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

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Abstract
Trastuzumab with a taxane as first-line therapy is
now the standard of care for patients with human epi-
dermal growth factor receptor 2 (HER-2)-positive
metastatic breast cancer (MBC). The search for addi-
tional and more effective trastuzumab-based thera-
pies continues. Novel combinations of trastuzumab
with chemotherapeutic agents, including vinorel-
bine, gemcitabine, and capecitabine, and hormonal
therapy agents, such as tamoxifen and aromatase
inhibitors, are currently under investigation in clini-
cal 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 progres-
sion and retreatment after (neo)adjuvant relapse is
being explored to assist in clinical decision making.
Already, the use of trastuzumab in the metastatic set-
ting 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 treat-
ment options for patients with HER-2-positive MBC.
The Oncologist 2006;11(suppl 1):34–41

Introduction significant clinical benefit [8–11], and trastuzumab plus

Human epidermal growth factor receptor 2 (HER-2) is a taxanes as first-line therapy is now the standard of care
transmembrane receptor tyrosine kinase with a key role in for patients with HER-2-positive disease. In order to fur-
normal cell growth and differentiation. Overexpression of ther improve patient care, the search for even more effec-
HER-2, usually as a result of her-2 gene amplification, can tive trastuzumab-based therapies continues in preclinical
result in malignant transformation of cells and is seen in research and within clinical trials.
tumor tissue in up to 30% of patients with metastatic breast
cancer (MBC) [1–5]. HER-2 overexpression is usually asso- Pivotal Trastuzumab Trials in MBC
ciated with a more aggressive tumor phenotype, and women The pivotal randomized combination trials of trastuzumab
with HER-2-positive disease have a poor overall prognosis (H0648g and M77001) demonstrated that trastuzumab plus
and faster relapse times at all stages of cancer development a taxane is associated with a clinical benefit that is superior
[1, 6, 7]. to that of a taxane alone [9, 11].
The advent of trastuzumab (Herceptin®; F. Hoffmann- Four hundred sixty-nine HER-2-positive MBC patients
La Roche, Basel, Switzerland), a humanized monoclonal who had not received prior treatment for advanced disease
antibody against the extracellular domain of HER-2, rep- were enrolled in the H0648g trial. Patients who had pre-
resented a major breakthrough in the treatment of women viously received anthracyclines in the adjuvant setting or
with HER-2-positive MBC. Pivotal trials of trastuzumab who were not suitable to receive anthracyclines (n = 188)
alone or in combination with taxanes have resulted in were randomized to receive paclitaxel with or without
Correspondence: Christian Jackisch, M.D., Klinikum Offenbach GmbH, Department of Gynecology and Obstetrics, Starkenburgring
66, D-63069 Offenbach, Germany. Telephone: 49-0-69-8405-3850; Fax: 49-0-69-8405-4456; e-mail: christian.jackisch@klinikum-
offenbach.de Received June 12, 2006; accepted for publication June 21, 2006. ©AlphaMed Press 1083-7159/2006/$20.00/0

The Oncologist 2006;11(suppl 1):34–41 www.TheOncologist.com

Jackisch
trastuzumab. All other patients (n = 281) were random-
ized to receive an anthracycline plus cyclophosphamide
with or without trastuzumab. The combination of trastu-
zumab with paclitaxel or with an anthracycline plus cyclo-
phosphamide improved all clinical end points over pacli-
taxel or an anthracycline plus cyclophosphamide alone
(median follow-up, 30 months). The overall survival dura-
tion was longer (22.1 vs. 18.4 months) with trastuzumab
plus paclitaxel and with trastuzumab plus an anthracy-
cline plus cyclophosphamide (26.8 vs. 21.4 months ) [9].
Despite these improvements in survival, the number of
cardiac events reported in that trial was higher than antici-
pated from initial clinical data. A retrospective analy-
sis 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 pacli-
taxel, 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 immu-
nohistochemistry (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 with-
out 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 symp-
tomatic heart failure (1%). Another patient experienced
symptomatic heart failure 5 months after discontinuation
of trastuzumab because of disease progression and fol-
lowing treatment with an investigational anthracycline for
4 months [11].
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35
Both pivotal trials demonstrated a favorable safety pro-
file for the combination of trastuzumab with a taxane. The
addition of trastuzumab did not significantly add to the tox-
icity profile of taxanes alone.
Novel Trastuzumab–Chemotherapy
Combinations
There is continuing interest in new trastuzumab–chemother-
apy combinations, arising from the ongoing aim of improv-
ing treatment efficacy. Also, taxanes are increasingly being
used in the adjuvant setting, and trastuzumab-based treat-
ment 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,
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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, first-
line therapy produced higher response rates. One single-
center study allowed more direct comparison of first-line
(84% response rate, 34 weeks TTP) and second- or third-
line therapy (67% and 16 weeks, respectively) [16], indi-
cating 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 ther-
apy in patients with metastatic breast cancer [14–22].
36
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/m2 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/m2 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 trastu-
zumab with 5-fluorouracil found that this combination was
less effective than either drug alone, suggesting an antago-
nism in vitro [25]. However, further studies indicated that
trastuzumab and the 5-fluorouracil prodrug capecitabine
had at least additive antitumor activity in human breast can-
cer models [26], and this has been supported by recent stud-
ies in the clinical setting. In a multicenter phase II study of
weekly trastuzumab with capecitabine (1,250 mg/m2 twice
a day [bid] on days 1–14, 3-weekly) in patients with pre-
treated 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 first-
line trastuzumab–capecitabine therapy (capecitabine,
1,250 mg/m2 bid on days 1–14, 3-weekly), in which an objec-
tive response rate of 76% (five complete responses, 14 par-
tial 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.
Trastuzumab in HER-2+ Metastatic Breast Cancer
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 explor-
ing 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 can-
cer (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 Novem-
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ber, 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 fea-
sible 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 liposo-
mal formulations of doxorubicin.
Initial analyses of the Herceptin, Cyclophosphamide,
and Epirubicin (HERCULES) trial, a multicenter phase
I–II trial of trastuzumab plus epirubicin–cyclophospha-
mide (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
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Jackisch 37

Table 1. Trastuzumab-based triple combinations

Study Regimen n ORR (%)
Yardley et al. [36] Carboplatin/paclitaxel 61 66
Perez et al. [32] Carboplatin/paclitaxel weekly 48 81
Carboplatin/paclitaxel 3-weekly 43 65
Robert et al. [33] Carboplatin/paclitaxel 93 52
Paclitaxel 95 36
Pegram et al. [31] Cisplatin/docetaxel 62 79
Pegram et al. [31] Carboplatin/paclitaxel 59 58
Venturini et al. [37] Epirubicin/docetaxel 45 67
Miller et al. [34] Gemcitabine/paclitaxel 45 62
Yardley et al. [35] Vinorelbine/docetaxel 34 70
Abbreviation: ORR, objective response rate.

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combination, it is feasible to combine trastuzumab with trastuzumab pivotal trials, approximately 50% of patients
EC [38]. In phase I of this trial, patients with HER-2-posi- with HER-2-positive metastatic disease were also ER
tive disease initially received trastuzumab plus 60 mg/m 2 positive [43]. Together, these data show that ER/HER-
epirubicin (EC60; n = 26). Once it was established that this 2-copositive disease is common, and it is of interest to
regimen was not associated with any dose-limiting toxicity, explore specific treatment options for these patients. In
phase II of the trial was initiated. Patients with HER-2-posi- the pivotal trials, hormone-receptor status did not affect
tive disease were then enrolled into an arm of trastuzumab the efficacy of trastuzumab given as a single agent or
plus 90 mg/m2 epirubicin (EC90; n = 25) and HER-2-nega- combined with chemotherapy [8–11, 44], indicating that
tive patients received EC90 alone (n = 24). Both trastu- trastuzumab is equally effective in ER-negative and ER-
zumab-containing arms met the criteria for acceptable positive disease (Fig. 2).
tolerability, with only three patients experiencing a cardiac Resistance to hormonal therapy, particularly tamoxi-
event: asymptomatic decline in LVEF to <50% in one patient fen, appears to be a characteristic of ER-positive, HER-2-
receiving trastuzumab plus EC60 and congestive heart fail- positive tumors [45], and it has been hypothesized that the
ure in two patients receiving trastuzumab plus EC90. One addition of trastuzumab to hormonal therapy may overcome
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 combin-
ing trastuzumab with the liposomal doxorubicin TLC D-99
(Myocet®; Elan Pharmaceuticals, Princeton, NJ) was inves-
tigated [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/m2, weekly) plus TLC
D-99 (50 mg/m2, 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
Figure 2. Objective response rates with trastuzumab in
active, as evidenced by an objective response rate of 93% in
patients with human epidermal growth factor receptor 2-
54 evaluable patients [39]. positive and estrogen receptor (ER)-positive or ER-negative
disease [8–10]. Abbreviation: HR, hormone receptor. From
Trastuzumab in Combination with Brufsky A, Lembersky B, Schiffman K et al. Hormone recep-
tor status does not affect the clinical benefit of trastuzumab
Hormonal Therapy
therapy for patients with metastatic breast cancer. Clin Breast
In estrogen receptor (ER)-positive patient populations, Cancer 2005;6:247–252, with permission from Cancer Infor-
the rate of HER-2 positivity is 11%–35% [40–42]. In the mation Group, copyright 2005.

www.TheOncologist.com
38
this relative resistance. In preclinical studies, the combina-
tion 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 com-
bining 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 trastu-
zumab 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 2006. 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 part-
ner is a topic of considerable interest in clinical practice.
To date, no results from randomized trials have been pub-
lished; 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
Figure 3. Addition of trastuzumab to paclitaxel in the human
breast cancer xenograft model KPL-4 progressing on trastu-
zumab monotherapy [50].
Trastuzumab in HER-2+ Metastatic Breast Cancer
with a taxane after progression on trastuzumab mono-
therapy 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].
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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 ben-
efit 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 regi-
mens (Table 2) [53].
One large randomized trial investigating trastu-
zumab 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 demon-
strated 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-
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 Objective TTP (95%
treatment response (%) CI), mos
First (n = 54) 42.6 6 (5.40–6.60)
Second (n = 54) 25.9 6 (5.36–6.64)
Beyond second (n = 33) 30 6 (5.32–6.68)
Abbreviations: TTP, time to progression; CI, confidence
interval.
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Jackisch
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 deter-
mine 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 first-
line 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 accord-
ing to HER-2 expression, women with HER-2-positive dis-
ease treated with vinorelbine plus trastuzumab had a bet-
ter prognosis than patients with HER-2-negative disease
treated with vinorelbine alone, thus suggesting that trastu-
zumab 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 ben-
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Disclosure of Potential Conflicts
of Interest
C.J. has acted as a consultant and performed contract work
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 HER-2-Positive Metastatic Breast Cancer: Optimizing Trastuzumab-Based
Therapy
Christian Jackisch
Oncologist 2006;11;34-41
DOI: 10.1634/theoncologist.11-90001-34
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