ARTICLE
Auteur(s) :, Filip Janku, Olga Pribylova, Martina Zimovjanova, Gabriela Pazdrova, Martin Safanda, Milad Zemanova, Lubos Petruzelka
Department of Oncology, First Faculty of Medicine, General
Teaching Hospital, Charles University. U Nemocnice 2, 128 08 Praha
2, Czech Republic
<filip.janku@vfn.cz>
The HER2/neu oncogene encodes a 185 kD transmembrane protein
with tyrosine kinase activity. This glycoprotein belongs to the
family of epidermal growth factor receptors [1]. Overexpression of
HER2/neu was found in several solid tumors including breast
cancer, lung cancer, prostate cancer, ovarian, gastric and
pancreatic cancer [2,3]. In breast cancer overexpression of
HER2/neu has important biological consequences. In
preclinical models HER2/neu was associated with higher
tumorigenicity and metastatic potential [4]. HER2/neu
overexpression is considered as a negative prognostic factor in
women with breast cancer leading to shorter disease free survival,
overall survival and more aggressive tumor behavior [5].
HER2/neu receptor creates homodimers or heterodimers with
other members of epidermal growth factor receptor family (EGFR,
HER3, HER4) on the cell surface, which leads to triggering a
cascade of growth signals. Studies performed with viral ligands
suggest that HER2/neu evolved as ligandless receptor [6] or
this ligand has not been identified so far. The most common and
most potent association occurs between HER2/neu and HER3.
Interestingly, HER3 has no intrinsic tyrosine kinase activity and
cannot respond to ligand binding unless associates with another
receptor, such as HER2/neu, which provides the intracellular
signaling [6].
HER2/neu overexpression is found in 25 %-30 %
breast cancers usually as a consequence of HER2/neu gene
amplification [5,7]. There are many techniques of HER2/neu
testing. Immunohistochemistry (IHC) measuring protein expression on
the cell surface is widely practiced by pathologists around the
world and is fast and relatively cheap. Fluorescence in-situ
hybridization (FISH) measuring gene amplification is easily
reproducible but expensive. In general, there is a good agreement
between the testing strategies. However, there are cases of IHC
“positive” tests with no evidence of gene amplification. There are
conversely cases of genetic amplification without increased surface
expression [8]. Currently used scoring system for
immunohistochemistry has the scale from 0 to 3+. Results 0 and 1+
are understood as negative and 2+ and 3+ as positive [9]. Nowadays,
only 3+ expression is indication for treatment with
anti-HER2/neu monoclonal antibody, because concordance with
FISH is over 75 % [10]. All 2+ cases should be confirmed by
FISH (agreement with FISH only 24 %-39 %) [10,11]. The
definition and standardization of optimal HER2/neu assay is
still in a process.
Using the specific humanized anti- HER2/neu monoclonal
antibody trastuzumab (Herceptin®, Roche®) we
can block the activity of HER2/neu protein and stimulate
antibody dependent cellular cytotoxicity [12]. Trastuzumab
demonstrated activity in clinical trials in women with
HER2/neu overexpressing metastatic breast cancer as a single
agent achieving response rates ranged from 12 % to 27 %
[13–15]. The pivotal phase III trial compared trastuzumab +
chemotherapy to chemotherapy alone (either doxorubicin,
cyclophosphamide or paclitaxel; all given in 3 week cycles). Data
indicated that trastuzumab in combination with chemotherapy
produced significantly increased time to progression (TTP),
response rate (RR) and overall survival (OS). Of particular note is
that addition of trastuzumab to 3-weekly paclitaxel therapy more
than doubled median TTP and almost doubled RR [16]. Combination of
trastuzumab and paclitaxel administered both weekly might have
further potential to improve therapeutic results achieved with
weekly trastuzumab and 3-weekly paclitaxel. When we designed our
trial there was no study available confirming the activity of
weekly paclitaxel with trastuzumab.
Patients and methods
Eligibility
Women with histologically confirmed advanced breast cancer
overexpressing HER2/neu were eligible for the purpose of
this study. Patients had to be from 18 to 75 years old, with
performance status at least 60 % and higher according to the
Karnofsky scale. All patients signed written informed consent.
Patients were pretreated with two or more regimens for advanced
disease. In case of early recurrence after adjuvant chemotherapy
(less than 12 month) patients pretreated only with one regimen for
advanced disease were also eligible. All patients were previously
treated with antracyclines (mainly in the adjuvant setting) and all
except one with taxanes. Any hormonal treatment except LHRH analogs
had to be discontinued before study entry. Laboratory criteria
included absolute neutrophile count (ANC) > 1 000/ll, hemoglobin
> 80g/l, platelets > 10 000/μl, adequate hepatic and
renal function. Left ventricular ejection fraction had to exceed
50 %. Patients with history of serious cardiac disease were
excluded. Patients with clinically unstable metatastases to the
brain were not allowed to enter the study. Patients were ineligible
if they had a history of other malignancy (except carcinoma in-situ
of the cervix or nonmelanoma skin carcinoma). Women with
childbearing potential had to use reliable contraception while on
study and had a negative pregnancy test before entering. Baseline
evaluation included a complete physical examination, history,
complete blood count with differential and platelet count,
chemistry, echocardiogram, and lesion measurement as appropriate
for disease assessment. Her2/neu status was determined using
rabbit 4D5 antihuman HER2/neu polyclonal antibody
(HercepTest®, Dako).
Treatment
Trastuzumab was administered 4 mg/kg intravenously over 90
minutes as a loading dose with subsequent weekly doses 2 mg/kg
over 30 minutes. Paclitaxel 80 mg/m2 was
administered intravenously over 60 minutes the day after
trastuzumab loading dose and subsequently the same day after
trastuzumab infusion. The treatment was delivered in the outpatient
clinic of our department. Treatment was administered every week
until disease progression or unacceptable toxicity. Paclitaxel
could have been discontinued due to toxicity with further
administration of trastuzumab alone until disease progression.
Routine premedication before paclitaxel infusion consisted of
8 mg of dexamethasone intravenously (IV), 100 mg
cimetidine or 20 mg famotidine IV and 1 mg clemastine IV.
Paclitaxel had to be omitted or discontinued for hematologic
toxicity (ANC < 1 000/μl, platelets < 100 000/μl),
peripheral neuropathy grade 3 and higher.
Response and toxicity evaluation
Complete blood count was obtained every week or every other week
when paclitaxel was discontinued. Serum biochemistry was repeated
every four weeks. Echocardiography was performed at least every 16
weeks and at any other time if necessary. Toxicity was graded
according to Common Toxicity Criteria National Cancer Institute
Version 2.0.
Responses to therapy were evaluated according to WHO criteria
[17]. The same method as at baseline was used throughout the study.
Complete response (CR) was defined as a complete disappearance of
all signs of tumor confirmed after 4 weeks or later. A partial
response (PR) was defined as a more than 50 % reduction in the
sum of products. Progressive disease (PD) was defined as 25 %
or bigger increase in the sum of products. All other cases were
evaluated as a stable disease (SD).
Immunohistochemical analysis
Specimens of either primary or metastatic tumor from all 17
patients were tested for overexpression of HER2/neu with
polyclonal antihuman antibody as described before. We used widely
accepted scale when score 3+ is strongly positive, score 2+ is
moderately positive, score 1+ means weak positivity, and score 0 is
negative. Only patients with 3+ and 2+ results were eligible the
for protocol. FISH analyses were not performed. Based on increasing
knowledge that trastuzumab might have been ineffective in majority
of 2+ FISH unconfirmed cases we enrolled since May 2000 only
patients with 3+ score.
Statistical methods
Statistical analysis was performed using software Statistica
version 6 (StatSoft® 2003). The primary endpoint of this
trial was the overall response (OR) to the regimen combining
trastuzumab and paclitaxel. Secondary endpoints were TTP, OS and
toxicity. TTP was defined as a time from study entry to documented
progression. OS was defined as a time from study entry to death.
The median TTP and median OS were estimated by the Kaplan-Meier
method. TTP was censored in the following circumstances: patient
was still receiving treatment without evidence of progression,
patient died of unknown cause without evidence of clinical
deterioration due to breast cancer and patient discontinued
treatment for any reason without evidence of clinical deterioration
due to breast cancer before discontinuation. The same criteria were
applied for OS. All patients treated with advanced breast cancer
documented at study entry and treated were included in the efficacy
intent-to-treat population. Safety analysis included all patients
who received at least one dose of study drug.
Results
Efficacy data
Between July 1999 and January 2001, 17 eligible patients were
enrolled in our institution onto this study. The characteristics
are listed in Table 1. Only two
patients had IHC 2+, all other IHC results were 3+. All patients
except one were pretreated with taxanes for metastatic disease (14
with docetaxel and 2 with paclitaxel administered every 3 weeks).
Altogether 710 cycles of treatment including 528 cycles of
trastuzumab plus paclitaxel were delivered. The median number of
treatment cycles per patient was 33 (1-169). In one case only first
dose of trastuzumab was given with subsequent severe hypersensitive
reaction. This patient could not have been evaluated for OR. There
were no principal protocol deviations. Paclitaxel was discontinued
or omitted due to toxicity in 12 patients with permanent
discontinuation in 7 patients.
Table 1. Patient
characteristics (n = 17)
|
Characteristics
|
Patients
|
|
Nb
|
%
|
|
Age
|
|
– Median
|
50
|
|
|
|
– Range
|
36-66
|
|
|
|
Prior chemotherapy
|
|
|
|
– 2 prior regimens
|
|
6
|
35
|
|
– ≥ 3 prior regimens
|
|
11
|
65
|
|
No. of metastatic sites
|
|
– 1
|
|
7
|
41
|
|
– 2
|
|
4
|
24
|
|
– ≥ 3
|
|
6
|
35
|
|
Visceral metastases
|
11
|
64
|
|
IHC HER2/neu (Herceptest)
|
|
– 3+
|
|
15
|
88
|
|
– 2+
|
|
2
|
12
|
|
IHC ER
|
|
– ER +
|
|
4
|
24
|
|
– ER -
|
|
11
|
64
|
|
Unknown
|
|
2
|
12
|
|
Taxne free interval
|
|
– > 1 year
|
|
7
|
41
|
|
– ≤ 1 year
|
|
9
|
53
|
|
Not pretreated with taxanes
|
|
1
|
6
|
Response data are listed in Table 2.
There were 2 CRs and 8 PRs with an objective response rate
59 % in the intent-to-treat population. Two patients had
stable disease for at least 24 weeks and 4 patients progressed on
therapy. One patient was not evaluated for reasons mentioned
before. The first CR was proven in 53 years old woman with
infiltration of soft tissues of chest wall, and the second CR
occurred in 36 years old women with multiple liver involvement. The
first CR was maintained for 25 weeks and the second CR for 152
weeks since first documented. One patient with PR after 16 cycles
was referred to surgery for removal of residual disease in
contralateral breast. She remains disease free for next 68
weeks.
Table 2. Response to
therapy
|
Response
|
Patients
|
|
Nb
|
%
|
|
Overall response
|
10
|
59
|
|
Complete response
|
2
|
12
|
|
Partial response
|
8
|
47
|
|
Stable disease
|
2
|
12
|
|
Disease progression
|
4
|
23
|
|
Not Assessed
|
1
|
6
|
|
Response in patients with TFI ≤ 1 year
|
6
|
66,6
|
|
> 1 year
|
4
|
57
|
|
Response in 3+ IHC population (N=15)
|
10
|
66,6
|
In the median follow up 4,3 years the median TTP in the
intent-to-treat population was 6 month (range: 1-43). The median
survival was 23 months (range: 2-62) with 3 patients alive at the
time of analysis. The 1-year survival in the intent-to-treat
population was 71 %, 2-years survival 47 %, 3-years
survival 29 %, and 4 years survival 18 % of patients. In
the subgroup with TFI > 1 year 3 PRs and 1 CR were observed. In
the subgroup with TFI ≤ 1 year there were achieved 5 PRs and 1 CR.
There was no statistically significant correlation between TFI and
response to therapy. TFI did affect neither TTP (p = 0.75) nor OS
(p = 0.87).
Safety and toxicity data
All 17 patients were evaluated for toxicity table 3. In total there were delivered 710
cycles including 528 cycles of paclitaxel plus trastuzumab with no
dose adjustments. The median number of cycles per patient was 33
(range: 1-169). Paclitaxel was omitted or discontinued in 12
patients. Paclitaxel toxicity, mainly neurotoxicity, led to
permanent discontinuation of the drug in 7 patients. Infusion
related pyretic reaction after the first trastuzumab infusion
occurred in 6 patients (35 %). One patient experienced serious
hypersensitivity reaction with dyspnea, shortness of breath and
hypertension when receiving first trastuzumab infusion. This event
led to the treatment discontinuation. The therapy limiting adverse
effect was cardiotoxicity. Left ventricular ejection fraction
decline grade 2 occurred in 1 and grade 3 in 1 patient. The
treatment was discontinued in both cases. One patient achieved CR
and another PR with no further tumor regression. Hematological
toxicity was very modest. We noted only 1 episode of grade 4
neutropenia and 1 episode of grade 3 anemia. No growth factors were
administered and only 3 units of blood transfusion were given.
There were observed 4 episodes of grade 3 infection without
neutropenia treated with antibiotics with no further complications.
Grade 3 elevation of liver function tests occurred in 1 patient
with no need of dose reduction. Five patients experienced grade 3
neuropathy, which eventually led to paclitaxel discontinuation. We
observed grade 3 weight gain in 1 patient, grade 2 weight gain in 6
patients and 1 episode of grade 3 hyperglycemia. Other toxicity was
very rare.
Table 3. Toxicity profile of
weekly trastuzumab and paclitaxel
|
Toxicity
|
NCI grade (% of patients)
|
|
2
|
3
|
4
|
|
Neutropenia
|
|
-
|
-
|
1 (6 %)
|
|
Leucopenia
|
|
3 (18 %)
|
-
|
-
|
|
Anemia
|
|
1 (6 %)
|
1 (6 %)
|
-
|
|
Infusion related reaction:
|
6 (35 %)
|
|
|
|
|
Cardiotoxicity
|
|
1 (6 %)
|
1 (6 %)
|
-
|
|
Edema
|
|
5 (29 %)
|
-
|
-
|
|
Neuropathy
|
|
3 (18 %)
|
5 (29 %)
|
-
|
|
Infection
|
|
7 (41 %)
|
4 (24 %)
|
-
|
|
Nausea/vomiting
|
|
1 (6 %)
|
-
|
-
|
|
Heartburns
|
|
1 (6 %)
|
-
|
-
|
|
Diarrhea
|
|
1 (6 %)
|
-
|
-
|
|
Hypacusis
|
|
2 (12 %)
|
-
|
-
|
|
Onycholysis
|
|
3 (18 %)
|
-
|
-
|
|
Weight gain
|
|
6 (35 %)
|
1 (6 %)
|
-
|
|
Transaminitis
|
|
3 (18 %)
|
1 (6 %)
|
-
|
|
Hyperglycemia
|
|
-
|
1 (6 %)
|
-
|
Discussion
When the accrual started there were no published phase II or III
data regarding trastuzumab plus paclitaxel given weekly. We assumed
sufficient efficacy based on results of pivotal phase III trial
with 469 HER2/neu overexpressing metastatic breast cancer
patients treated in the first line with combination of weekly
trastuzumab with paclitaxel at a dose 175 mg/m2 every 3
weeks [16]. The addition of trastuzumab to paclitaxel almost
doubled RR and prolonged TTP and OS. However the response rate in
paclitaxel montherapy arm was only about 17 %. Most potent
combination of AC and trastuzumab was not recommended for clinical
use due to high number of cardiac events. Number of cardiac events
reported in trastuzumab/paclitaxel arm was smaller. In previous
clinical studies, paclitaxel administered as a single agent in
doses similar to that used in this study produced response rates
ranging from 21 % to 53 % in women with metastatic breast
cancer [18,19]. Relative efficacy, safety, and impact on quality of
life of the conventional every 3-week dosing of paclitaxel at a
dose of 175 mg/m2 by 3-hour infusion with weekly
trastuzumab compared with the weekly regimen evaluated in this
study have been studied in CALGB 9840. This study was just recently
presented at the annual meeting of American Society of Clinical
Oncology in June this year [20]. Weekly paclitaxel in metastatic
breast cancer were significantly more effective in terms of RR
(40 % versus 28 %) and TTP (9 months versus 5 months). OS
also favored weekly administration however results did not reach
statistical significance. In our subset we reported RR 59 %,
TTP 6 month and OS almost 2 years. These results are better than
one might expect in this heavily pretreated population.
The evaluation of HER2/neu expression has been thoroughly
investigated last several years. There was found 75-89 %
concordance between FISH positivity and 3+ result of IHC [10,11]
but only 24-39 % of patients who were 2+ positive by IHC had
also positive FISH result. The relative lack of benefit in 2+
population implicated the suggestion that all 2+ results should be
confirmed by FISH before the treatment initiation. Therefore after
May 2000 no patients with 2+ results were enrolled on our trial.
None of 2+ patients achieved objective response. One patient
progressed on therapy while the other was not even assessed because
of severe hypersensitive reaction during first trastuzumab
infusion. RR evaluated in IHC 3+ population was 66,6 % (10 out
of 15 patients).
Docetaxel and paclitaxel are frequently used in breast cancer
therapy. After positive results of several adjuvant trials [21–23]
they are increasingly used in the adjuvant setting. Therefore we
decided to perform previously unplanned analysis whether there is
any relationship between the time after the completition of
previous taxane therapy and treatment outcomes. TFI did not affect
response to therapy, TTP and OS duration.
Because there is the potential for cardiac dysfunction in patients
treated with trastuzumab [24], cardiac function was monitored in
all patients. In the majority of patients, LVEF was maintained
during study treatment. There were only two patients who had some
cardiac complications. However, the decline in left ventricular
ejection fraction was reversible after discontinuation of study
medication. The mechanism of trastuzumab induced cardiac damage is
not well understood. Clinicopathologic studies are underway to
identify the molecular principles of trastuzumab-associated cardiac
toxicity.
Pyretic reaction following the first trastuzumab infusion was
described in 35 % of patients, which is more than in pivotal
trial [16]. In contrast to other groups we observed some unexpected
weight gain and hyperglycemia that might have been related to
dexamethasone premedication.
Combination of trastuzumab and paclitaxel administered both weekly
has the potential to further improve treatment outcomes with weekly
trastuzumab and paclitaxel administered every 3 weeks. The
evaluation of this active doublet is ongoing in the adjuvant
setting in a large randomized intergroup adjuvant trials (NCCTG
9831, NSABP B31) for patients with axillary lymph node–positive,
HER2/neu-overexpressing breast cancer. In this single
institution prospective open labeled clinical trial we showed that
weekly administration of trastuzumab and paclitaxel is active in
the treatment of HER2/neu overexpressing advanced breast
cancer patients with only limited number of adverse event.. n
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