Herceptin

ADIS DRUG EVALUATION
Drugs 2010; 70 (2): 215-239

0012-6667/10/0002-0215/$55.55/0
2010 Adis Data Information BV. All rights reserved.
Trastuzumab
A Review of its Use as Adjuvant Treatment in Human
Epidermal Growth Factor Receptor 2 (HER2)-Positive Early
Breast Cancer
Karly P. Garnock-Jones, Gillian M. Keating and Lesley J. Scott
Adis, a Wolters Kluwer Business, Auckland, New Zealand
Various sections of the manuscript reviewed by:
E. Briasoulis, Department of Medical Oncology, University of Ioannina Medical School, Ioannina, Greece;
A.M. Brufsky, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania,
USA; A.U. Buzdar, Department of Breast Medical Oncology, MD Anderson Cancer Center, University of
Texas, Houston, Texas, USA; E. de Azambuja, Medical Oncology Clinic, Breast Data Centre, Institut Jules
Bordet, Brussels, Belgium; W. Jacot, Val dAurelle Clinic, Montpellier, France; E.A. Perez, Division of
Hematology/Oncology, Mayo Clinic, Jacksonville, Florida, USA.
Data Selection
Data Selection Sources: Medical literature published in any language since 1980 on trastuzumab, identified using MEDLINE and
EMBASE, supplemented by AdisBase (a proprietary database). Additional references were identified from the reference lists of published
articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: MEDLINE, EMBASE and AdisBase search terms were ((trastuzumab) and (early breast cancer)) or (((trastuzumab)
and (breast cancer)) not (advanced or metastatic)). Searches were last updated 7 January 2010.
Selection: Studies in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer who received adjuvant
treatment with trastuzumab. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well
controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also
included.
Index terms: Trastuzumab, HER2-positive, early breast cancer, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.
Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1 Concurrent Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.1 NSABP B-31 and NCCTG N9831 Trials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.2 BCIRG 006 Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2 Sequential Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.1 HERA Trial. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.2 FNCLCC-PACS-04 Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.3 NCCTG N9831 Sequential Treatment Arm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3 Sequential Versus Concurrent Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1 General Tolerability Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2 Cardiac Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
216
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230
Garnock-Jones et al.
216
5.3 Other Adverse Events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232

6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
7. Place of Trastuzumab in the Treatment of HER2-Positive Early Breast Cancer . . . . . . . . . . . . . . . . . . . . 233
Abstract
Trastuzumab (Herceptin) is a humanized IgG1 k monoclonal antibody, specifically targeted against the extracellular domain of the human epidermal growth
factor receptor 2 (HER2), and is indicated for the treatment of HER2-positive
early or metastatic breast cancer. This review discusses the available data regarding its use in early breast cancer.
Trastuzumab, when administered concurrently with chemotherapy regimens,
consistently prolonged disease-free survival (primary endpoint) and overall survival (secondary endpoint) in patients with HER2-positive early breast cancer in
well designed trials; studies evaluating sequential trastuzumab treatment have
produced mixed results for these endpoints. Further study is required to ascertain
the optimal trastuzumab treatment regimen, including the duration of treatment.
Trastuzumab was generally well tolerated when added to, or administered following, a chemotherapy regimen in clinical trials. While cardiac adverse events,
such as a decreased left ventricular ejection fraction and congestive heart failure,
are a concern, these effects are treatable and appear to be mostly reversible. Thus,
trastuzumab is a valuable component of treatment regimens for HER2-positive
early breast cancer.
1. Introduction
Breast cancer is the most common cancer in
women worldwide; with >1.2 million diagnoses
every year, it affects 1012% of women.[1] It also
accounts for a worldwide death toll of 500 000 per
annum, making it the leading cause of cancerrelated death among women.[1] Breast cancer is more
common in industrialized than in nonindustrialized
countries; however, the incidence in nonindustrialized countries is rising.[1] In industrialized countries
in recent years, mortality rates for breast cancer have
been falling; this has been linked to the introduction
of widespread screening programmes and the use of
adjuvant systemic treatments.[1]
The overall economic burden of breast cancer in
the US in 2001 was $US1520 billion; since this
time, increased use of more expensive, targeted
therapies, higher incidence of disease and improved
survival of patients are likely to have increased this
figure.[2] Estimates of lifetime per-patient costs of
breast cancer in the US are $US20 000100 000.[2]
Early breast cancer is currently treated with

surgery and/or radiotherapy and with additional
adjuvant systemic treatments, including chemotherapy, endocrine therapy (e.g. tamoxifen), biological therapy (e.g. trastuzumab [Herceptin])
or a combination of these.[3] Several factors
determine the choice of treatment, including tumour histology, clinical and pathological characteristics of the primary tumour, axillary node
status, patient age, hormone receptor status and
human epidermal growth factor receptor 2 (HER2)
status.[3]
Increased levels of HER2 on cell surfaces
(caused by the amplification of the HER2 gene
[HER2] or overexpression of the HER2 protein)
leads to increased intracellular tyrosine kinase
activity and activation of signal transduction
pathways; this, in turn, leads to inhibition of
apoptosis and promotion of cell growth, cell
division, angiogenesis and metastasis.[4] HER2
protein overexpression or gene amplification occurs in 1525% of breast tumours.[5-8]
Drugs 2010; 70 (2)
Trastuzumab: A Review
217
Table I. Potential mechanisms of action of trastuzumab (TRA)

Inhibited both basal and induced HER2 cleavage in human breast adenocarcinoma cell lines,[15] thus preventing the production of an active
truncated HER2 fragment
Inhibited the activity of cyclin E/Cdk2 complex (through regulation of p27Kip1 sequestration proteins in human breast cancer cell lines),[16,17]
thus reducing cellular proliferation
Inhibited the activity of PI3K[18] and Akt[18] in human breast cancer cell lines by disrupting the ligand-independent HER2/HER3/PI3K
complex,[19] thus reducing cellular proliferation
Reduced angiogenesis (the diameter, volume and vascular permeability of tumour blood vessels[38]) in human HER2-positive breast
tumour models in mice[38,39] through modulation of the effects of pro- (VEGF, TGFa, Ang-1 and PAI-1) and anti- (TSP-1) angiogenic
factors[38]
Mice without the Fc receptor (binds to the Fc domain of TRA) in natural killer cells experienced significantly less inhibition of tumour growth than
those with the Fc receptor[40]
An ex vivo study showed increased cell-mediated cytotoxic activity with TRA in 51Cr-labelled HER2-positive target cells from pts with primary
operable breast tumours[35]
Associated with a strong infiltration of lymphocytes in TRA recipients with primary operable HER2-positive breast tumours, suggesting TRAassociated cellular cytotoxicity[35]
Induced apoptosis in 35 pts with locally advanced HER2-overexpressing breast cancer[41]
Ang-1 = angiopoietin-1; Cdk = cyclin-dependent kinase; HER = human epidermal growth factor receptor; PAI-1 = plasminogen-activator
inhibitor-1; PI3K = phosphatidylinositol-3 kinase; pts = patients; TGFa = transforming growth factor-a; TSP-1 = thrombospondin-1;
VEGF = vascular endothelial growth factor.
Trastuzumab is a targeted biological treatment, indicated for the adjuvant treatment of

early HER2-positive breast cancer and the treatment of metastatic HER2-positive breast cancer.
This review examines the pharmacological properties, clinical efficacy and tolerability of adjuvant
trastuzumab in women with early HER2-positive
breast cancer. Trastuzumab as a treatment for
metastatic HER2-positive breast cancer has been
extensively reviewed elsewhere,[9-11] and will not
be specifically discussed further. The cost effectiveness of this drug in early breast cancer is well
established (reviewed by McKeage and LysengWilliamson[12]); discussion of these data are beyond the scope of this review.
2. Pharmacodynamic Properties
As the pharmacodynamic properties of trastuzumab have been extensively reviewed elsewhere,[9,11,13,14] only a brief overview of the data
is presented here. Data are from in vitro,[15-34] ex
vivo,[30,35] animal[36-40] and human[35,41,42] studies.
Trastuzumab is a humanized IgG1 k monoclonal antibody, specifically targeted against the
extracellular domain of HER2,[43,44] where it
binds with high affinity.[43]
The mechanism of action underlying the antitumour effect of trastuzumab has not yet been
fully determined, and may involve several different mechanisms (table I). Trastuzumab may
exert its effects by the activation of antibodydependent cellular cytotoxicity,[35,40] prevention
of HER2 dimerization,[14] the inhibition of the
cleavage of the extracellular domain of HER2,[15]
interactions with signalling pathways,[16-19] cellcycle arrest during the G1 phase,[16,17] induction
of apoptosis[41] or inhibition of angiogenesis.[38,39] HER2 downregulation had also been
suggested as a possible mechanism;[14] however,
in a pilot study, HER2 levels remained constant in 11 patients with breast cancer receiving
trastuzumab.[35]
Potential pharmacodynamic drug interactions
exist between trastuzumab and several cytotoxic
agents. Enhanced antitumour activity has been
demonstrated with concurrent trastuzumab and
paclitaxel,[33,34,36,39] doxorubicin,[33,34,36] capecitabine,[37] cyclophosphamide,[34] methotrexate,[34]
etoposide,[34] vinblastine[34] or epirubicin.[33]
Both synergistic[31] and antagonistic[28] effects
have been observed with concurrent trastuzumab
and tamoxifen. Additionally, trastuzumab has
been shown to sensitize breast cancer cells to the
effects of radiation.[32,42]
Drugs 2010; 70 (2)
218
Table II. Pharmacokinetics of trastuzumab (TRA) [administered via intravenous infusion] in women with human epidermal growth factor
receptor 2 (HER2)-positive early breast cancer. All values are means
Study
No. of pts
Cmax
(mg/mL)
Ctrough
(mg/mL)
tmax
(h)
AUCa
(mg h/mL)
CLb
(mL/h)
TRA monotherapy once-weekly regimen (4 mg/kg LD - 2 mg/kg qw)

Cobleigh et al.[47]c
195
100
25
TRA monotherapy 3-weekly regimen (8 mg/kg LD - 6 mg/kg q3w)

Baselga et al.[45]d
22
239
49e
3.5
43 534
11.2
Leyland-Jones et al.[46]f
15
237
72.3
2.7
55 529
8.2
50.1
4.4
42 040
9.8
TRA (8 mg/kg LD - 6 mg/kg q3w) with PAC (175 mg/m2 q3w)

Leyland-Jones et al.[46]f
25
196
At the end of the dosage interval[45] or up to the last sampling.[46]
At steady state[45] or not specified.[46]
Results after first dose. Mean Ctrough after 20 wks ranged from 65 to 75 mg/mL, after plateauing (estimated from a graph).
At cycle 6.
Included patients not included in the rest of the pharmacokinetic substudy (n = 48).
TRA without PAC group data are for cycle 12; TRA + PAC group data are for cycle 4.
AUC = area under the serum concentration-time curve; CL = clearance; Cmax = maximum serum concentration; Ctrough = trough serum
concentration; LD = loading dose; PAC = paclitaxel; qw = once weekly; q3w = every 3 weeks; tmax = time to Cmax; - indicates followed by.
Several in vitro studies have been undertaken to

determine the potential mechanisms involved in
trastuzumab resistance. Data from these studies
suggest resistance to trastuzumab treatment may
be associated with p27kip1 downregulation,[23]
increased insulin-like growth factor-I receptor signalling[21] and heterodimerization,[27] decreased
phosphatase and tensin homologue activity (increasing Akt activity),[22] increased Ras-related C3
botulinum toxin substrate 1 activity,[24] increased
levels of the cleaved form of mucin 1 (MUC1),[20]
increased expression of MUC4,[29] HER2 mutations,[11] increased epidermal growth factor receptor
and HER3 expression,[25] increased transforming
growth factor-a expression[30] and increased levels
of Met receptor tyrosine kinase.[26] However, whether these in vitro results translate into clinical outcomes remains to be determined.
3. Pharmacokinetic Properties
Pharmacokinetic data in this section were taken
from fully published clinical trials in patients with
metastatic[45-48] or advanced[49,50] breast cancer and
two pharmacokinetic population analyses (one
fully published[51] and one in abstract form with a
poster[52]), supported by data from the US manufacturers prescribing information[43] and the
European Medicines Agency (EMEA) Summary

of Product Characteristics (SPC).[44]
The pharmacokinetic properties of intravenous
trastuzumab in patients with metastatic breast
cancer are summarized in table II.[45-47] The volume
of distribution of trastuzumab approximated that
of serum volume (44 mL/kg[43] or 2.95 L[44]). Steady
state was generally reached by 20 weeks of treatment[44] (range 637 weeks[43] or 1824 weeks[44]).
Mean steady-state concentrations, where reported,
were 60 mg/mL for the once-weekly regimen[47] and
65.47 mg/mL for the 3-weekly regimen.[45]
Accumulation of trastuzumab occurred, with
an increase in mean trough serum concentration
(Ctrough) values of 45%[46] and 94%[45] over 8[46]
and 13[45] cycles of treatment with a 3-weekly regimen (see table II for dosage details). Ctrough
values with the once-weekly regimen[47] (see
table II for dosage details) also increased, from
25 mg/mL after the first dose to a plateau of
6575 mg/mL after 20 weeks. Average exposure at
any time during trastuzumab treatment was
found to be similar between the once-weekly and
3-weekly regimens, based on a simulation study
and comparisons between 3-weekly regimen data
and those for the once-weekly regimen reported
in previous studies.[45] Relative to historical
data for the once-weekly regimen,[47] the mean
Drugs 2010; 70 (2)
Ctrough value was 20% lower and the mean

maximum serum concentration value was 70%
higher using the 3-weekly regimen.[45] Ctrough values varied widely between individuals receiving
the 3-weekly regimen, with a >10-fold variation at
cycle 6.[45]
Trastuzumab pharmacokinetics were dose dependent[43,44] (mean half-life increased and clearance decreased when the dose was increased[43]).
Half-lives in pharmacokinetic studies were 6.2 days
(elimination half-life) with the once-weekly regimen (this may have been underestimated as a
result of a short sampling period)[47] and 16.4[45]
or 18.3[46] days (terminal elimination half-life
[tg]) with the 3-weekly regimen. Trastuzumab
has at least two elimination phases after infusion;
the first has a half-life of 4 days and the second,
starting 1 week after the end of infusion, has a
longer half-life (numerical data not available).[45]
Population pharmacokinetic analyses, using
pooled data and based on a two-compartment
model, predicted a long tg[51,52] (28.5 days[51]),
and also concluded there was no dosage regimen
effect on clearance or volume of distribution.[52]
No data on the metabolism of trastuzumab are
available.
Trastuzumab disposition was not altered
as a result of age or serum creatinine levels
(<2.0 mg/dL [<177 mmol/L]);[43,44] however, these
studies were not designed to investigate the
pharmacokinetics of trastuzumab in renally impaired patients.[44]
Paclitaxel had no clinically significant effect
on trastuzumab pharmacokinetics (table II).[46]
While the Ctrough value was 1.5-fold higher
when patients received trastuzumab alone than
when they received concurrent trastuzumab and
paclitaxel, this was assumed to be a result of accumulation of the drug (patients continued trastuzumab treatment after paclitaxel treatment had
ended; this was when the trastuzumab monotherapy data were taken).[46] Moreover, trastuzumab had no effect on the pharmacokinetics of
paclitaxel.[46] Additionally, trastuzumab had no
effect on the pharmacokinetics of docetaxel;[43]
cisplatin, cyclophosphamide and carmustine
(administered concurrently);[49] gemcitabine;[50]
or epirubicin.[48]
219
4. Therapeutic Efficacy
The efficacy of intravenous trastuzumab as
concurrent (section 4.1) or sequential therapy
(section 4.2) in patients with HER2-positive early
breast cancer has been evaluated in several large
(n >500), randomized, open-label, multicentre
trials.[7,53-55] In addition, the relative efficacy of
concurrent versus sequential trastuzumab therapy, based on efficacy data from one of these
studies, is briefly discussed (available as oral
presentations[56,57]) [section 4.3]. All trial acronyms used here are presented in table table III.
4.1 Concurrent Treatment
The efficacy of adjuvant trastuzumab treatment concurrent with chemotherapy in early

breast cancer has been investigated in several
trials, including three phase III trials, known as
NSABP B-31 and NCCTG N9831 (published
together as an interim pooled analysis)[54,62] and
BCIRG 006.[55,58,63] See table IV for key inclusion criteria and treatment regimens. Another
trial, FinHer,[8] also investigated concurrent
treatment; however, as the regimen used in this
trial is not currently an approved regimen in the
US or EU, it will not be discussed in this section
(it is briefly discussed in section 7).
In both NSABP B-31 and NCCTG N9831,
whole-breast radiotherapy was used in patients
treated with lumpectomy; regional radiotherapy
after lumpectomy or mastectomy was optional in
NSABP B-31 but was required in patients with at
Table III. Trial acronyms
Acronym
Trial name
BCIRG 006
Breast Cancer International Research

Group 006
FinHer
Finnish Herceptin study
FNCLCC-PACS-04
Federation Nationale des Centres de

Lutte Contre le Cancer-Programme
dActions Concertees Sein-04
HERA (BIG 01-01)
HERceptin Adjuvant trial (Breast

International Group 01-01)
NCCTG N9831
North Central Cancer Treatment

Group N9831
NSABP B-31
National Surgical Adjuvant Breast and

bowel Project B-31
Drugs 2010; 70 (2)
220
Table IV. Trial details of randomized, open-label, multicentre, phase III trials investigating adjuvant (i.e. postoperative) trastuzumab (TRA)
therapy in patients (pts) with human epidermal growth factor receptor 2 (HER2)-positivea early breast cancer. All drugs were given intravenously
Key inclusion criteria
Treatment regimenb
BCIRG 006[11,58]
Node-positive or high-risk
node-negative
AC 60/600 mg/m2 q3w 4 cycles - DOC 100 mg/m2 q3w

4 cycles + concurrent TRA 6 mg/kg q1w 12 cycles (8 mg/kg LD) - TRA 6 mg/kg
q3w (total TRA treatment time of 1 y)
DOC 75 mg/m2 + CAR AUC6 q3w 6 cycles + concurrent TRA 6 mg/kg
q1w 18 cycles (8 mg/kg LD) - TRA 6 mg/kg q3w (total TRA treatment time of
1 y)
AC 60/600 mg/m2 q3w 4 cycles - DOC 100 mg/m2 q3w 4 cycles
NSABP B-31[54]
Node-positive;
chemotherapy-naive
AC 60/600 mg/m2 q3w 4 cycles - PAC 175 mg/m2 q3w 4 cycles

(or 80 mg/m2 q1w 12 cyclesc) + concurrent TRA 2 mg/kg q1w 52 cycles
(4 mg/kg LD)d
(or 80 mg/m2 q1w 12 cyclesc)
HERA (BIG 0101)[53,60,61]
node-negative; prior
adjuvant and/or
neoadjuvant
chemotherapye with or
without RT
TRA 6 mg/kg q3w 2 y (8 mg/kg LD)f,g

TRA 6 mg/kg q3w 1 y (8 mg/kg LD)g
Observation alone
FNCLCC-PACS-04[7]
Node-positive
FEC 500/100/500 mg/m2 q3w 6 cycles - RT - TRA 6 mg/kg q3w 1 y

(8 mg/kg LD)
ED 75/75 mg/m2 q3w 6 cycles - RT - TRA 6 mg/kg q3w 1 y
(8 mg/kg LD)
FEC 500/100/500 mg/m2 q3w 6 cycles - RT - observation
ED 75/75 mg/m2 q3w 6 cycles - RT - observation
Study
Concurrent studies
Sequential studies
Sequential vs concurrent study

NCCTG N9831[54]
node-negative;
chemotherapy-naive
AC 60/600 mg/m2 q3w 4 cycles - PAC 80 mg/m2 q1w

12 cycles + concurrent TRA 2 mg/kg q1w 52 cycles (4 mg/kg LD)d
AC 60/600 mg/m2 q3w 4 cycles - PAC 80 mg/m2 q1w 12 cycles - TRA
2 mg/kg q1w 52 cycles (4 mg/kg LD)d
HER2 status was determined by IHC and/or FISH for all studies and confirmed centrally. Pts had to have a HER2 status of 3+ by IHC,[7,53,54]
2+ by IHC and a FISH-positive HER2 tumour,[7,53] or a FISH-positive HER2 tumour.[54,58]
Endocrine therapy was administered in patients with hormone receptor-positive tumours.
Following a regimen amendment partway through the study,[59] at the investigators discretion the PAC regimen could be modified.
TRA administration was dependant on continued acceptable cardiac function.
Previous chemotherapy included no ANT (6% of pts), ANT but no taxanes (68%), and ANT and taxanes (26%).[60]
Results are not yet available for this treatment arm.
The TRA regimen was modified in cases of delayed administration or specific adverse events.
AC = doxorubicin plus cyclophosphamide; ANT = anthracyclines; AUC6 = target area under the concentration-time curve of 6 mg min/mL;
CAR = carboplatin; DOC = docetaxel; ED = epirubicin plus DOC; FEC = fluorouracil plus epirubicin plus cyclophosphamide; FISH = fluorescence in situ hybridization; IHC = immunohistochemistry; LD = loading dose; PAC = paclitaxel; qxw = every x weeks; RT = radiation therapy;
- indicates followed by.
least four positive nodes in NCCTG N9831.[54]

Radiotherapy was initiated after chemotherapy
completion; trastuzumab was administered during radiotherapy.[54]
Interim data from these two studies were retrospectively pooled for a joint analysis (n = 3351),
approved by the US FDA and the US National
Cancer Institute, combining data from NSABP B-31
Drugs 2010; 70 (2)
with data from the concurrent trastuzumab arm

and the control chemotherapy arm of NCCTG
N9831.[54] The two studies differed in terms of the
scheduling of paclitaxel treatment and some aspects of hormonal therapy and radiotherapy, but
were deemed to be sufficiently similar to justify
pooling the data.[54] Pooled results (focus of discussion) from the two trials are from a median
follow-up of 2.0 years (2.4 years in NSABP B-31
and 1.5 years in NCCTG N9831);[54] updated
results at a median follow-up of 2.9 years are also
available as an abstract plus oral presentation.[62]
Eligible women in the three phase III trials had
(pathologically confirmed[54]) breast cancer[54,58]
and had undergone surgery with axillary-node
dissection or sentinel-node biopsy (in NCCTG
N9831).[54] The tumour was required to be axillary node-positive or high-risk node-negative in
BCIRG 006 and NCCTG N9831;[54,58] NSABP
B-31 only included patients with node-positive
tumours.[54] Other inclusion criteria included
adequate haematopoietic, hepatic and renal
function,[54] and a left ventricular ejection fraction (LVEF) that met or exceeded the lower limit
of normal (LLN) [trastuzumab therapy was only
initiated if there was a <16% decrease from
baseline in LVEF to after doxorubicin and
cyclophosphamide treatment].[54]
Exclusion criteria included metastatic disease[54]
or cardiac disease (angina pectoris requiring
medication, arrhythmia requiring medication, a
severe conduction abnormality, clinically significant valvular disease, cardiomegaly, left ventricular hypertrophy [NSABP B-31 only], poorly
controlled hypertension, clinically significant
pericardial effusion [NCCTG N9831 only], or a
history of myocardial infarction, congestive heart
failure [CHF] or cardiomyopathy).[54]
The primary endpoint was disease-free survival in all three studies,[54,58] with analyses based
on the modified intent-to-treat (ITT) population,
where stated.[54] Where defined,[54] disease-free
survival was the time from randomization to detection of local, distant or contralateral invasive
breast cancer, death or other second primary
cancer.[54] Other (secondary[58]) endpoints included overall survival,[54,58] time to recurrence
and distant recurrence,[54] death from breast
221
cancer,[54] contralateral breast cancer[54] other

second primary cancers[54] and quality of life
(QOL; assessed by the European Organisation
for Research and Treatment of Cancer Quality of
Life Questionnaires C-30 [EORTC QLQ C-30]
and BR-23 [EORTC QLQ BR-23]).[64]
At baseline, 51% of patients in the pooled population of NSABP B-31 and NCCTG N9831,[54]
and 53% of patients in BCIRG 006[58] were aged
<50 years. A total of 3341% of patients had more
than three positive nodes[54,58] and the tumour was
>2 cm in diameter in 60% of patients.[54,58] The
tumour was estrogen receptor-negative in 52% of
patients and progesterone receptor-negative in
59% in the pooled population of NSABP B-31
and NCCTG N9831;[54] 46% of BCIRG 006 patients were negative for both estrogen and progesterone receptors.[58]
In the pooled population of NSABP B-31 and
NCCTG N9831, tumour grade was good in 2%
of patients, intermediate in 28% and poor in
69%.[54] Other cancer therapy among patients in
BCIRG 006 included mastectomy (61% of patients), radiotherapy (62%) and endocrine therapy (51%), and 80% of patients had a Karnofsky
performance status of 100.[58] Baseline characteristics were generally well balanced between
treatment groups in all three studies.[54,58]
In BCIRG 006, a small number of patients in
the control chemotherapy arm (23 of 1073; 2.1%)
crossed over to trastuzumab treatment after
the announcement of the first interim results.[55]
Patients in the control chemotherapy groups
of NCCTG N9831 and NSABP B-31 were given
the option of crossing over to trastuzumab
treatment following the initial efficacy report;
255 of 958 patients in NCCTG N9831 (112 started trastuzumab during and 143 started trastuzumab following paclitaxel treatment) and 158
of 1021 patients in NSABP B-31 crossed over.
These patients remained in the control chemotherapy group for all analyses, as part of the ITT
population.[62]
4.1.1 NSABP B-31 and NCCTG N9831 Trials
Adjuvant trastuzumab treatment administered

over 1 year, concurrent with chemotherapy, was
Drugs 2010; 70 (2)
222
Table V. Efficacy of adjuvant treatment with trastuzumab (TRA) in women with node-positive (NSABP B-31 and NCCTG N9831) or high-risk
node-negative (NCCTG N9831) human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. Pooled data from two
randomized, open-label, multicentre trials (NSABP B-31 and NCCTG N9831) after a median follow-up of 2.0 y (2.4 y in NSABP B-31 and 1.5 y
in NCCTG N9831)[54] and 2.9 y (available only as an abstract and oral presentation).[62] Following surgery, patients received doxorubicin
(DOX) plus cyclophosphamide (CYC) then paclitaxel (PAC) plus TRA (TRA regimen), or DOX plus CYC then PAC alone (control regimen).
Refer to table IV for details of these treatment regimens
Endpoints
Median follow-up
duration (y)
TRA regimen
(n = 1672a)
Control regimen
(n = 1679a)
HR (95% CI)
2.0
133
261
0.48 (0.39, 0.59)***
2.9
222
397
0.48 (0.41, 0.57)***
Primary endpoint
Disease-free survival (no. of
events)
Prespecified other endpoints
Overall survival (no. of deaths)
Time to recurrence (no. of events)
Time to distant recurrence (no. of
events)
a
0.67 (0.48, 0.93)*
2.0
62
92
2.9
NR
NR
0.65 (0.51, 0.84)**
2.0
117
235
0.47 (0.38, 0.59)***
2.9
189
344
NR
2.0
96
193
0.47 (0.37, 0.61)***
Modified intent-to-treat population.[54]
HR = hazard ratio; NR = not reported; * p = 0.015, ** p < 0.001, *** p < 0.0001.
effective in patients with HER2-positive early

breast cancer, with regard to the primary endpoint
of disease-free survival, in the pooled analysis of
NSABP B-31 and NCCTG N9831 (table V).[54]
There were significantly fewer disease-free survival
events among trastuzumab recipients than among
patients receiving the control regimen.[54]
After a median follow-up of 2.0 years, the 3-year
disease-free survival rate was 87.1% among trastuzumab recipients versus 75.4% among recipients of
the control chemotherapy regimen (absolute difference 11.8%) [4-year rate 85.3% vs 67.1%; absolute difference 18.2%].[54] This difference crossed
the prespecified early stopping boundary for the
trials.[54] Updated data from a median follow-up
of 2.9 years showed respective 2-year disease-free
survival rates of 92.3% versus 86.4% (3-year rate
87.9% vs 77.6%; 4-year rate 85.9% vs 73.1%).[62]
Adjustment for patient characteristics in NSABP
B-31 and NCCTG N9831 minimally altered the
efficacy of trastuzumab versus the control chemotherapy regimen with regard to disease-free survival.[54] No evidence of trastuzumab efficacy
differing between the two studies was found.[54]
Previous data have suggested that increased
serum HER2 levels are associated with a poor
prognosis.[65] In the control chemotherapy arm of
NCCTG N9831, patients with high serum HER2

levels (15 ng/mL) had significantly worse diseasefree survival than those with lower levels (hazard
ratio [HR] 1.71; p = 0.004); this significant difference was not observed among patients receiving chemotherapy plus trastuzumab (HR 1.42;
p = 0.22).[65]
Overall survival was also significantly improved
with the chemotherapy plus trastuzumab versus
the control chemotherapy regimen (table V).[54]
After a median follow-up of 2 years, the 3-year
overall survival rate in the pooled analysis was
94.3% in trastuzumab recipients versus 91.7% in
recipients of the control chemotherapy regimen
(absolute difference 2.5%) [4-year rate 91.4% vs
86.6%; absolute difference 4.8%].[54] Updated data
from a median follow-up of 2.9 years showed a
2-year overall survival rate of 97.5% versus 95.9%
(3-year rate 94.6% vs 92.7%; 4-year rate 92.6% vs
89.4%).[62]
Chemotherapy plus trastuzumab also provided
significant benefit versus control chemotherapy with
regard to both time to recurrence and time to distant
recurrence (table V).[54] The 3-year distant recurrence event-free survival rate was 90.4% in trastuzumab recipients versus 81.5% in recipients of the
control chemotherapy regimen (absolute difference
Drugs 2010; 70 (2)
4.1.2 BCIRG 006 Trial
Adjuvant trastuzumab treatment for 1 year, concurrent with anthracycline- or non-anthracyclinebased chemotherapy, was effective in patients
with HER2-positive early breast cancer with
regard to the primary endpoint of disease-free
survival, with significantly fewer disease-free
survival events occurring in the two trastuzumab
groups than in the chemotherapy alone group
(table VI).[55,58] Disease-free survival rates are
shown in figure 1.[55,58]
At 36 months follow-up, stratification of
patients based on lymph node status, hormone
receptor status or the size of the tumour at baseline indicated that anthracycline-based chemotherapy plus trastuzumab provided better
disease-free survival than anthracycline-based
chemotherapy alone in all subgroups of patients, with all HRs being <1.0.[58] This was also
generally the case for non-anthracycline-based
chemotherapy plus trastuzumab versus anthra 2010 Adis Data Information BV. All rights reserved.
AC DOC + TRA
DOC + CAR + TRA
AC DOC
100
90
80
70
60
50
40
30
20
10
0
Patients (%)
8.8%), with 4-year rates of 89.7% and 73.7%

(absolute difference 15.9%).[54]
Isolated brain metastases as first events affected 21 trastuzumab recipients versus 11 recipients of the control chemotherapy regimen in
NSABP B-31 and 12 versus 4 patients in NCCTG
N9831.[54] As a result of following patients in
NSABP B-31 for additional events beyond the
first, it was concluded that the higher number of
brain metastases among trastuzumab recipients
was a result of earlier failures at other distant sites
among control chemotherapy-group patients
(brain metastases as first or subsequent events
were present in 28 trastuzumab recipients and 35
recipients of the control chemotherapy regimen;
HR 0.79; p = 0.35).[54]
Chemotherapy plus trastuzumab was also
generally more favourable than the control chemotherapy regimen in terms of other secondary
endpoints in the pooled analysis,[54] including
death from breast cancer (HR 0.66 [95% CI 0.47,
0.94]; p = 0.02; 53 vs 79 events) and other second
primary cancer (HR 0.24 [95% CI 0.09, 0.64];
p = 0.002; 5 vs 20 events), although it provided no
benefit in terms of contralateral breast cancer
(HR 0.64 [95% CI 0.18, 2.27]; 4 vs 6 events).[54]
223
2-year 3-year 4-year 5-year 2-year 3-year 4-year 5-year

DFS rate
OS rate
Fig. 1. Efficacy of adjuvant treatment with trastuzumab (TRA) in

women with node-positive or high-risk node-negative human epidermal growth factor receptor 2 (HER2)-positive early breast cancer.
Rates of 2-, 3-, 4- and 5-year disease-free survival (DFS) [primary
endpoint] and overall survival (OS) among women in the randomized, open-label, multicentre BCIRG 006 trial after a median
follow-up of 36 months (2-, 3- and 4-year data; second planned
analysis)[58] or 65 months (5-year data; third planned analysis).[55]
Following surgery, women were randomized to treatment with an
anthracycline-based chemotherapy regimen plus TRA (doxorubicin
plus cyclophosphamide [AC] - docetaxel [DOC] + TRA; n = 1074)
or alone (AC - DOC; n = 1073), or a non-anthracycline-based
chemotherapy regimen plus TRA (DOC + carboplatin [CAR] + TRA;
n = 1075). Refer to table IV for trial regimen details. - indicates followed by.
cycline-based chemotherapy alone, except in patients with a hormone receptor-positive tumour

and those with a tumour size <2 cm, in whom
there was no significant difference in disease-free
survival.
At 65 months in lymph-node negative patients,
anthracycline-based chemotherapy plus trastuzumab (p = 0.003) but not non-anthracyclinebased chemotherapy plus trastuzumab recipients
(p = 0.057) retained a significantly greater diseasefree survival versus recipients of anthracyclinebased chemotherapy alone; significance was
retained for both trastuzumab groups versus the
control group (p = 0.0003 and p = 0.013, respectively) in patients who were lymph-node positive.[55]
Overall survival was also significantly improved
with chemotherapy plus trastuzumab versus anthracycline-based chemotherapy alone at 36[58] and
65 months[55] follow-up, with significantly fewer
deaths among trastuzumab recipients than among
patients receiving the control chemotherapy regimen
Drugs 2010; 70 (2)
224
Table VI. Efficacy of adjuvant treatment with trastuzumab (TRA) in women with node-positive or high-risk node-negative human epidermal
growth factor receptor 2 (HER2)-positive early breast cancer. Women in the open-label, multicentre, BCIRG 006 trial (data available only from
abstracts and oral presentations)[55,58,63] were randomized to treatment with an anthracycline-based chemotherapy regimen with (n = 1074) or
without (n = 1073) TRA, or a non-anthracycline-based chemotherapy regimen plus TRA (n = 1075), following surgery. Results are available
after median follow-ups of 23,[63] 36[58] and 65[55] mo. Refer to table IV for trial regimen details
Median
follow-up
duration (mo)
23[63]
36[58]
65[55]
Regimen
Disease-free survivala
no. of events
HR (95% CI) vs AC - DOC
Overall survival
no. of deaths
HR (95% CI) vs AC - DOC
AC - DOC + TRA
77
0.49 (0.37, 0.65)***
20
NR
DOC + CAR + TRA
98
0.61 (0.47, 0.79)***
28
NR
AC - DOC
147
AC - DOC + TRA
128
0.61 (0.48, 0.76)***
49
0.59 (0.42, 0.85)**
DOC + CAR + TRA
142
***
0.67 (0.54, 0.83)
56
0.66 (0.47, 0.93)*
AC - DOC
192
AC - DOC + TRA
185
0.64 (0.53, 0.78)***
94
DOC + CAR + TRA
214
0.75 (0.63, 0.90)**
113
AC - DOC
257
36
80
0.63 (0.48, 0.81)***
0.77 (0.60, 0.99)*
141
Primary endpoint.
AC = doxorubicin plus cyclophosphamide; CAR = carboplatin; DOC = docetaxel; HR = hazard ratio; NR = not reported;- indicates followed by;
*
p < 0.05, ** p < 0.01, *** p < 0.001.
(table VI).[55,58] Overall survival rates are shown

in figure 1.[55,58]
Subgroup analyses at 36 months follow-up
indicated that in some, but not all, subgroups of
patients there was a significant between-group
difference favouring trastuzumab regimens over
anthracycline-based chemotherapy alone in
terms of overall survival.[58] For example, overall
survival rates were significantly (p-value not stated) better in the anthracycline-based chemotherapy plus trastuzumab group than in the
anthracycline-based chemotherapy alone group
in patients who were lymph node-negative
or -positive, hormone receptor-positive or had a
tumour of <2 cm, whereas there was no significant between-group difference in those with a
hormone receptor-negative tumour or a tumour
size of 2 cm.[58]
Overall survival at 65 months in patients who
were lymph-node negative remained significantly
greater in anthracycline-based chemotherapy plus
trastuzumab (p = 0.02) but not non-anthracyclinebased chemotherapy plus trastuzumab recipients
(p = 0.11) versus recipients of anthracycline-based
chemotherapy alone.[55]
The numbers of metastatic events in anthracycline-based chemotherapy plus trastuzumab,
non-anthracycline-based chemotherapy plus

trastuzumab and anthracycline-based chemotherapy alone recipients were 52, 67 and 113 at
23 months, 93, 98 and 143 at 36 months, and 124,
144 and 188 at 65 months.[55] The numbers of
breast cancer deaths, respectively, were 19, 21
and 33 at 23 months, 44, 47 and 69 at 36 months,
and 83, 97 and 122 at 65 months.[55]
QOL did not significantly differ between
treatment groups for most measurements.[64]
Recipients of non-anthracycline-based chemotherapy plus trastuzumab had significantly
(p = 0.008) worse results than recipients of anthracycline-based chemotherapy plus trastuzumab in the mid-treatment assessment of change
in physical function score.[64] Recipients of nonanthracycline-based chemotherapy plus trastuzumab showed significantly better results than
recipients of anthracycline-based chemotherapy
both with trastuzumab and alone (both p < 0.001)
in the end-of-chemotherapy assessment of change
in systemic therapy adverse effects score; recipients of anthracycline-based chemotherapy
plus trastuzumab also showed significantly
better results than recipients of anthracyclinebased chemotherapy alone in this measure
(p = 0.0007).[64]
Drugs 2010; 70 (2)
4.2 Sequential Treatment
Two trials have solely investigated sequential

adjuvant treatment of early breast cancer with
chemotherapy followed by trastuzumab: the
HERA study[53,60,61] (section 4.2.1) and the
FNCLCC-PACS-04 study[7] (section 4.2.2). Additionally, a sequential treatment arm[56,57] was
included in the NCCTG N9831 trial (see section
4.1 and table IV for treatment details), which is
briefly discussed (section 4.2.3).
Eligible women (aged >18 and 65 years[7])
had histologically confirmed (unilateral[7]) early
breast cancer[7,53] that had been completely excised[7,53] and was axillary node-positive[7,53] or
high-risk node-negative,[53] had received at least
4 cycles of chemotherapy,[7,53] had adequate cardiac function (e.g. no signs of CHF and an LVEF
55% [or 5055%, according to the cardiologists
decision[7])[7,53] and had adequate baseline hepatic, renal and bone marrow function.[53]
Exclusion criteria included metastatic disease,[7,53]
use of hormone-based contraceptives,[53] previous invasive breast cancer,[53] clinical stage T4
tumours[53] or a neoplasm not involving the
breast.[53]
The primary endpoint was disease-free survival, assessed in the ITT population.[7,53] Diseasefree survival was the time from randomization to
the first occurrence of a disease-free-survival
event (e.g. breast cancer recurrence, second nonbreast malignant disease [not including basal-cell
or squamous-cell skin carcinoma or carcinoma
in situ of the cervix[53]] or death from any
cause)[7,53]. Other (secondary[53]) endpoints included overall survival,[7,53] site of first diseasefree survival event[7,53] and time to distant recurrence (the time between randomization and first
distant tumour recurrence).[53]
At baseline, just over half of the patients in
FNCLCC-PACS-04 were premenopausal (56%);
the median age was 48 years.[7] A much lower
proportion of patients in HERA were premenopausal (14%), and 44% were aged between
35 and 49 years.[60] A total of 51% of the observation and 60% of the trastuzumab groups in
FNCLCC-PACS-04 had a pathological tumour
size >2 cm and 44% and 40% had more than three
225
positive nodes.[7] Forty-nine percent of patients

in HERA had a tumour >2 cm and 28% had at
least four positive nodes.[60] Hormone receptor
status was negative for both estrogen and progesterone receptors in 48% of HERA patients[60]
and 40% of patients in FNCLCC-PACS-04.[7]
Baseline demographics in both trials were generally well balanced between treatment groups.[7,60]
4.2.1 HERA Trial
Following chemotherapy, patients in HERA

were randomized to observation (n = 1698 [1693
in the interim analysis]) or 1 (n = 1703 [1694]) or 2
(n = 1701 [1694]) years of treatment with trastuzumab (table IV).[60] Randomization occurred
within 7 weeks from day 1 of the last chemotherapy cycle or 6 weeks from the end of radiotherapy or surgery, whichever came later. The
median time between breast cancer diagnosis and
trastuzumab initiation was 8.4 months. Fully
published data are available for a planned interim
analysis (n = 5081) at 12 months follow-up[53]
and a full population analysis (n = 5102) at 23.5
months follow-up,[60] and 48-month follow-up
data are available as an oral presentation.[61]
Results from the treatment arm receiving 2 years
of trastuzumab are not yet available.
Following the first interim analysis of data
from HERA (median follow-up of 12 months),
which showed a significant disease-free survival
benefit for 1 year of trastuzumab treatment versus observation only (table VII),[53] and after
most recruitment had been completed (five patients were yet to be recruited), patients in the
observation group were permitted to cross over
to trastuzumab treatment, irrespective of the time
since randomization.[60]
At median follow-ups of 12,[53] 23.5[60] and
[61]
months, significantly fewer disease-free
48
survival events (primary endpoint) occurred
among patients with HER2-positive early breast
cancer receiving adjuvant, sequential trastuzumab than among those undergoing observation
(table VII).[53,60,61]
The 2-year disease-free survival rate was 85.8% in
the trastuzumab group versus 77.4% in the observation group (absolute difference 8.4%; 95% CI 2.1,
Drugs 2010; 70 (2)
226
Table VII. Efficacy of 1 year of adjuvant trastuzumab (TRA) treatment following chemotherapy in women with human epidermal growth factor
receptor 2 (HER2)-positive early breast cancer. The HERA trial[53,60,61] was a randomized, open-label, multicentre study in which patients who
had received 4 cycles of chemotherapy were randomized to 1 (n = 1703) or 2 (n = 1701) years of treatment with TRA or observation only
(n = 1698).[60] Results are available for the 1-year TRA and observation groups after 12,[53] 23.5[60] and 48 (available only as an oral presentation)[61] months of follow-up (refer to table IV for the trial regimen). Results from the 12-month follow-up are from an interim analysis
including 1694 patients in each of the TRA groups and 1693 patients in the observation group.[53] Analyses were in the intent-to-treat
population[53]
Endpoints
Median follow-up
duration (mo)
TRA group
Observation
group
HR (95% CI)
Primary endpoint
Disease-free survival (no. of events)
12[53]
127
220
0.54 (0.43, 0.67)**
23.5[60]
218
321
0.64 (0.54, 0.76)**
48[61]
369
458
0.76 (0.66, 0.87)**
12[53]
29
37
0.76 (0.47, 1.23)
23.5[60]
59
90
0.66 (0.47, 0.91)*
Prespecified secondary endpoints

[61]
182
213
0.85 (0.70, 1.04)
12[53]
89
171
0.49 (0.38, 0.63)**
152
233
0.60 (0.49, 0.73)**
48
Time to distant recurrence (no. of events)
23.5[60]
HR = hazard ratio; * p = 0.0115, ** p < 0.0001.
14.8);[53] the 3-year disease-free survival rate was

80.6% versus 74.3% (absolute difference 6.3%)[60]
and the 4-year disease-free survival rate was
78.6% vs 72.2% (absolute difference 6.4%).[61]
Results varied with length of follow-up with
regard to overall survival.[53,60,61] At the 12-[53]
and 48-month[61] follow-up, there was no significant difference in overall survival between the
trastuzumab and observation groups, whereas
trastuzumab recipients had a significantly lower
risk of death than those undergoing observation
only at 23.5 months[60] follow-up (table VII).
Respective overall survival rates were 96.0%
versus 95.1% at 2 years (absolute difference
0.9%),[53] 92.4% versus 89.7% at 3 years (absolute
difference 2.7%)[60] and 89.3% versus 87.7% at
4 years (absolute difference 1.6%).[61]
Of the 1698 patients originally randomized
to observation in HERA, 1354 were alive and
disease-free, and thus eligible for crossover to
trastuzumab treatment, when the option to cross
over was made available; 344 patients were ineligible.[61] A total of 885 patients crossed over
and 469 remained on observation.[61] The median
time to crossover from randomization was 22.8
months. This high proportion (65%) of patients
who crossed over may have affected the statistical
comparisons between the trastuzumab treatment

and observation groups.[61]
An analysis censoring observation-group
patients at the time of crossover to trastuzumab
treatment was conducted, with a median time
from switching of 2.6 months.[60] A total of 705
patients were censored at the date of switching
treatment. Results from this analysis were similar
to those from the ITT analysis.[60] The HR for
disease-free survival benefit in the censored analysis was 0.63 (95% CI 0.53, 0.75; p < 0.0001);
the HR for overall survival was 0.63 (0.45, 0.87;
p = 0.0051).[60]
Trastuzumab therapy was associated with a
significantly lower risk of a distant recurrence
event than observation (table VII), with approximately two-thirds of first events reported
being distant metastases.[53,60] The 2-year distant
recurrence event-free survival rate was 90.6% in
trastuzumab recipients versus 82.8% in patients
undergoing observation;[53] the 3-year distant recurrence event-free survival rate was 85.7% versus 79.4% (absolute difference 6.3%).[60] A total
of 1.2% of trastuzumab and 0.9% of observation
patients had metastases in the CNS at 12 months
follow-up;[53] corresponding proportions at 23.5
months follow-up were 2% and 1%.[60]
Drugs 2010; 70 (2)
In subgroup analyses of the HERA study, no

evidence of heterogeneity in the relative treatment effect was observed based on baseline
characteristics,[53,60] and those groups considered
at relatively low risk of relapse (e.g. patients with
node-negative disease) demonstrated similar
treatment benefit to that seen in the overall cohort.[66] Moreover, no evidence was found in the
HERA study to suggest that the degree of HER2
amplification has any effect on the efficacy of
trastuzumab.[67]
4.2.2 FNCLCC-PACS-04 Trial
Patients in FNCLCC-PACS-04 (n = 3010)

were initially randomized into two chemotherapy
regimens: fluorouracil plus epirubicin plus cyclophosphamide, or epirubicin plus docetaxel;
both regimens were followed by radiotherapy
(delivered within 4 weeks after the last chemotherapy cycle).[7] As soon as HER2 status was
established, HER2-positive patients were randomized to treatment with trastuzumab (n = 260) or
observation (n = 268), following the radiotherapy
(table IV). Data for this study are fully published.[7] Only data from HER2-positive patients
are discussed. There has been some criticism regarding the validity of data from the FNCLCCPACS-04 study; this is discussed in section 7.
No significant difference in the incidence of
disease-free survival events (primary endpoint) was
observed after a median follow-up of 47 months
between patients with HER2-positive early breast
cancer receiving adjuvant, sequential trastuzumab and those undergoing observation.[7] A total
of 59 patients in the trastuzumab group and
70 patients in the observation group had a first
event defining disease-free survival at 47 months
follow-up (HR 0.86; 95% CI 0.61, 1.22); the respective 3-year disease-free survival rates were
80.9% versus 77.9%.[7]
There was also no significant difference in
overall survival between the trastuzumab and
observation groups (HR 1.27; 95% CI 0.68, 2.38)
at 47 months follow up.[7] The 3-year overall
survival rate was 95% in trastuzumab recipients
and 96% in those undergoing observation only.[7]
With regard to first events, distant recurrence
occurred in 44 patients (17.0%) in the trastuzu 2010 Adis Data Information BV. All rights reserved.
227
mab group and 52 patients (19.0%) in the observation group, 6 (2.3%) and 5 (1.8%) had local
recurrence, 1 (0.4%) and 4 (1.5%) had regional
recurrence, 5 (1.9%) and 3 (1.1%) had contralateral breast recurrence, and 2 (0.8%) and 1
(0.4%) died of causes not related to breast cancer.[7]
4.2.3 NCCTG N9831 Sequential Treatment Arm
Two interim analyses compared the sequential

treatment arm of the NCCTG N9831 trial with
the control arm and included a total of 979 patients receiving doxorubicin plus cyclophosphamide then paclitaxel (control arm) and 985
receiving doxorubicin plus cyclophosphamide
then paclitaxel then trastuzumab (sequential
treatment arm) in the first interim analysis (at a
median of 1.5 years follow-up);[56] respective
patient numbers were 1087 and 1097 for the second interim analysis (at a median of 5.5 years
follow-up).[57] See table IV for treatment regimen
details.
Following the initial release of data from the
joint analysis,[54] patients in the control treatment
group were permitted to cross over to trastuzumab treatment, and patients in the sequential
trastuzumab treatment group could cross over to
receive concurrent trastuzumab treatment.[57]
These patients were censored in the analyses discussed here.[57]
At baseline, 33% of patients were aged
4049 years.[56] Forty-one percent of patients had
at least four positive nodes, 32% had tumours
2 cm in diameter, and 45% of patients had tumours that were negative for both estrogen and
progesterone receptors.[56]
No significant difference in disease-free survival
(primary endpoint) was observed between treatment groups after a median follow-up of 1.5 years
(first interim analysis);[56] however, after a median
of 5.5 years follow-up (second interim analysis),
disease-free survival was significantly (p = 0.0005)
improved in patients with HER2-positive early
breast cancer receiving adjuvant, sequential chemotherapy then trastuzumab compared with those
undergoing chemotherapy only (crossing the prespecified OBrien-Fleming boundary [p = 0.001];
Drugs 2010; 70 (2)
228
Table VIII. Efficacy of 1 year of adjuvant trastuzumab (TRA) treatment following chemotherapy in women with human epidermal growth factor
receptor 2 (HER2)-positive early breast cancer. The NCCTG N9831 trial was a randomized, open-label, multicentre study in which patients
received chemotherapy alone, chemotherapy followed by sequential TRA or chemotherapy and concurrent TRA.[56] Presented here are
results from the control chemotherapy (n = 1087) and sequential TRA (n = 1097) treatment arms[56,57] after a median of 1.5[56] or 5.5 years[57]
follow-up (both available as oral presentations)
Endpoints
Disease-free survivala (no. of events)
a
Median follow-up
duration (y)
Sequential TRA
regimen (n = 1097)
Control chemotherapy
regimen (n = 1087)
HR (95% CI)
1.5
103
117
0.87 (0.67, 1.13)
5.5
164
222
0.70 (0.57, 0.86)*
1.5
NR
NR
0.85 (0.55, 1.33)
5.5
NR
NR
0.86 (0.65, 1.13)
Primary endpoint.
HR = hazard ratio; NR = not reported; * p = 0.0005.
table VIII).[57] The difference between treatment

groups remained significant after adjusting for
age, tumour size, number of positive nodes and
estrogen receptor presence (HRadjusted 0.67; 95%
CI 0.55, 0.82).[57] In the second interim analysis,
the 3- and 5-year disease-free survival rates were
85.2% and 80.1% among trastuzumab recipients
and 79.7% and 71.9% among control chemotherapy recipients.[57]
In the first interim analysis, no significant
difference in overall survival was observed between treatment groups (table VIII);[56] the
second interim analysis did not report overall
survival.
4.3 Sequential Versus Concurrent Treatment
This section discusses data from the NCCTG

N9831 trial, comparing the sequential and concurrent trastuzumab treatment arms, which included 954 and 949 patients (see table IV for
treatment regimen details and section 4.2.3 for
baseline characteristics).[57] Data from the earlier
sequential versus concurrent trastuzumab treatment analysis[56] were preliminary and are not
discussed further. Crossover patients were censored in the analyses discussed here.[57] Additionally, enrolment in the concurrent trastuzumab treatment arm was temporarily closed for
cardiac analysis (for 8 months[68]); patients enrolled in the sequential trastuzumab treatment
arm during this time were also censored in these
analyses.[57]
The difference in disease-free survival (primary endpoint) between concurrent trastuzumab
treatment and sequential trastuzumab treatment

(HR 0.77; 95% CI 0.61, 0.96; p = 0.019) did not
cross the prespecified OBrien-Fleming boundary
for statistical significance (p = 0.00116) after a
median follow-up of 5.3 years among patients
with HER2-positive early breast cancer.[57] A total of 174 patients in the sequential trastuzumab
group and 138 patients in the concurrent trastuzumab group had a first event defining diseasefree survival.[57] After adjusting for tumour size,
number of positive nodes and estrogen receptor
presence, the HRadjusted was 0.75 (95% CI 0.60,
0.94; p = 0.0134).[57] The 3- and 5-year diseasefree survival rates were 85.7% and 79.8% among
sequential trastuzumab recipients and 89.1% and
84.2% among concurrent trastuzumab recipients.[57]
There was no significant difference between
treatment groups in overall survival (HR 0.79;
95% CI 0.59, 1.08).[57]
5. Tolerability
Tolerability data for the use of adjuvant trastuzumab treatment in women with HER2-positive early breast cancer are available from the
clinical trials discussed in section 4.[7,53-55,60,61]
This section also includes tolerability data from
the US manufacturers prescribing information[43] and the EMEA SPC.[44] Additional cardiac data for HERA,[69] NCCTG N9831[68] and
NSABP B-31[59] were taken from separately
published cardiac safety analyses. Where specified, adverse events were graded according to the
National Cancer Institutes Common Terminology Criteria for Adverse Events, version 2.0.[53,54]
Drugs 2010; 70 (2)
Safety populations in the studies, where specified, were as follows: HERA: 1678 trastuzumab
recipients and 1708 undergoing observation (at
12 months),[44] and 1688 trastuzumab recipients
and 1442 undergoing observation (at 23.5 months)
[the cardiac safety population remained at
1678 and 1708 patients at this timepoint];[60]
FNCLCC-PACS-04: 260 trastuzumab recipients
and 268 undergoing observation;[7] NSABP B-31
and NCCTG N9831 joint analysis: 1635 trastuzumab recipients and 1571 recipients of the control chemotherapy regimen.[43]
5.1 General Tolerability Profile
Sequential or concurrent adjuvant trastuzumab was generally well tolerated in patients with
HER2-positive early breast cancer participating
in clinical trials discussed in section 4.[53-55,60]
Trastuzumab administered concurrently with
adjuvant chemotherapy did not appear to greatly
exacerbate chemotherapy-related tolerability issues in the NCCTG N9831, NSABP B-31 and
BCIRG 006 trials.[54,55] For example, in the
NSABP B-31 and NCCTG N9831 trials, after a
median treatment duration of 50 weeks, most
adverse events were grade 2 in severity.[43] Grade
25 noncardiac adverse events that occurred in
5% of trastuzumab recipients and that had an
incidence 2% higher than in recipients of the
control chemotherapy regimen included arthralgia (31% of trastuzumab recipients vs 28% of
recipients of the control chemotherapy regimen),
fatigue (28% vs 22%), infection (22% vs 14%), hot
flushes (17% vs 15%), anaemia (13% vs 7%),
dyspnoea (12% vs 4%), rash/desquamation (11%
vs 7%), neutropenia (7% vs 5%), diarrhoea (6% vs
5%) and headache (6% vs 4%), during and up to 3
months following treatment in the NSABP B-31
trial,[43] and arthralgia (11% vs 8%), myalgia
(10% vs 8%) and nail changes (9% vs 7%) during
treatment in NCCTG N9831.[43] These studies
differed slightly in how noncardiac adverse
events were investigated: NSABP B-31 collected
grade 35 adverse events, treatment-related grade
2 adverse events and grade 25 dyspnoea, and
NCCTG N9831 collected treatment-related
229
grade 4 and 5 haematological toxicities, grade

35 nonhaematological toxicities and grade
25 toxicities associated with taxanes.[43]
In the joint interim analysis of NSABP B-31
and NCCTG N9831 at a median follow-up of
2 years, trastuzumab therapy appeared to be potentially related to interstitial pneumonitis, which
occurred in four patients in NSABP B-31 and five
patients in NCCTG N9831; two of these patients
died (one in each study).[54] Both of these deaths
were considered treatment-related, as was another
in the trastuzumab group (cardiomyopathy).[54]
A total of 2.3% of trastuzumab recipients discontinued treatment as a result of noncardiac
adverse events or death.[54]
In BCIRG 006, grade 3 or 4 nonhaematological adverse events that occurred with an incidence of 5% in any treatment group included
infection (25% in recipients of anthracyclinebased chemotherapy plus concurrent trastuzumab
and 21% in recipients of non-anthracycline-based
chemotherapy plus concurrent trastuzumab vs
23% in recipients of anthracycline-based chemotherapy alone),[43] myalgia (5.2% and 1.8% vs
5.2%),[55] fatigue (7.2% and 7.2% vs 7.0%),[55]
diarrhoea (5.6% and 5.4% vs 3.0%),[55] nausea
(5.7% and 4.8% vs 5.9%),[55] vomiting (6.7% and
3.5% vs 6.1%)[55] and irregular menses (24.3%
and 26.5% vs 27.0%).[55] Corresponding rates of
grade 3 or 4 haematological adverse events that
occurred with an incidence of 5% in any group
included neutropenia (71.6% and 66.2% vs
63.5%), leukopenia (60.4% and 48.4% vs 51.9%),
febrile neutropenia (10.9% and 9.6% vs 9.3%),
neutropenic infection (12.1% and 11.2% vs
11.5%), anaemia (3.1% and 5.8% vs 2.4%) and
thrombocytopenia (2.1% and 6.1% vs 1.6%).[55]
Among patients who received sequential
therapy with trastuzumab following adjuvant
chemotherapy in the HERA study, the most
common adverse events during trastuzumab
treatment were headache, arthralgia, fatigue,
nasopharyngitis and diarrhoea (figure 2).[44] At
1 year, 70% of trastuzumab recipients and 46%
of those undergoing observation only had reported at least one adverse event of any grade, with
5248 and 2251 adverse events reported in each of
these groups.[44] At the 23.5-month follow-up,
Drugs 2010; 70 (2)
230
TRA
Observation
The US manufacturers prescribing information for trastuzumab has a black box warning regarding cardiomyopathy (section 6).[43]
Trastuzumab treatment may result in subclinical
or clinical cardiac failure (CHF or decreased
LVEF), with a higher incidence and severity of
left ventricular cardiac dysfunction among patients receiving concurrent anthracycline-based
chemotherapy plus trastuzumab.[43] The EMEA
SPC[44] specifies that heart failure (New York Heart
Association [NYHA] class IIIV) occurs particularly following anthracycline-based chemotherapy.
Headache
Arthralgia
Fatigue
Nasopharyngitis
Diarrhoea
Hot flushes
Pyrexia
Nausea
Chills
Peripheral oedema
Back pain
Cough
0
5.2 Cardiac Adverse Events
4
6
8
10
Incidence (% of patients)
12
Fig. 2. Comparative tolerability of adjuvant trastuzumab (TRA)

treatment and observation only in women with human epidermal
growth factor receptor 2 (HER2)-positive early breast cancer.
Adverse events of any grade that occurred with an incidence of
5% during either 1 year of TRA treatment (n = 1678) or observation only (n = 1708) following 4 cycles of chemotherapy in the
randomized, open-label, multicentre HERA trial (as reported in
the European Medicines Agency Summary of Product Characteristics[44]). Refer to table IV for the trial design and regimen details.
y indicates incidence of 0%; j indicates incidence reported as
<1%.
11% of trastuzumab recipients and 6% of those

undergoing observation only had experienced at
least one grade 3 or 4 adverse event (p < 0.0001).[60]
Any one individual grade 3 or 4 adverse event
occurred in less than 1% of patients, the most
common of these events included hypertension
(n = 5 patients) in the observation group and, in
the trastuzumab group, hypertension (12), depression (8), diarrhoea (7), CHF (7), vomiting (6),
arthralgia (5), cardiac failure (5), hot flushes (5),
headache (5) and back pain (5).[60]
At least one serious adverse event occurred in
9% of trastuzumab recipients and 7% of those
undergoing observation only (p = 0.0103).[60] The
corresponding incidence of fatal adverse events
was 0.5% and 0.2%, with none of the events occurring in the trastuzumab group considered to
be trastuzumab-related.[60] A total of 6.8% of
trastuzumab recipients stopped treatment because of safety issues.[60]
In patients with HER2-positive early breast

cancer in clinical trials discussed in section 4,
trastuzumab treatment for 1 year (administered
concurrently or sequentially with chemotherapy)
appeared to be associated with a decrease in
LVEF,[7,55,59,60,68] an increase in the incidence of
CHF (where specified, this was severe [NYHA
class III or IV[54,59,60,68] or grade 3 or 4[55]] or
symptomatic[7] CHF) and discontinuation of treatment as a result of cardiac adverse events. However, the cardiotoxicity observed with concurrent
or sequential trastuzumab treatment appeared to
be mostly reversible following trastuzumab discontinuation,[59,68-70] and no significant increase
in cardiac death was reported.[7,55,59,60,68]
When concurrent therapy was considered, in
NSABP B-31, the median absolute decreases
from baseline in LVEF were 5% in trastuzumab
recipients versus 3% in recipients of the control
chemotherapy regimen at 6 months (p < 0.0001
for between-group difference); with corresponding decreases of 6% versus 2% at 9 months
(p < 0.0001) and 4% versus 3% at 18 months
(p = 0.01).[59]
In NSABP B-31, the 3-year relative risk (RR) of
a cardiac event (confirmed class III or IV CHF or
possible/probable cardiac death[59]) was 5.9 for recipients of concurrent trastuzumab treatment versus
recipients of the control chemotherapy regimen
(p < 0.0001).[59] The 3-year cumulative incidence of
cardiac events was 4.1% vs 0.8%, respectively.[59] A
5-year update on the incidence of cardiac events did
not appear to differ greatly from 3-year data, with a
Drugs 2010; 70 (2)
5-year cumulative incidence of cardiac events of

3.8% in trastuzumab recipients and 0.9% in recipients of the control chemotherapy regimen.[70]
The majority of events were CHF at both timepoints.[59,70] A total of 18.6% of the 714 evaluable
patients discontinued trastuzumab as a result of
cardiac adverse events.[59]
In the third planned analysis of data from
BCIRG 006, the proportions of patients with
a >10% relative decline in LVEF were 19% in
recipients of anthracycline-based chemotherapy
plus concurrent trastuzumab, 9% in recipients
of non-anthracycline-based chemotherapy plus
concurrent trastuzumab and 11% in recipients of
anthracycline-based chemotherapy alone.[55] A
significant difference was found between anthracycline-based chemotherapy plus trastuzumab
and anthracycline-based chemotherapy alone
(p < 0.001) and between anthracycline-based
chemotherapy plus trastuzumab and nonanthracycline-based chemotherapy plus trastuzumab (p < 0.001), but no significant difference
was found between non-anthracycline-based
chemotherapy plus trastuzumab and anthracyclinebased chemotherapy alone.[55]
Anthracyclines were associated with an increased incidence of trastuzumab-associated
CHF in BCIRG 006, with a significant difference
in incidence between recipients of anthracyclinebased chemotherapy plus trastuzumab and recipients of nonanthracycline-based chemotherapy
plus trastuzumab (2.0% vs 0.4%; p < 0.001).[55]
The incidence among recipients of anthracyclinebased chemotherapy alone was 0.7% (p = 0.0121
vs anthracycline-based chemotherapy plus trastuzumab, not significant vs non-anthracyclinebased chemotherapy plus trastuzumab).[55] There
were no cardiac deaths reported in the BCIRG
006 trial.[55]
In terms of sequential therapy, in HERA,
a confirmed significant LVEF drop (defined as
an asymptomatic [NYHA class I] or mildly
symptomatic [NYHA class II] significant drop in
LVEF, confirmed on repeat assessment 3 weeks
following the first drop; alternately, it was identified as a confirmed significant LVEF drop by
the cardiac advisory board) occurred in 3% of
trastuzumab 1-year recipients and 0.5% of pa 2010 Adis Data Information BV. All rights reserved.
231
tients undergoing observation at the 23.5-month

follow-up (p < 0.0001 for between-group difference)[60] and 3.7% and 0.8% at the 48-month
follow-up.[61] The proportion of patients in
FNCLCC-PACS-04 who had a severe drop in
LVEF (<45% of normal or 4549% of normal
plus 15% decline) was 11.1% in trastuzumab
recipients and 2.6% in patients undergoing observation (no statistical data were reported).[7]
In the 23.5-month follow-up of HERA, a significant (p < 0.0001) difference between 1 year of
trastuzumab and observation was found in the
incidence of severe CHF (0.6% vs 0% of patients)
and discontinuation as a result of cardiac adverse
events (4.3% in trastuzumab recipients).[60] Corresponding results from the 48-month follow-up
appear to be generally similar (0.8% vs 0% and
5.2%, respectively)[61] to those from the 23.5month follow-up,[60] but lack statistical analyses.
No significant difference was found between
trastuzumab recipients and those undergoing
observation in the incidence of cardiac death (0%
vs 0.1%) at 23.5 months follow-up;[60] the incidence was 0% versus 0.1% at 48 months followup.[61] Among patients in the observation group
who crossed over to trastuzumab (n = 885) versus
those who did not cross over (n = 469), no patients in either group experienced cardiac death
or severe CHF (NYHA III or IV) at 48 months
follow-up;[61] however, 1.0% and 0.2% experienced symptomatic CHF (NYHA IIIV) and
2.9% and 1.1% experienced a confirmed significant LVEF drop; 4.9% discontinued trastuzumab treatment as a result of cardiac adverse
events.[61]
In FNCLCC-PACS-04, 1.5% of trastuzumab
recipients versus 0.4% of those undergoing observation had CHF, no patients in either group
had cardiac death, and 15.8% of trastuzumab
recipients discontinued as a result of cardiac adverse events.[7]
In NCCTG N9831, the proportions of patients
who had an absolute decrease from baseline in
LVEF of >15%, or an absolute decrease of 1015%
to a value below the LLN, were 7.810.4% during
trastuzumab treatment (i.e. at 9 months in the sequential trastuzumab arm and at 6 and 9 months in
the concurrent trastuzumab arm) and 5.45.8%
Drugs 2010; 70 (2)
232
following trastuzumab treatment (i.e. at 21

months in the sequential trastuzumab arm and at
18 months in the concurrent trastuzumab arm)
versus 4.05.1% at evaluations when patients had
not received trastuzumab (i.e. all evaluations in
the control chemotherapy arm and at 6 months in
the sequential trastuzumab arm).[68]
The 3-year cumulative incidence of cardiac
events in sequential and concurrent trastuzumab
recipients versus recipients of the control chemotherapy regimen in the NCCTG N9831 trial was
2.8% and 3.3% versus 0.3% (RR and statistical
analysis not reported).[68] An update of the cumulative incidence of cardiac events reported
CHF in 22 of 875 recipients of concurrent trastuzumab treatment compared with 1 of 767 recipients of the control chemotherapy regimen,
and a cardiac-related death in one recipient of the
control chemotherapy regimen.[62] The risk of
cardiac dysfunction was increased in elderly patients compared with younger patients in NSABP
B-31 and NCCTG N9831 (statistical data not
available).[43]
Of the patients in NCCTG N9831 who had
discontinued trastuzumab treatment as a result of
an absolute decrease from baseline in LVEF of
>15% or an absolute decrease of 1015% to a
value below the LLN, 50% were eligible to restart treatment at the next evaluation, because
they recovered LVEF function.[68] Of the 35
trastuzumab recipients with confirmed CHF at
the 5-year update of NSABP B-31, 33 were
followed-up for 6 months; 28 of these patients
were symptom free and 20 were receiving cardiac
medication.[70] Of the six control chemotherapy
recipients with confirmed CHF, four were
followed-up for 6 months (two were symptomfree, two were receiving cardiac medication).[70]
In HERA, eight of ten patients with severe CHF
regained an LVEF 55% within a median of 124
(range 36409) days following trastuzumab discontinuation; 35 of 51 patients with a confirmed
significant LVEF drop regained an LVEF 55%
within a median of 191 (13831) days; 41 of
61 patients with any type of cardiac endpoint
regained an LVEF 55% within a median of
189 (13831) days.[69]
5.3 Other Adverse Events
The US manufacturers prescribing information

for trastuzumab has a black box warning regarding
infusion reactions and pulmonary toxicity (section
6).[43] Serious[44] and severe[43] infusion reactions
that have been reported include dyspnoea,[44]
hypotension,[43,44] wheezing,[44] hypertension,[44]
bronchospasm,[43,44] supraventricular tachyarrhythmia,[44] reduced oxygen saturation,[43,44] anaphylaxis,[43,44] respiratory distress,[44] urticaria[44]
and angioedema.[43,44] Fatal infusion reactions have
occurred with trastuzumab administration, within
hours to days following a serious infusion reaction.[43] The majority of infusion reactions have
occurred during or within 2.5[44] or 24[43] hours of
trastuzumab administration. During the first infusion of trastuzumab, chills and fever are commonly
observed;[43,44] these are usually mild to moderate in
severity.[44]
Pulmonary toxicity, while rare, has been reported with the use of trastuzumab in the postmarketing setting, with the events occasionally
being fatal (see section 6 also).[44] Events include
dyspnoea,[43] interstitial pneumonitis,[43,44] pneumonia,[44] pulmonary infiltrates,[43,44] pleural
effusions,[43,44] non-cardiogenic pulmonary oedema,[43,44] pulmonary insufficiency and hypoxia,[43,44] acute respiratory distress syndrome[43,44]
and pulmonary fibrosis.[43,44]
Glomerulopathy has been rarely reported in
the trastuzumab postmarketing setting.[43]
6. Dosage and Administration
Trastuzumab is indicated in the EU for the treatment of HER2-positive (3+ score by immunohistochemistry or a positive fluorescence or chromogenic
in situ hybridization result) early breast cancer following surgery, neoadjuvant or adjuvant chemotherapy, and radiotherapy (if applicable).[44] In the US,
trastuzumab is indicated for adjuvant treatment
of HER2-positive, node-positive or -negative (hormone receptor-negative or with one high-risk feature) early breast cancer either (i) as part of a
regimen that consists of doxorubicin, cyclophosphamide and paclitaxel or docetaxel; (ii) with docetaxel
and carboplatin; or (iii) as a single agent following
Drugs 2010; 70 (2)
233
Table IX. Dosage and administration of adjuvant trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive
early breast cancer
EU[44]a
US[43]
Initial dose
8 mg/kg as an intravenous infusion over

90 minutes
8 mg/kg as an intravenous infusion over 90 minutes
Subsequent doses

90 minutes every 3 weeks

3090 minutes every 3 weeks
Duration
1 year or until disease recurrence within this period
1 year
Initial dose
4 mg/kg
Subsequent doses
2 mg/kg weekly

weekly during chemotherapy, then 6 mg/kg as an
intravenous infusion over 3090 minutes every
3 weeks starting 1 week after chemotherapy
Treatment parameters
Sequential treatment
Concurrent treatment
Duration
1 year or until disease recurrence within this period
1 year
Timing of trastuzumab
and concurrent therapy
Following 4 cycles of doxorubicin (60 mg/m2

intravenous push every 3 weeks) +
cyclophosphamide (600 mg/m2 over 2030 minutes
every 3 weeks), during and following paclitaxel
(administered weekly [80 mg/m2] or every 3 weeks
[175 mg/m2] for a total of 12 weeks)
During and following paclitaxel (12 weeks

treatment), docetaxel (12 weeks treatment), or
docetaxel/carboplatin (18 weeks treatment)
Based on dosages used in clinical trials.[53,54]
multi-modality anthracycline-based therapy.[43]

Table IX shows dosage and administration guidelines for trastuzumab therapy in these regions.
The US manufacturers prescribing information has a black box warning regarding cardiomyopathy (section 5.2) and infusion reactions
and pulmonary toxicity (section 5.3).[43] Trastuzumab treatment should be discontinued in the
event of a clinically significant decrease in left
ventricular function, anaphylaxis, angioedema,
interstitial pneumonitis or acute respiratory distress syndrome.[43] Trastuzumab infusion should
be interrupted for dyspnoea or clinically significant hypotension.[43] The incidence and severity of left ventricular cardiac dysfunction was
highest among patients receiving trastuzumab
concurrent with chemotherapy regimens containing anthracycline.[43] Both the US manufacturers prescribing information and the
EMEA SPC recommend monitoring cardiac
function, as assessed by LVEF, at regular intervals during, and for at least 2 years following,
trastuzumab treatment.[43,44]
Trastuzumab should be administered to pregnant women only if the potential benefit to the
mother justifies the potential risk to the fetus.[43,44]
Local manufacturers prescribing information

should be consulted for contraindications, precautions and warnings, drug interactions, dosage modifications and patient monitoring requirements.
7. Place of Trastuzumab in the Treatment
of HER2-Positive Early Breast Cancer
Trastuzumab has become a standard component
of adjuvant therapy for the treatment of HER2positive early breast cancer.[3,71] US National
Comprehensive Cancer Network guidelines recommend adjuvant trastuzumab treatment (as well
as adjuvant chemo- and endocrine [if the tumour is
hormone-receptor positive] therapy) in patients with
HER2-positive disease if the tumour is node positive, node negative but >1 cm in diameter, or (in
some cases) node negative, <1 cm in diameter and
microinvasive, moderate or poorly differentiated or
with unfavourable features.[3] Treatment with trastuzumab every 3 weeks for 1 year is recommended
in the UK as adjuvant treatment for HER2-positive
early invasive breast cancer, following the appropriate cardiac function assessments.[71] Data from
clinical trials suggest that trastuzumab is more
effective in patients with higher levels of HER2
Drugs 2010; 70 (2)
234
overexpression;[43,44] thus, it is important to accurately detect levels of overexpression or gene

amplification when selecting patients for trastuzumab therapy.
favourable concurrent treatment result), in which

similar proportions of patients to those observed
in FNCLCC-PACS-04 did not start or did not
complete the treatment regimen.[72]
Adjuvant trastuzumab has demonstrated efficacy in patients with HER2-positive early breast
cancer when administered over 1 year in clinical
trials, with regard to the primary endpoint of
disease-free survival (section 4). While all trials
investigating trastuzumab treatment concurrent
with various chemotherapy regimens have demonstrated benefits for this approach over
control chemotherapy regimens in terms of disease-free survival (section 4.1), trials investigating
sequential trastuzumab treatment have produced
mixed results for this endpoint (section 4.2). For
example, in the HERA study and later (5.5 years
follow-up) interim data from the sequential
treatment arm of NCCTG N9831, sequential
trastuzumab treatment was more effective than
observation (or a control chemotherapy regimen)
with regard to disease-free survival, whereas
FNCLCC-PACS-04 and earlier interim data
(1.5 years follow-up) from the sequential arm of
NCCTG N9831 showed no significant difference
between sequential trastuzumab and observation
with regard to this measure (section 4.2). In an
interim analysis of NCCTG N9831, while the
prespecified stringent significance level of an
analysis investigating disease-free survival between concurrent and sequential trastuzumab
treatment was not reached (section 4.3), the authors recommend that trastuzumab be administered concurrently rather than sequentially with
chemotherapy, based on the positive benefit-torisk ratio observed.[57]
Interestingly, sequential trastuzumab treatment provided benefits in overall survival over

observation only at the 23.5-month follow-up in
HERA, and did not significantly differ from
those undergoing observation only in FNCLCCPACS-04 or the control chemotherapy regimen
in NCCTG N9831 (section 4.2). Conversely,
concurrent treatment with trastuzumab and chemotherapy was consistently associated with benefits in overall survival compared with control
chemotherapy regimens (section 4.1). Also, data
from the HERA study suggest that sequential
trastuzumab treatment may have less efficacy
over time relative to observation only, with an
apparent trend towards an increase in the diseasefree survival HR across 1248 months follow-up
and the overall survival HR at the 48-month
follow-up compared with the 12-month followup (section 4.2.1); however, this may have been
due to the confounding effects of observation
patients crossing over to trastuzumab treatment.
While concurrent treatment in the combined
analysis of NCCTG N9831 and NSABP B-31 has
been followed up for a shorter time (2.9 years)
than in HERA, the benefits of concurrent
trastuzumab treatment appear to be sustained
(section 4.1.1).
Some of these data may need to be interpreted

with caution, as there has been some criticism
regarding the validity of data from the
FNCLCC-PACS-04 study (and thus its apparent
conclusion regarding the lack of efficacy of sequential trastuzumab treatment), namely that
some patients in the trastuzumab group did not
start trastuzumab treatment and some did not
receive the full 12 months treatment.[72] This also
occurred with the combined data from NCCTG
N9831 and NSABP B-31 (which demonstrated a
To date, there are no published data available

regarding long-term treatment with trastuzumab.
Additionally, most trials investigating adjuvant
trastuzumab treatment have been confounded by
crossover of control chemotherapy patients to
the trastuzumab arm (section 4), making it difficult to accurately assess whether trastuzumab
prevents or merely delays recurrence, as well as
whether the long-term adverse events eventually
outweigh early survival benefits.
Economic factors are an important consideration
when determining the choice of agents in todays
healthcare systems. Both sequential[12] and concurrent[12,73] trastuzumab treatment have been generally
predicted to be cost effective versus standard care
from a healthcare payer or societal perspective in
Drugs 2010; 70 (2)
modelled analyses in several countries, with the

cost per quality-adjusted life-year and life-year
gained being beneath accepted cost-effectiveness
thresholds. In addition, in a modelled analysis,
concurrent non-anthracycline-based chemotherapy plus trastuzumab was predicted to be dominated by anthracycline-based chemotherapy plus
trastuzumab from a societal perspective in the
US.[73] These analyses all relied on a number of
assumptions and used data from a variety of
sources, including efficacy data from HERA (for
sequential treatment)[12] and NCCTG N9831,
NSABP B-31 and BCIRG 006 (concurrent
treatment);[12,73] further analyses may be required
that incorporate the data from FNCLCC-PACS04 and the sequential treatment arm of NCCTG
N9831 to fully define the cost effectiveness of sequential trastuzumab treatment.
Concurrent or sequential trastuzumab treatment was generally well tolerated in clinical trials
involving patients with HER2-positive early
breast cancer (section 5.1); however, it appeared
to be associated with a decrease in LVEF and an
increased incidence of CHF and discontinuation
of treatment as a result of cardiac adverse events
(section 5.2). Indeed, the US manufacturers
prescribing information for trastuzumab has a
black box warning regarding cardiomyopathy.[43]
This cardiotoxicity appears to be mostly reversible (allowing for retreatment with trastuzumab) and may be less common with sequential
trastuzumab treatment than with concurrent
treatment (section 5.2). Further warnings regarding infusion reactions and pulmonary toxicity are also present in the US manufacturers
prescribing information[43] and the EMEA
SPC.[44] With regard to concurrent treatment,
trastuzumab did not appear to greatly exacerbate
chemotherapy-related tolerability issues in the
clinical trials (section 5.1).
The mechanism of trastuzumab-related cardiotoxicity is fundamentally different from that observed with anthracyclines; anthracycline damage causes myocyte loss and is likely to be permanent and irreversible, whereas trastuzumab
damage has a high likelihood of recovery and
is associated with histologically normal myocytes.[74] The left ventricular dysfunction ob 2010 Adis Data Information BV. All rights reserved.
235
served with trastuzumab treatment is likely to

occur through the binding of trastuzumab to
HER2 on cardiac myocytes, thus blocking
ErbB2-ErbB4 signalling (a cell-protective and
growth-promoting pathway required for cell
survival and function which is stimulated upon
cell stress, such as with anthracycline therapy).[74]
This may explain the apparent lack of cardiotoxicity in the 9-week, multicentre FinHer study
evaluating concurrent trastuzumab plus chemotherapy followed by further, anthracyclinebased, chemotherapy:[8,75] cardiac stress signals
had not yet been activated by anthracyclines at
the time of trastuzumab treatment.
Trastuzumab has shown both synergistic and
additive action with several chemotherapy agents
in preclinical studies (section 2). Most clinical
studies discussed in section 4 included anthracyclines in the trastuzumab regimen; however, in
one study,[55] non-anthracycline-based chemotherapy plus trastuzumab was significantly better
tolerated than anthracycline-based chemotherapy plus trastuzumab with regard to the decrease
in LVEF and the incidence of CHF (section 5.2).
This regimen did not differ significantly from
anthracycline-based chemotherapy alone in this
regard. Efficacy did not appear to be adversely
affected by the lack of anthracyclines, with each
trastuzumab regimen demonstrating a greater
efficacy than anthracycline-based chemotherapy
alone with regard to both disease-free and overall
survival (section 4.1.2).[55]
The ideal trastuzumab treatment regimen is still
to be fully determined: whether to use sequential or
concurrent administration; if administering concurrently with chemotherapy, whether to administer
it before or after anthracyclines (or even whether to
use anthracycline-based chemotherapy at all); and
whether to administer it for a short period (e.g. 9
weeks or 6 months) or a longer period (1 or 2 years).
Some of these questions will be answered upon
publication of data from the 2-year arm of HERA,
full publication of the data from the sequential
versus concurrent treatment arm analysis of
NCCTG N9831, and completion of several ongoing
trials.[76-80] More data, including a longer follow-up
period, are required to fully determine the relative
benefits and optimal treatment regimen.
Drugs 2010; 70 (2)
236
Final results from the FinHer study indicated

that 9 weeks adjuvant trastuzumab treatment
(currently off label in the US and EU) plus concurrent chemotherapy was not effective with
regard to the primary endpoint at 5 years followup compared with chemotherapy alone in patients with HER2-positive early breast cancer
(distant disease-free survival HR 0.65 [95% CI
0.38, 1.12]; p = 0.12),[75] although it was effective
in an interim analysis at 3 years follow-up (recurrence-free survival HR 0.42 [95% CI 0.21,
0.83]; p = 0.01);[8] however, it was generally well
tolerated with an apparent lack of cardiotoxicity,[8,75] and was also cost effective versus standard care from a healthcare payer perspective in
Switzerland[81] and Belgium.[82]
While not yet indicated for neoadjuvant treatment, neoadjuvant trastuzumab has shown
positive results in combination with different
chemotherapy regimens in clinical trials in patients
with HER2-positive early breast cancer;[83-85] a
higher pathological complete response rate was
demonstrated with trastuzumab therapy versus a
control chemotherapy regimen.
In summary, trastuzumab, when administered
concurrently with chemotherapy regimens, consistently prolonged disease-free survival (primary
endpoint) and overall survival (secondary endpoint) in patients with HER2-positive early breast
cancer in well designed trials; studies evaluating
sequential trastuzumab treatment have produced
mixed results for these endpoints. Further study is
required to ascertain the optimal trastuzumab
treatment regimen, including the duration of
treatment. Trastuzumab was generally well tolerated when added to, or administered following, a
chemotherapy regimen in clinical trials. While
cardiac adverse events, such as a decreased LVEF
and CHF, are a concern, these effects are treatable
and appear to be mostly reversible. Thus, trastuzumab is a valuable component of treatment regimens for HER2-positive early breast cancer.
Disclosure
The preparation of this review was not supported by any
external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity
to comment on this article. Changes resulting from comments

received were made on the basis of scientific and editorial
merit.
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Correspondence: Karly P. Garnock-Jones, Adis, a Wolters

Kluwer Business, 41 Centorian Drive, Private Bag 65901,
Mairangi Bay, North Shore 0754, Auckland, New Zealand.
E-mail: demail@adis.co.nz
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ADIS DRUG EVALUATION

Drugs 2010; 70 (2): 215-239

2010 Adis Data Information BV. All rights reserved.

5.3 Other Adverse Events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232

Early breast cancer is currently treated with

Table I. Potential mechanisms of action of trastuzumab (TRA)

Trastuzumab is a targeted biological treatment, indicated for the adjuvant treatment of

TRA monotherapy once-weekly regimen (4 mg/kg LD - 2 mg/kg qw)

TRA monotherapy 3-weekly regimen (8 mg/kg LD - 6 mg/kg q3w)

TRA (8 mg/kg LD - 6 mg/kg q3w) with PAC (175 mg/m2 q3w)

At the end of the dosage interval[45] or up to the last sampling.[46]

At steady state[45] or not specified.[46]

Several in vitro studies have been undertaken to

European Medicines Agency (EMEA) Summary

Ctrough value was 20% lower and the mean

The efficacy of adjuvant trastuzumab treatment concurrent with chemotherapy in early

Breast Cancer International Research

Finnish Herceptin study

Federation Nationale des Centres de

HERA (BIG 01-01)

HERceptin Adjuvant trial (Breast

North Central Cancer Treatment

National Surgical Adjuvant Breast and

Drugs 2010; 70 (2)

AC 60/600 mg/m2 q3w 4 cycles - DOC 100 mg/m2 q3w

AC 60/600 mg/m2 q3w 4 cycles - PAC 175 mg/m2 q3w 4 cycles

HERA (BIG 0101)[53,60,61]

TRA 6 mg/kg q3w 2 y (8 mg/kg LD)f,g

FEC 500/100/500 mg/m2 q3w 6 cycles - RT - TRA 6 mg/kg q3w 1 y

Sequential vs concurrent study

AC 60/600 mg/m2 q3w 4 cycles - PAC 80 mg/m2 q1w

Endocrine therapy was administered in patients with hormone receptor-positive tumours.

TRA administration was dependant on continued acceptable cardiac function.

Results are not yet available for this treatment arm.

least four positive nodes in NCCTG N9831.[54]

with data from the concurrent trastuzumab arm

cancer,[54] contralateral breast cancer[54] other

Adjuvant trastuzumab treatment administered

0.48 (0.39, 0.59)***

0.48 (0.41, 0.57)***

0.67 (0.48, 0.93)*

0.65 (0.51, 0.84)**

0.47 (0.38, 0.59)***

0.47 (0.37, 0.61)***

Modified intent-to-treat population.[54]

effective in patients with HER2-positive early

NCCTG N9831, patients with high serum HER2

4.1.2 BCIRG 006 Trial

8.8%), with 4-year rates of 89.7% and 73.7%

2-year 3-year 4-year 5-year 2-year 3-year 4-year 5-year

Fig. 1. Efficacy of adjuvant treatment with trastuzumab (TRA) in

cycline-based chemotherapy alone, except in patients with a hormone receptor-positive tumour

HR (95% CI) vs AC - DOC

0.49 (0.37, 0.65)***

DOC + CAR + TRA

0.61 (0.47, 0.79)***

0.61 (0.48, 0.76)***

0.59 (0.42, 0.85)**

DOC + CAR + TRA

0.67 (0.54, 0.83)

0.66 (0.47, 0.93)*

0.64 (0.53, 0.78)***

DOC + CAR + TRA