Download when should trastuzumab be stopped after

Tumori, 93: 491-492, 2007
WHEN SHOULD TRASTUZUMAB BE STOPPED
AFTER ACHIEVING COMPLETE RESPONSE IN HER2-POSITIVE METASTATIC
BREAST CANCER PATIENTS?
Manuela Beda, Umberto Basso, Cristina Ghiotto, and Silvio Monfardini
Department of Medical Oncology, Istituto Oncologico Veneto-IOV, Padua, Italy
We report the case of a woman with HER2-positive metastatic breast cancer who achieved prolonged complete remission of multiple liver metastases after treatment with weekly
trastuzumab plus paclitaxel but relapsed in the brain soon
after stopping trastuzumab maintenance therapy which had
been prosecuted for almost three years. In the absence of
randomized trials, the optimal duration of trastuzumab administration after achieving complete remission of metastatic breast cancer remains questionable.
Key words: brain metastasis, breast cancer, duration of treatment, HER2, trastuzumab.
Introduction
The association of trastuzumab and a taxane is the
standard chemotherapy option for patients with
metastatic HER2-positive breast cancer, with published
complete remission rates of about 7-8%1,2 and a median
time to progression of 6.92 to 11.7 months1. Following
the design of the first registrative trials1,2, the drug prescription label recommends that trastuzumab be administered as far as the patient is responsive, but no data is
available concerning the real benefit of such prolonged
therapy and the potential long-term toxicities are practically unknown, especially for the cardiovascular system. At the same time, the huge costs associated with
prolonged trastuzumab administration pose a serious
limitation to its unconditioned use in the absence of
demonstrated efficacy.
Case report
A 36-year-old white woman came to our observation
4 years ago with locally advanced breast cancer, clinical
stage T3N2. In December 2002 neoadjuvant chemotherapy with epirubicin (70 mg/m 2 ) plus docetaxel
(70 mg/m2) was administered for 4 cycles every 21
days, obtaining a partial clinical response. In April 2003
she underwent conservative surgery plus axillary node
dissection for invasive ductal carcinoma, pT2N1, grade
3, with vascular invasion, 4 positive lymph nodes out of
12 removed, hormone receptor negative status, Mib1
10-15%, and HER2 positivity (DAKO HercepTest 3+).
She received adjuvant chemotherapy with 4 cycles of
CMF on days 1 and 8 every 28 days, plus radiation
therapy to the right breast. Abdominal and brain CT
scan performed in April 2003 were negative for recurrence. In February 2004 a liver MRI revealed multiple
liver nodules (2 cm maximum diameter), which were
confirmed to be breast cancer metastases by fine-needle
aspiration biopsy. She immediately started first-line
chemotherapy with weekly paclitaxel (80 mg/m2) and
Herceptin (4 mg/kg first dose and 2 mg/kg thereafter).
The first revaluation with MRI performed in June 2003
showed a complete response in the liver. We therefore
decided to continue only with maintenance trastuzumab,
which was given every 3 weeks. Subsequent chest and
abdomen CT scans were performed every 3-4 months
and were all negative, and cardiac monitoring with
echocardiography did not show any signs of cardiac
damage. In April 2006 the patient was still in complete
remission, and we decided to stop trastuzumab after almost 3 years of absence of any signs or symptoms of
disease. Unfortunately, after 2 months the woman reported episodes of transient headache and dizziness,
with a slight impairment of movement of the upper right
limb. She therefore underwent a brain CT scan in June
2006, which revealed multiple brain lesions with contrast enhancement. The patient was soon referred for
whole-brain irradiation and at the end of radiotherapy
restarted systemic chemotherapy with trastuzumab plus
weekly paclitaxel, although chest and abdomen CT scan
did not reveal any other sites of disease, because evidence of benefit from continued use of trastuzumab after
first progression is accumulating3.
Discussion
HER2 is a membrane-bound protein with tyrosinekinase properties which is overexpressed in approximately 20% to 30% of breast cancers. Overexpression
of HER2 protein has been shown to be associated with
increased tumor proliferation and relative resistance to
Correspondence to: Manuela Beda, MD, Divisione di Oncologia Medica, Istituto Oncologico Veneto, Via Gattamelata 64, 35126 Padova, Italy.
Tel +39-049-8215931; fax +39-049-8215932; e-mail [email protected]
Received November 17, 2006; accepted March 19, 2007.
492
some cytotoxic and endocrine therapies. Trastuzumab,
a humanized monoclonal antibody directed against
HER2 protein, has been shown to be an efficacious and
well-tolerated treatment for HER2-overexpressing
metastatic breast cancer, especially when it is used in
combination with chemotherapy 4. Brain metastases
from breast cancer typically occur in 10-15% of patients and are associated with a survival of 3-6 months.
Recent series have shown that women with HER2-postive metastatic breast cancer receiving trastuzumab
more frequently develop brain metastases, up to 2534% of cases5,6. CNS metastases in these patients may
develop despite response achieved in extracerebral
sites. This pattern of failure has mainly been attributed
to the lack of penetration of trastuzumab to the CNS
owing to its high molecular weight (145 kDa). Additionally, increased risk of CNS relapse may be associated with improved systemic control of extracerebral
metastases and prolonged survival without brain protection (a sanctuary site)6. Finally, it was postulated
that HER2/neu overexpression and/or amplification
might predispose to brain metastases7. Our patient had
a complete and long-lasting response of her liver
metastases as long as trastuzumab was administered,
and relapsed within 3 months after its cessation. Even
if one might argue that the brain is a sanctuary that is
not exposed to maintenance trastuzumab, the close
time link between trastuzumab interruption and relapse
makes us wonder if at least some type of biohumoral or
immunological mechanisms might have played a role.
M BEDA, U BASSO, C GHIOTTO, S MONFARDINI
If the treatment had not been stopped, might the relapse
have been avoided or at least delayed? No one has an
answer. The high incidence of brain relapse in HER2positive breast cancer has prompted some authors to
recommend close monitoring of the CNS in all HER2positive patients by means of CT or MRI brain scans
(to be performed every 3 or 6 months), in order to allow early detection of brain metastases in asymptomatic patients and to improve the results of surgery or
radiosurgery in these patients8. Others have provocatively advocated prophylactic cranial irradiation strategies in patients achieving complete response after systemic chemotherapy9. Since such intensive follow-up
might enhance patients’ anxiety and further increase the
cost of care of HER2-positive breast cancer, we think
that proof of efficacy should be produced before recommending its indiscriminate use in the clinical practice. Our patient did not undergo brain CT scan at regular intervals, so cerebral disease might have been developing before maintenance trastuzumab was stopped.
Yet, the rapid onset of symptoms soon after cessation of
treatment supports our theory that the withdrawal of
trastuzumab might have altered the biology of the disease and its complex interactions with the host. The objective efficacy of prolonged maintenance trastuzumab
compared to observation in HER2-positive patients
achieving complete response to first-line treatment
should be tested in randomized trials. Meanwhile, the
decision of whether trastuzumab should be stopped or
not in such patients remains strongly controversial.
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