symposium article Annals of Oncology 18 (Supplement 6): vi74–vi76, 2007

doi:10.1093/annonc/mdm230

Management of advanced breast cancer

L. Orlando1, M. Colleoni1, P. Fedele2, A. Cusmai2, P. Rizzo2, M. D’Amico2,
M. C. Chetri2 & S. Cinieri2,3*
1
Unit of Research Medical Senology, European Institute of Oncology, Milano; 2Medical Oncology Division, Brindisi; 3Ematoncology Division, European Institute of
Oncology, Milano, Italy

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Metastatic breast cancer (MBC) is usually considered an incurable situation, for which treatments chosen to
control the disease, should take into account the maintenance of a good quality of life. The end points of
treatment of patients with MBC are influenced by consideration about efficacy and toxicity of the different
therapeutic options. The availability of markers predicting response to treatment as well as the discovery of new
agents have led to the identification of patients likely to obtain significant advantage from different treatment
options. Due to the chronic nature of the MBC, the clinical benefit which encompasses objective response and
long stabilization of disease has often become a goal in the metastating setting.
Key words: metastatic breast cancer, predictive factors

introduction (ER)-positive disease, usually endocrine therapy can achieve an

overall response rate ranging from 30% to 60%, while similar
symposium

Metastatic breast cancer (MBC) is a chronic disease requiring results are obtained with the use of chemotherapy in case of
article

specific strategies to control disease progression and related
symptoms. Treatment can assure a significant prolongation of
survival, symptomatic control and maintenance of quality of
life [1, 2]. The decision-making strategy in choosing therapies
for patients with MBC depends on different factors involving
tumor features, host factors, physician and patient preferences.
MBC is considered not curable, with a median survival of 2–4
years for women with MBC at diagnosis [3]. Despite the
introduction of new therapeutic options, the impact of
therapies on survival is usually very small. Improvement in
time to progression (TTP) and in duration of response,
however, has been achieved with newer combination or new
agent.
The course of MBC is heterogeneous and treatment options
should be chosen to increase total duration of the time with no
or few disease-related symptoms, with the lowest costs in terms
of side-effects of treatment.
treatment options
It is generally accepted that treatment should be offered
immediately after diagnosis of metastases, attempting to defer
the appearance of symptoms. The decision-making process is
complex and requires tailored therapies on the basis of
extension of disease, tumor-related symptoms, comorbidities,
initial estimation of survival, time to expected response to
treatment, patient preference and quality of life. The
appropriate therapy is based on predictive factors able to guide
the therapeutic decision. In the presence of estrogen receptor
*Correspondence to: Dr S. Cinieri, Medical Oncology Division, ASL BR, Brindisi, Italy.
Tel: +39-0831-537218; Fax: +39-0831-537918; E-mail: saverio.cinieri@auslbr1.it
ER-negative disease. Between these scenarios there is a range of
different diseases defined by the grade of endocrine
responsiveness or by the lack of information about hormonal
receptors for which clinical information assume great relevance.
The presence of a long disease-free interval (DFI) from the first
diagnosis of breast cancer and the onset of metastasis, bone
and/or soft tissue involvement, response to previous endocrine
manipulations, and absence of HER2/neu overexpression
define a subpopulation more likely to benefit from endocrine
therapy.
endocrine therapy
Endocrine therapies are usually well tolerated, enhancing their
acceptability as a therapeutic option for patients with MBC.
Endocrine therapy should generally be considered as initial
treatment of patients with newly diagnosed metastatic disease if
the patient’s tumor is ER positive, progesterone receptor (PR)
positive, or ER/PR unknown, about one third of patients
respond to endocrine therapy with median duration of
response of 8–14 months. Chances of response are higher if ER
positive (50%–60% response rate) and/or prolonged DFI, with
metastatic presentation of soft tissue or bone alone. Moreover,
response to one endocrine therapy predicts a higher chance of
effectiveness with subsequent hormonal manipulations. The
chance of subsequent response, however, decreases after the
first line of endocrine therapy [4].
The third-generation aromatase inhibitors have provided
new approaches to the endocrine treatment of MBC. Letrozole
and anastrozole have been shown to be superior to tamoxifen
as first-line treatment of advanced disease. Letrozole resulted in
more tumor regression and was associated with longer time to

ª 2007 European Society for Medical Oncology

Annals of Oncology
disease progression than tamoxifen (9.4 versus 6.0 months;
P = 0.0001) [5]. Also anastrozole resulted in a longer time to
disease progression than tamoxifen (11.1 versus 5.6 months;
P = 0.0005) and a trend towards more tumor regressions [6].
Another trial failed to confirm the superiority of anastrozole
over tamoxifen [7].
chemotherapy
Chemotherapy should be given as initial treatment for all
patients whose aggressive disease requires a fast objective tumor
regression or in case of hormone receptor-negative disease. At
this time, there are no data supporting the superiority of any
particular regimen. The use of taxanes as first-line
chemotherapy has indicated an impact on response rate and
TTP while no clear benefit on survival has been shown. The use
of taxanes should be considered in case of healthy patients and
disease highly symptomatic or life threatening. Recently, the
availability of oral drugs has lead to their extensive use in MBC
patients.
It is not clear whether single-agent or combination
chemotherapy is preferable for first-line treatment. The use of
combination regimens rather than sequential strategies (i.e. use
of different drug after the progression of disease) has shown
a greater response rate and TTP, without advantage in terms of
overall survival (OS) and with increased toxicity compromising
the dose and frequency of the schedule.
A cooperative study randomly assigned patients to receive
paclitaxel and doxorubicin both given as a combination and
sequentially. Response rate was 47% versus 36% versus 34%
and TTP better for the combination (8 versus 6 versus 5.8
months); however, survival resulted to be similar in the three
groups (22 versus 22.2 versus 18.9 months) [8].
Few chemotherapy clinical trials in MBC have claimed an OS
benefit for a particular regimen compared with another [9].
This advantage, however, seemed to disappear after crossover
to combination arm for patients randomly assigned to the
single-agent arm. For the majority of patients with MBC ÔcureÕ
is not the goal of treatment, so more conservative treatments in
order to improve quality of life and palliate symptoms are
required. Another important question concerns the dose and
schedule of chemotherapy. The strategies usually implied to
improve the response rate are based on increased dose intensity,
increased dose density, increased frequency (without reducing
dose) usually with autologous stem-cell support. The
Philadelphia trial failed to show an advantage in terms of OS
(25.8 versus 26.1 months) and TTP (9.6 versus 9.1 months)
with the use of high-dose chemotherapy and autologous stem-
cell transplantation compared with conventional dose
chemotherapy [10].
The question of the duration of chemotherapy for advanced
breast cancer is the goal of the meta-analyses of randomized
studies comparing shorter with longer duration which have
shown a statistically significant advantage in terms of OS and
quality of life for patients treated with longer chemotherapy.
This evidence supports a policy of continuing therapy in the
absence of progression or prohibitive toxicity [11].
Chronically, administration of lower doses and more
frequent schedule of cytotoxics (metronomic delivery) have
been tested, in order to optimize the antiangiogenic effects, to
Volume 18 | Supplement 6 | June 2007
symposium article
minimize toxicity and overcome the repair of endothelial cells.
The availability of low toxic and easily delivered regimens that
may be administered for a long duration without significant
toxicity could provide an effective therapy and a good quality of
life. Recently, two trials have shown a response rate of 19% and
20.9% and a clinical benefit (partial remission plus complete
remission plus stable disease ‡24 weeks) of about 40% with the
use of low-dose cyclophosphamide (50 mg daily) plus
methotrexate (5 mg daily twice a week) in patients with MBC
[12, 13].
biologic therapy
The overexpression of Her2/neu (human epidermal growth
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factor receptor 2) represents the only reliable predictive factor
other than hormone receptors of response to treatments. Her2/
neu is overexpressed in 20%–25% of breast cancer, indicating
a role for its overexpression in tumorigenesis. Breast cancer that
overexpresses Her2 has a more aggressive course and higher
relapse and mortality. Trastuzumab is a humanized mAb
directed against the extracellular domain of Her2. Trastuzumab
alone or in combination with chemotherapy has led to an
increase in overall response rate and survival for cancers
overexpressing Her2/neu.
Trastuzumab as a single agent resulted in a response rate of
21% in patients pretreated with chemotherapy. Patients treated
with chemotherapy plus trastuzumab had an OS advantage as
compared with those receiving chemotherapy alone (25.1
versus 20.3 months, P = 0.05) [14].
Vascular endothelial growth factor (VEGF) is the most
potent and specific antigenic factor and has been identified as
a crucial regulator of both normal and pathological
angiogenesis. The recombinant humanized anti-human VEGF
mAb (bevacizumab) inhibits several activities of VEGF,
including endothelial cell growth, vascular permeability and
angiogenesis.
Synergy with many cancer chemotherapeutic agents was
observed in preclinical studies and in phase I and phase II trials
and confirmed in phase III trials. Bevacizumab both alone and
in combination with chemotherapy was well tolerated, with
hypertension, proteinuria, thrombosis and bleeding being the
most commonly reported toxic effects.
A phase II, open-label clinical trial of bevacizumab
monotherapy produced encouraging results in patients with
breast cancer [15]. This study treated 75 patients with MBC
with bevacizumab at escalating doses of 3 (n = 18), 10 (n = 41),
and 20 mg/kg (n = 16) administered intravenously every other
week. Objective responses were documented in seven of 75
(9.3%, 6.7% confirmed) patients. The median duration of
confirmed response was 5.5 months (range 2.3–13.7 months),
with one ongoing partial response at 10 months. The optimal
dosage of bevacizumab in that trial was found to be 10 mg/kg
every other week, and toxicity was deemed to be acceptable, as
only four patients (5.3%) stopped bevacizumab because of
adverse events. In another phase II trial, patients received
bevacizumab (at a dose of 10 mg/kg every 2 weeks) and
vinorelbine at a dose of 25 mg/m2/week until progression. This
trial has observed 17 responses (one complete and 16 partial)
among 55 patients (31% objective response rate) [16].
Bevacizumab was also studied in a phase III clinical trial in
doi:10.1093/annonc/mdm230 | vi75
symposium article
which previously treated patients with MBC were randomized
to treatment with capecitabine alone or capecitabine plus
bevacizumab. Although adding bevacizumab to capecitabine
produced a highly statistically significant greater objective
response rate (19.8% versus 9.1%), in the primary end point of
the study, there was no effect on progression-free survival
(PFS). Responses to bevacizumab tended to be short and were,
therefore, not translated into improved PFS times, which were
equivalent at 4.9 months in the combination arm and 4.2
months in the capecitabine-alone arm. Recently, a phase III
randomized trial which compared paclitaxel with
a combination of bevacizumab plus paclitaxel as first-line
treatment of MBC reported an increased objective response rate
(28.2% versus 14.2%) and improved PFS with bevacizumab
and paclitaxel.
conclusions
Metastatic disease is a chronic disease and the impact of
therapy on improvement in quality of life and palliation of
symptoms is an important goal of treatment of patients with
MBC. All the treatment options should be discussed with the
individual patient with clear explanation of the risk-to-benefit
ratio. The subjective attitude of the patient is one of the major
factors which influence the choice and acceptance of
a therapeutic program.
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Volume 18 | Supplement 6 | June 2007