Key words breast cancer - Her-2/neu - metastasis - chemotherapy - trastuzumab
Schlüsselwörter Mammakarzinom - Her-2/neu - Metastasierung - Chemotherapie - Trastuzumab
Introduction
Breast cancer is the most common malignancy in women. Despite increasing treatment
options and the
availability of potentially curative therapy for primary disease, metastatic disease
is still considered
incurable [1 ]. Therapeutic approaches for metastatic disease are of a
palliative nature and must be evaluated according to their potential to preserve patientsʼ
quality of
life. For this reason, AGO recommends the administration of less toxic substances
as first-line
treatment of metastatic disease (http://www.ago-online.de ). Treatment therefore consists primarily of endocrine and
targeted therapies.
Human epidermal growth factor receptor (HER2) is overexpressed in around 20 % of breast
cancers. HER2
overexpression is associated with more aggressive tumor growth and a poorer prognosis
[2 ], [3 ]. Compared to HER2-negative tumors,
HER2-positive tumors occur more frequently in younger women and node-positive women
and often respond
less well to cytotoxic or endocrine therapies [4 ], [5 ]. The monoclonal antibody trastuzumab (Herceptin®) plays an important role in the
treatment
of HER2-positive metastatic breast cancer. It binds to the extracellular domains of
HER2-receptors,
inhibiting the HER2 signaling pathway and promoting the destruction of tumor cells
by the immune system
[6 ], [7 ]. Trastuzmab was approved for treatment
of metastatic breast cancer by the FDA in 1998 and in Europe in 2000.
Trastuzumab is effective both as a monotherapy and in combination with other substances
[8 ]. The current standard for first-line therapy is a combination of trastuzumab
with the taxanes paclitaxel and docetaxel [9 ], [10 ]. Synergies between trastuzmab administration and other cytostatic substances have
also been
reported [11 ], [12 ]. The combination of
trastuzumab with endocrine therapies results in a less toxic therapy regimen [13 ]. The continued administration of trastuzumab across different therapy lines (treatment
beyond progression, TBP) has been shown to offer benefits for the treatment of HER2-positive
metastatic
breast cancer [14 ], [15 ].
Trastuzumab is generally well tolerated. Apart from rare allergic reactions, the most
important side
effect associated with trastuzumab therapy is cardiotoxicity, which manifests primarily
as an
asymptomatic decrease in left ventricular ejection fraction (LVEF) [16 ].
Cardiac dysfunction occurring with trastuzumab administration has been particularly
noted in patients
who had prior anthracycline-based therapy. Regular echocardiographic follow-up every
three months of
patients to monitor LVEF is therefore recommended during trastuzumab therapy [17 ]. As decreases in LVEF are usually reversible, therapy with trastuzumab can often
be
continued as long as cardiovascular risks are closely monitored ([Table
1 ]).
Table 1 Management of cardiac side-effects.
LVEF
Trastuzumab administration
Echocardiography
Modification of [33 ]
slightly reduced
continue therapy
every 4 weeks
reduced to < 45 %
continue therapy
every 2–4 weeks
reduced to < 30 %
temporarily discontinue therapy
every 2 weeks
reduced to > 30 %
stop therapy
Although approval of trastuzumab was based on large prospective studies, there is
not much data on the
long-term administration of trastuzumab. The aim of this study was to evaluate the
tolerability and
clinical practice of long-term trastuzumab administration (> 1 year) in metastatic
breast cancer
patients treated in a large university breast center.
Material and Method
The clinical data of all female patients with metastatic breast cancer treated at
the University Hospital
of Tübingen between August 1999 and February 2012 who received at least 18 doses of
trastuzumab were
included (administration interval: 3 weeks; dosage: 6 mg/kg, intravenous; loading
dose: 8 mg/kg).
Treatment cycles administered in the (neo-)adjuvant situation were only counted if
metastatic disease
occured during or directly after (neo-)adjuvant treatment and if tratstuzumab therapy
was continued for
at least 18 applications in the metatstatic setting. Patients were also excluded from
the study if there
were no records of regular (every 3 months) follow-up with echocardiography done either
by the
Cardiology Department of the Medical University Hospital of Tübingen or by an external
physician.
The patientʼs HER2 status was evaluated using the HerceptTest™ (DAKO, Glostrup, Denmark).
The
HerceptTest™ uses immunohistochemical staining for the semi-quantitative detection
of HER2 expression,
which is assessed using a scale from 0 to 3+. A score of 3+ conclusively indicates
a HER2-positive
status, while a score between 0 and 1+ signifies that the tumor is HER2-negative.
If the score is 2+,
FISH test (Pathvysion® Kit, Vysis, Downers Grove, IL, USA) is used to re-evaluate
HER2
amplification.
All data were recorded on Excel spreadsheets (Version 2007, Microsoft, Redmond, Washington
DC, USA).
Statistical evaluation was done using PASW Statistics 20 (SPSS Inc., Chicago, IL,
USA). Figures were
produced using Prism 5 (GraphPad Software, La Jolla, CA, USA). The measures of central
tendency, mean
and standard deviation were calculated for continuous variables; frequency distributions
were calculated
for categorical variables. Survival curves were calculated using the Kaplan-Meier
method. Time from the
start of trastuzumab administration till progression was analyzed. If no progression
occurred during the
period under observation (i.e. during trastuzumab therapy), these cases were removed
from analysis at
the end of the period observation (i.e. at the end of trastuzumab treatment).
Results
Description of cohort
A total of 72 patients were included in the study ([Table 2 ]). The
majority of patients (68 %) were node-positive at primary diagnosis. Tumor size at
primary operation
was more than 2 cm in the majority of patients (pT2–4, 67 %) and the tumor grade was
G1–2 in the
majority of patients (63 %). 31 % of patients had primary metastasis, 56 % were ER-positive
and 44 %
were PR-positive.
Table 2 Clinical data at primary diagnosis.
Characteristic
n (%)
IDC: invasive ductal carcinoma, ILC: invasive lobular carcinoma, IHC:
immunohistochemistry
Grading
45 (63)
25 (35)
2 (3)
Tumor size
22 (31)
48 (67)
2 (3)
Lymph node status
49 (68)
18 (25)
5 (6)
Metastasis
45 (63)
22 (31)
5 (6)
Histology
57 (79)
15 (21)
ER status
40 (56)
32 (44)
PR status
32 (44)
40 (56)
HER2 status (IHC)
16 (22)
56 (78)
Average age at the start of trastuzumab treatment was 59 years (standard deviation
[SD]: 11 years;
median: 62 years). The youngest patient at first administration was 29 years old,
the oldest patient
was 83 years old ([Table 2 ]). Most patients (75 %) were post-menopausal.
The average number of administrations was 50.14 ([Fig. 1 ]), the lowest
number was 18 and the highest was 149 (SD: 27.51).
Fig. 1 Number of trastuzumab administrations. Median, lower/upper quartile (box) and the
lowest/highest number of administrations (whisker) are shown.
Type of initial trastuzumab therapy
Two patients (3 %) had previously received trastuzumab in the (neo-)adjuvant treatment
setting ([Table 3 ]). These patients received at least 18 further doses of
trastuzumab in the metastatic setting. The majority of patients (54 patients, 69 %)
received
trastuzumab as a first-line therapy. Trastuzumab was administered as a second-line
therapy in 8
patients (11 %), as a third-line therapy in 5 patients (7 %) and as a fourth-line
therapy in 3 (4 %)
patients.
Table 3 Clinical data at the start of trastuzumab treatment.
SD: standard deviation
Age in years, mean ± SD (range)
59 ± 11 (29–83)
Menopausal status, n (%)
9 (13)
54 (75)
9 (13)
Type of initial trastuzumab therapy, n (%)
2 (3)
54 (75)
8 (11)
5 (7)
3 (4)
Previous anthracycline-based therapy, n (%)
42 (58)
Cardiac risk factors, n (%)
34 (47)
1 (1)
24 (77)
6 (19)
7 (22)
4 (13)
Combination therapy, n (%)
29 (40)
30 (42)
14 (19)
11 (15)
6 (8)
1 (1)
30 (42)
Treatment beyond Progression, n (%)
53 (74)
37 (51)
12 (17)
4 (6)
Therapy discontinued (n) %
12
11
1
13 (3–20)
Previous cardiac risk factors
Forty-two patients (58 %) had previously received anthracycline-based treatment ([Table 3 ]). One patient had previous symptomatic cardiac disease (coronary
heart disease). At the beginning of trastuzumab therapy, 34 patients (47 %) presented
with classic
cardiac risk factors (coronary heart disease, arterial hypertension, diabetes mellitus,
hypercholesterolemia, nicotine abuse).
Treatment beyond progression and discontinuation of therapy
In 53 of 60 patients who experienced disease progression during trastuzumab therapy,
the TBP
principle was used for an average of 2.4 therapy lines ([Table 3 ]). The
most commonly used combination agents were taxanes (42 % of patients) and aromatase
inhibitors (42 %
of patients), followed by vinorelbine (40 % of patients) and capecitabine/gemcitabine
(19 % of
patients). Treatment was temporarily discontinued in 12 patients for an average of
12 months ([Table 3 ]). Disease progression was responsible for discontinuing therapy
in the large majority of these cases. In three of these patients treatment was switched
to
lapatinib. Median progression-free survival from the start of trastuzumab therapy
was 13.44 (95 %
confidence interval: 7.46–19.43) months ([Fig. 2 ]).
Fig. 2 Kaplan-Meier curve showing time to progression (in months) since the start of
trastuzumab therapy.
Side effects and termination of therapy
Seven (10 %) patients had an asymptomatic decrease in LVEF during trastuzumab treatment
([Table 4 ]). In 6 of 7 cases, LVEF normalized again over the course of
treatment. Only 1 patient terminated therapy because she experienced progressive decrease
of LVEF
with the development of symptomatic cardiac insufficiency despite pausing therapy.
Interestingly,
none of the patients temporarily discontinued therapy because of cardiac side effects.
Nine patients
(13 %) had hypersensitivity reactions with flu-like symptoms. One patient had to terminate
trastuzumab therapy due to intolerance. The most common reason for terminating therapy
was disease
progression (22 patients, 31 %); 17 (24 %) patients terminated therapy at their own
request, and 7
(10 %) patients died during therapy. Twenty-two patients (31 %) were still receiving
treatment at
the time of data analysis.
Table 4 Side effects.
* 1 × intolerance; 1 × symptomatic cardiac insufficiency
Side effects, n (%)
7 (10)
9 (12,5)
Reasons for discontinuing therapy, n (%)
22 (31)
22 (31)
17 (24)
7 (10)
2 (3)*
1 (1)
Discussion
The introduction of targeted therapies was an important milestone in the treatment
of HER2-positive
breast cancer. In 1998, trastuzumab was the first recombinant antibody drug to be
approved for the
treatment of metastatic breast cancer. Trastuzumab is effective as a monotherapy as
well as in many
different combinations with established cytostatic drugs, aromatase inhibitors and
other targeted
substances [9 ], [10 ], [11 ], [13 ], [18 ]. The wide range of
combinations, the option of using trastuzumab across different therapy lines and the
good tolerability
of trastuzumab mean that patients with HER2-positive metastatic breast cancer often
receive trastuzumab
over lengthy periods of time.
The most significant side effect of trastuzumab therapy is its cardiotoxicity [9 ]. Depending on the therapeutic setting, the incidence of cardiotoxic side effects
is
between 1–27 %. The reported incidence of cardiotoxic side effects for trastuzumab
monotherapy is
2–11 %; when trastuzumab is administered in combination with anthracyclines up to
27 % of patients may
experience a decrease in LVEF [19 ], [20 ], [21 ]. The incidence of patients experiencing a decrease in LVEF was reported to
be lower in the adjuvant setting compared to the metastatic setting [22 ].
The decrease in LVEF is usually reversible. This means that treatment with trastuzumab
can usually be
continued when patients are asymptomatic and have only a limited drop in LVEF as long
as patients are
monitored carefully. If LVEF drops to below 30 %, trastuzumab administration should
be temporarily
discontinued; however, therapy can be resumed if the patient is asymptomatic and LVEF
recovers [17 ]. In our study, treatment was only terminated for one patient due to
symptomatic cardiac insufficiency; in 6 patients, the decrease in LVEF was asymptomatic
and transient,
which meant that treatment could be resumed.
The low rate of cardiac side effects found in our study corresponds to the data reported
in the
literature and appears to be due to that fact that no patient in our study received
combination therapy
of Herceptin with anthracyclines, as this approach is considered obsolete in the metastatic
setting.
However, the majority of patients had received anthracyclines prior to enrolment in
our study. Moreover,
more than half of our patients had no cardiac risk factors at the start of treatment
with trastuzumab.
The majority of these patients were older than 62 years (χ2 -test: p = 0.002, data not shown).
We found no association between the existence of cardiac risk factors, prior anthracycline-based
therapy
or patient age and the occurrence of decreased LVEF (Fisherʼs exact test, data not
shown). Although this
finding has only limited statistical significance due to the low number of cases,
it corresponds to the
results of a larger study by Guarneri et al. [23 ]. Trastuzumab therapy can
and should (under regular and close cardiac monitoring) therefore be also offered
to older patients or
patients with cardiac risk factors. Guarneri and colleagues do, however, point out
that cardiac toxicity
can be accompanied by an unremarkable LVEF. The use of alternative non-invasive screening
tools, for
example the determination of cardiac troponin and of brain natriuretic peptides, is
still being
evaluated in clinical trials [22 ], [24 ]. Moreover,
the selection of patients for our study was based on good tolerance a priori of trastuzumab,
as one
inclusion criterion was treatment duration of at least 1 year. A further limitation
of our study was the
lack of follow-up; possible long-term toxicities were not recorded.
Long-term administration of trastuzumab was well tolerated. Patients in the investigated
cohort also had
comparatively long progression-free survival rates. At the time of data analysis,
one patient with
pulmonary metastases had been receiving trastuzumab since 8 years and the course of
her disease had been
stable ever since. In this context, one could even say that, with trastuzumab, breast
disease in this
patient had become chronic. But when interpreting these data it is important to take
into account that
only patients who underwent treatment with trastuzumab for at least 1 year were included
in the study.
Overall survival was therefore per se at least 1 year.
The most common combination drugs used together with trastuzumab therapy were taxanes
and vinorelbine.
Compared to taxane monotherapies, a combination of paclitaxel or docetaxel and trastuzumab
is associated
with significantly improved survival [10 ], [11 ].
The combination of trastuzumab and vinorelbine has been shown to be similarly effective
and is
additionally tolerated better [11 ]. AGO has already recommended such a
regimen to treat HER2-positive metastatic breast cancer in early therapy lines (http://www.ago-online.de ). Cytostatic therapies were
generally terminated after 6 cycles or, in cases with intolerance or progression,
already after 3
cycles. If there was no progression of disease, almost all patients (depending on
their previous history
of therapy and hormone receptor status) received either maintenance therapy combined
with an aromatase
inhibitor or trastuzumab administration was continued as a monotherapy. The TBP principle
was used to
treat patients with disease progression. Another alternative was switching to lapatinib
(e.g. in
combination with capecitabine), particularly to treat patients with metastases of
the central nervous
system.
The synergies between trastuzumab and numerous substances used in the therapy of metastatic
breast cancer
is the basis for the TBP principle which was followed in around two thirds of all
patients. In addition
to various retrospective analyses, the prospective randomized GBG 26/BIG 03-05 study
was able to show
for the first time that the administration of trastuzumab beyond progression resulted
in longer
progression-free survival times [14 ], [15 ], [25 ]. The authors suggest that, while trastuzumab loses its anti-proliferative
effect as disease progresses, it still retains its efficacy as a chemosensitizer.
The antibody-drug
conjugate trastuzumab-emantasine (T-DM1) is an innovative approach which combines
the synergies of
HER2-targeted treatment with cytostatic therapies. It is used to selectively target
HER2-overexpressing
tumor cells, inhibits HER2-dependent signaling pathways and only releases the chemotherapeutic
component
DM1 inside the tumor cell. T-DM1 was approved for the treatment of metastatic breast
cancer in 2013
based on the results of the EMILIA trial.
Another option for extensively pretreated patients consists of combining the HER2-targeting
tyrosine
kinase inhibitor lapatinib and trastuzumab [26 ]. The successful principle of
a dual HER2 blockade is also achieved using the combination of trastuzumab plus pertuzumab
[27 ]. Based on data from the CLEOPATRA trial, AGO recommends the combination
therapy trastuzumab + pertuzumab + docetaxel as the new standard for first-line therapy
of metastatic
HER2-positive breast cancer (http://www.ago-online.de ).
As the HER2 status of the primary tumor is not necessarily representative of the HER2
status of
metastases [28 ], [29 ], [30 ], [31 ], AGO recommends reevaluating the receptor status of
metastatic tissue (http://www.ago-online.de ).
However, this is an invasive procedure which is associated with increased morbidity.
In our cohort the
positive HER2 status of metastatic tissue was reevaluated in 3 patients; one of these
3 patients was
initially HER2-negative (data not shown). The DETECT-III trial will prospectively
investigate whether
the HER2 status of circulating tumor cells obtained from 7.5 ml whole blood is suitable
to predict the
efficacy of HER2-targeted therapy in the metastatic setting [32 ].
Trastuzumab is usually administered as an intravenous infusion; a subcutaneous formulation
for the
administration of trastuzumab has recently been developed [33 ]. But this
formulation was not yet available for our study. Both the efficacy and the safety
profile of this new
formulation appear to correspond to those of a “classic” intravenous infusion. In
addition to
administering a fixed dosage, the advantage of the new form of administration is that
it significantly
reduces the time required for administration: the injection takes around 3 to 5 minutes
compared to
30–90 minutes for a standard intravenous infusion. This is the reason why patients
prefer subcutaneous
administration. Subcutaneous injection appears to offer a promising approach, particularly
for long-term
treatments and in the context of ensuring the best possible quality of life for patients
[34 ].
Conclusion
With the availability of trastuzumab therapy for HER2-positive breast cancer, the
a priori poorer
prognosis of these patients is now on a par with that of HER2-negative patients. The
experience in our
large university breast center shows that trastuzumab is well tolerated, even when
administered for
longer periods, and can be combined with different therapeutic options. The majority
of our patients
have received trastuzumab since their first-line therapy. Neither the existence of
cardiac risk factors
nor older patient age affected the good tolerability. Although cardiac side effects
only rarely required
the therapy to be terminated, regular cardiac monitoring is essential. Trastuzumab
appears not only to
improve survival but also contributes to improving the quality of life of patients
with metastatic
breast cancer. In future, subcutaneous administration of trastuzumab could further
improve patientsʼ
quality of life.
