phase II Study of Capecitabine Plus Trastuzumab in Human

VOLUME
25
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NUMBER
22
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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, Romanstra␤e 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
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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
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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
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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.
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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
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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
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5. O’Shaughnessy J, Miles D, Vukelja S, et al:
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6. Miwa M, Ura M, Nishida M, et al: Design of a
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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
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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
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trastuzumab. Expert Opin Drug Saf 3:317-327, 2004
11. O’Shaughnessy JA, Blum J, Moiseyenko V, et
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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:
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13. Pegram M, Hsu S, Lewis G, et al: Inhibitory
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Acknowledgment
We thank Bettina Conrad and Birgit Ruhmland for their collaboration on this manuscript.
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