review Annals of Oncology 20: 1771–1785, 2009

doi:10.1093/annonc/mdp261
Published online 16 July 2009

Third consensus on medical treatment of metastatic

breast cancer
S. Beslija1, J. Bonneterre2, H. J. Burstein3, V. Cocquyt4, M. Gnant5, V. Heinemann6, J. Jassem7,
W. J. Köstler8, M. Krainer8, S. Menard9, T. Petit10, L. Petruzelka11, K. Possinger12, P. Schmid13,
E. Stadtmauer14, M. Stockler15, S. Van Belle4, C. Vogel16, N. Wilcken17, C. Wiltschke8,
C. C. Zielinski8,18* & H. Zwierzina19 for the Central European Cooperative Oncology Group
(CECOG)
1
Institute of Oncology, Sarajevo, Bosnia and Herzegovina; 2Centre Oscar Lambret, Lille, France; 3Dana-Farber Cancer Institute, Boston, MA, USA; 4Oncologisch
Centrum, Universitair Ziekenhuis, Gent, Belgium; 5Department of Surgery, Medical University of Vienna, Vienna, Austria; 6Medizinische Klinik und Poliklinik III Klinikum
Großhadern, Munich, Germany; 7Department of Oncology and Radiotherapy, Medical University, Gdansk, Poland; 8Clinical Division of Oncology, Department of
Medicine I, Medical University of Vienna, Vienna, Austria; 9Istituto Tumori, Milan, Italy; 10Centre Paul Strauss, Strasbourg, France; 11Department of Oncology, Charles
University, Prague, Czech Republic; 12Medizinische Klinik der Charite, Berlin, Germany; 13Charing Cross Hospital, Imperial College, London, UK; 14University of
Pennsylvania Cancer Center, Philadelphia, PA, USA; 15Sydney Cancer Centre, Royal Prince Alfred Hospital and Concord Hospitals, University of Sydney,

review
Camperdown, Sydney, New South Wales, Australia; 16Breast Cancer for Aptium Oncology at Lynn Cancer Institute-West, Boca Raton, FL, USA; 17Department of
Medical Oncology and Palliative Care, Westmead Hospital, Sydney, Australia; 18Central European Cooperative Oncology Group, Vienna, Austria and 19Department of
Medicine l, Medical University of Innsbruck, Austria

Received 17 February 2009; revised 23 March 2009; accepted 30 March 2009

Background: Treatment options for patients with metastatic breast cancer (MBC) include a rapidly expanding
repertoire of medical, surgical and supportive care measures.
Design: To provide timely and evidence-based recommendations for the diagnostic workup and treatment of patients
with MBC, an international expert panel reviewed and discussed the evidence available from clinical trials regarding
diagnostic, therapeutic and supportive measures with emphasis on their impact on the quality of life and overall
survival of patients with MBC.
Results: Evidence-based recommendations for the diagnostic workup, endocrine therapy, chemotherapy, use of
targeted therapies and bisphosphonates, surgical treatment and supportive care measures in the management of
patients with MBC were formulated.
Conclusions: The present consensus manuscript updates evidence-based recommendations for state-of-the-art
treatment of MBC depending on disease-associated and biological variables.
Key words: diagnosis, metastatic breast cancer, prognosis, treatment

introduction patients with MBC [1]. In contrast to a series of very relevant

Breast cancer is the most common malignancy among women
in the developed countries. Although impressive improvements
have been made in the adjuvant treatment of early breast
cancer, 20% of patients initially diagnosed with regional stage
disease will develop metastatic breast cancer (MBC) [1, 2]. The
medical treatment of MBC offers a wide range of options
including chemotherapy, endocrine treatment, therapy with
antibodies directed against growth factors relevant to the
disease, tyrosine kinase inhibitors (TKIs) and supportive
measures. The abundance of treatment options has contributed
to an impressive amelioration of prognosis in a proportion of
*Correspondence to: Prof. C. C. Zielinski, Clinical Division of Oncology, Department of
Medicine I, General Hospital, Medical University of Vienna, 18–20 Waehringer Guertel,
A-1090 Vienna, Austria. Tel: +43-1-40400-4445; Fax: +43-1-40400-4428;
E-mail: christoph.zielinski@meduniwien.ac.at
consensus statements and recommendations on adjuvant
treatment of early breast cancer [3–6], only very few similar
initiatives have been undertaken to generate a consensus on the
medical treatment of MBC [7] with the one generated by the
Central European Cooperative Oncology Group (CECOG)
ranking among the first [8]. The second CECOG consensus on
the medical treatment of MBC was published only in 2007 [9].
Since then, a series of important new drugs have been
successfully brought to the market, and some well-known drugs
have been further developed in clinical trials necessitating an
update of treatment recommendations within an interval of 2
years.
The current consensus on the medical treatment of MBC
continues the tradition of previous similar publications by
CECOG [8–10] in that all participants had to agree upon its
content and evidence-based recommendations for state-of

ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
review
the-art treatment, considering available treatment options in
relation to various clinical and biological variables.
Encouraged by previous considerations and recent data, the
panel agreed to hold up its previous statement [9] that the
primary goals of treatment in MBC include
 maximizing the quality of life (QoL),
 prevention and palliation of symptoms and
 prolongation of survival
Concordant with the previous recommendation [9] and due to
the biological variability of the patient and her disease, the
decision for the optimal timing of treatment initiation and the
continuation of treatment has to be made on an individual
basis.
Treatment choices for MBC are guided by
 hormone receptor [estrogen receptor (ER) and progesterone
receptor (PgR)] status of the primary tumor or its metastases,
 HER-2/neu status,
 the duration of the relapse-free interval since primary
diagnosis and since completion of adjuvant therapy for breast
cancer,
 the location and extent of metastases (visceral versus
nonvisceral),
 previous treatment (including its effects and tolerance),
 patient symptoms,
 patient preferences,
 anticipated side-effects of treatment and
 the availability and access to treatment
methods of consensus formation
panel composition
The CECOG has invited an expert panel consisting of experts in clinical
medicine (i.e. medical oncology, radiotherapy and surgical oncology) and
clinical and translational research with a focus on expertise in breast cancer
to examine evidence focused upon medical treatment of MBC. In doing so,
experts were asked to consider previous recommendations made by the
group in preceding years [8, 9] and to put them into perspective with recent
data, with special emphasis upon their impact on clinical practice. The
panel participants were from Australia, Europe and the United States.
literature review and analysis
In accordance with previous reports [8, 9], MBC was defined according to
the tumor–node–metastasis system classification (6th edition) of the
American Joint Committee on Cancer [11] as any T, any N, M1 tumor of
the breast. Similar to previous publications, the present recommendations
of the consensus panel concern patients with stage IV disease.
In analogy to our methods, electronic and manual searches including
Medline and The Cochrane Library (search terms: breast cancer, metastatic
and clinical trial) and abstracts published in the proceedings of major
international oncology meetings including conferences of the American
Society of Clinical Oncology, the San Antonio Breast Cancer Symposium,
the European Conference of Clinical Oncology, the European Society of
Medical Oncology and the European Breast Cancer Conference were used
for identifying relevant literature. Articles or abstracts were selected for
inclusion to a systematic review of the literature on the management of
patients with MBC if they represented randomized controlled trials (RCTs)
with appropriate control groups or meta-analyses of RCTs in patients with
1772 | Beslija et al.
Annals of Oncology
stage IV breast cancer. Data from phase II clinical trials or retrospective
analyses were included only in case of lack of evidence from randomized
phase III clinical trials. As mentioned above, the main goals of treatment in
patients with MBC include prevention and palliation of symptoms,
maximizing the QoL and prolongation of survival. However, like in
previous reports [8, 9], the panel recognized that most randomized clinical
trials enrolling patients with MBC were not designed to provide
a quantitative comparison of differences in survival adjusted by the
concomitant changes in QoL, i.e. to measure differences in quality-adjusted
life years. Thus, the panelists agreed that for consensus formation regarding
therapies targeting the tumors, overall survival (OS) should be the primary
outcome of interest and that significant differences in QoL or toxicity
between interventions should be indicated. In contrast, differences in QoL
were the primary outcome of interest for supportive care interventions.
Progression-free survival (PFS) and response rates (RRs) or disease
stabilization were considered as secondary outcomes.
consensus formation
The panel formed subcommittees of two to six participants. Each
subcommittee was assigned a coordinator and independently reviewed
publications addressing particular aspects relating to the medical
management of MBC including (i) endocrine treatment, (ii) cytotoxic
therapy, (iii) treatment of Her-2/neu-overexpressing MBC, (iv)
bisphosphonates, (v) supportive care, (vi) surgery, (vii) high-dose therapy
and (viii) future directions.
Each subcommittee independently reviewed and summarized the data
available until December 2008 from articles published in peer-reviewed
medical journals and abstracts presented at international cancer conferences
for the assigned aspect in the management of MBC. Each subcommittee
presented a consensus proposal. Recommendations of the consensus panel
represent statements that all members of the panel agreed upon.
All members of the panel participated in the preparation of a draft
guideline document, which was then repeatedly disseminated for review by
the entire panel. Final text editing was completed by CCZ and WJK and
accepted by all panelists.
diagnosis of MBC and assessment of
biological variables
The panel continued to agree that histological or cytological
verification of metastatic disease is not required routinely,
although a biopsy of a metastatic lesion may be advisable to
confirm the presence of metastatic tumor (if there is ambiguity)
and to characterize the biological markers associated with
tumor recurrence including the reassessment of the ER and PgR
status by standardized immunohistochemistry (IHC) and of
Her-2/neu status by IHC or FISH.
Diagnostic imaging workup should include assessment of
frequent sites of metastases including the lung, liver and
bone. In addition, radiological imaging of the central nervous
system (CNS) should be considered in Her-2/neu-positive
patients [12].
recommendations for the assessment of steroid
receptor expression
Standardized testing and quality control of steroid receptor
determination remains to be mandatory due to the discordance
rate between local and central laboratory testing for ER and
PgR [13, 14]. Expression of ER and PgR should be reported in
a semiquantified way (e.g. by using the Allred score).
Volume 20 | No. 11 | November 2009
Annals of Oncology
recommendations for the assessment of Her-2/neu
protein overexpression and gene amplification
Her-2/neu status should be assessed by IHC, FISH or
chromogenic in situ hybridization (CISH). When carried out in
central laboratories with appropriate expertise, the level of
concordance between Her-2/neu 3+ overexpression assessed by
IHC and FISH or CISH is high [15–17]. Results of 3+ IHC or
FISH positivity in high-volume laboratories continue to be the
gold standard for the detection of Her-2/neu positivity.
In tumors with 2+ protein overexpression by IHC, FISH
testing should be carried out for the decision on an indication
for treatment with Her-2/neu-directed therapies such as
trastuzumab and lapatinib [18, 19]. The panel repeated
previous recommendations that efforts to standardize testing
for Her-2/neu overexpression should be strongly encouraged.
For IHC, Her-2/neu testing should be carried out by
a standardized assay and scoring system according to the
manufacturer’s recommendations (HercepTest
, DAKO Inc.,
Glostrup, Denmark) [18].
Data indicating a benefit for trastuzumab in the adjuvant
setting for patients who have neither overexpression by IHC
nor gene amplification by FISH should be considered as
hypothesis generating [20] in the light of results of the CALBG
9840 trial which failed to demonstrate any apparent clinical
benefit of trastuzumab in patients with Her-2/neu-negative
MBC receiving first-line paclitaxel chemotherapy [21].
The panel declared that the determination of Her-2/neu
status is obligatory in all breast cancer patients. Upon
occurrence of MBC, Her-2/neu status can be assessed on
histological samples from metastases or the primary tumor, as
changes in Her-2/neu expression/amplification have been
reported to occur occasionally [9].
prognostic factors
As stated in the previous consensus [9], a number of clinical
and biological prognostic factors are associated with long-term
clinical outcomes among women with MBC (Table 1). Since
breast cancer is a very heterogeneous disease, these criteria
do not lend themselves to dichotomize risk strata, but are
clinically relevant for the choice of treatment and determining
prognosis.
Table 1. Prognostic factors in patients with metastatic breast cancer
Prognostic factor Favorable Unfavorable
Performance status Good Poor
Sites of disease Bone, soft tissue Viscera, CNS
No. of sites of disease Few Multiple
Hormone receptor status Positive Negative
Her-2/neu status Negative Positive (significance
less clear in Her-2/neu
inhibitors era)
Disease-free interval >2 years <2 years
Prior adjuvant therapy No Yes
Prior therapy for MBC No Yes
CNS, central nervous system; MBC, metastatic breast cancer.
Volume 20 | No. 11 | November 2009
review
The panelists continued to acknowledge that this
classification should not be regarded as rigid, but may
constitute the basis for treatment recommendations [9].
endocrine treatment
In general and as recommended previously [9], endocrine
treatment should be offered as first option to most women with
hormone-sensitive MBC. This recommendation is based upon
lower toxicity of endocrine treatment and generally longer
durations of response in this subset as compared with cytotoxic
chemotherapy, with no difference in OS [22]. Patients with
hormone-sensitive MBC are typically characterized by
 a long disease-free interval (>2 years),
 no (or limited) visceral involvement,
 limited metastatic sites and disease-related symptoms and
 slow disease progression
Patients relapsing during or within 12 months after the end of
adjuvant endocrine treatment are considered resistant to the
specific endocrine drug and should be offered alternative
therapies. Based upon data from early breast cancer and MBC,
the concurrent use of endocrine treatment and cytotoxic
chemotherapy in MBC is discouraged [9]. In patients with very
limited metastatic disease, local treatments (e.g. surgical
resection and radiation therapy) or watchful waiting may be
considered, although there are no data from randomized trials
supporting or discouraging this practice.
Only a limited amount of new important data has been
generated in recent years, which would lead to a change in
recommendations reached by the panel previously [9].
Briefly, the following recommendations have been
reconfirmed for the endocrine treatment of postmenopausal
patients with hormone receptor-positive MBC:
 The use of a third-generation nonsteroidal (anastrozole and
letrozole) or steroidal (exemestane) aromatase inhibitor was
recommended as first-line treatment with tamoxifen
remaining to constitute a valuable option.
 Following tamoxifen failure, a third-generation aromatase
inhibitor or the selective ER downregulator fulvestrant is
recommended for second-line treatment.
 Following failure of a third-generation nonsteroidal
aromatase inhibitor, a steroidal aromatase inhibitor [23–25],
tamoxifen (or toremifen) [26], fulvestrant, progestins,
estrogens or androgens may be considered [27, 28]. In the
Evaluation of Faslodex versus Exemestane Clinical Trial trial,
which enrolled patients after treatment failure on
nonsteroidal aromatase inhibitors, RR, PFS and OS were
similar with exemestane and fulvestrant [29]. However, no
definitive recommendation for a treatment cascade can be
given at present.
 The different side-effect and toxicity profiles as well as the
route of administration of tamoxifen, aromatase inhibitors
and fulvestrant should be considered in the choice of
endocrine treatment in the individual patient.
In premenopausal patients with endocrine-dependent MBC,
tamoxifen, ovarian function suppression or a combination of
doi:10.1093/annonc/mdp261 | 1773
review
both continue to constitute suitable treatment options [30–32],
although the combination of luteinizing hormone–releasing
hormone (LH–RH) agonist and tamoxifen may be superior to
LH–RH agonist alone [33]. In this population of patients, there
are insufficient data on the use of aromatase inhibitors, which
should be given only in conjunction with some form of
adequate suppression of ovarian function [34].
cytotoxic chemotherapy
general recommendations
Chemotherapy remains the mainstay of treatment in MBC. The
goals of chemotherapy in this setting are to prolong survival,
alleviate or prevent tumor-related symptoms and improve QoL.
However, in contrast to endocrine therapy, chemotherapy is
more likely associated with considerable and notorious side-
effects that have to be balanced against potential benefits.
Therefore, primary chemotherapy should generally be offered
to patients whose tumors are not sensitive or are refractory to
hormone therapy. The candidates to chemotherapy are also
patients with bulky visceral disease, severe tumor-related
symptoms or rapid progression, irrespective of hormone-
receptor status. At the onset of chemotherapy, an assessment of
cancer-related symptoms and performance status should be
carried out. Initial disease staging should allow fair assessment
of the baseline tumor burden. During therapy, patient
symptoms and performance status have to be recorded with
each cycle. To avoid continuing ineffective therapy, tumor
response should be assessed every two or three cycles.
Laboratory tests should be carried out before each
chemotherapy administration to secure treatment safety.
Integrated assessment of chemotherapy benefits should include
anticancer efficacy, amelioration of cancer-related symptoms
and treatment-related side-effects. The current line of
chemotherapy should be stopped if prohibitive toxicity or overt
progression arises. At progression, in most instances further
treatment with new agents should be considered.
There is a paucity of data on prospectively evaluated
molecular predictors that could govern the individualized
choice of chemotherapeutic agents in patients with MBC [35,
36]. This shortcoming, however, is expected to resolve upon
successful validation of genomic information on predictors of
drug sensitivity and resistance in ongoing prospective clinical
trials [37].
When considering chemotherapy in MBC, the following
scenarios have to be considered:
 First-line treatment
 Chemotherapy after anthracycline pretreatment
 Chemotherapy after anthracycline and taxane pretreatment
first-line treatment
sequential single-agent versus multidrug chemotherapy. An
overview of randomized trials indicates that first-line multidrug
chemotherapy in MBC is associated with higher RRs, longer
PFS and a modest, if any, improvement in OS compared with
sequential single-agent treatment administered at the
maximum tolerated dose [38]. However, the randomized trials
1774 | Beslija et al.
Annals of Oncology
that compared combination chemotherapy with specified,
sequential single-agent treatment, while confirming higher RRs,
did not show improved survival [39–41]. Multidrug approach
has been usually associated with increased toxicity. In contrast,
a recently presented CECOG study has shown that sequential
use of docetaxel and gemcitabine could result in unexpectedly
higher toxicity as compared with their combined application,
probably due to higher chemotherapy dosages used in the
former [41]. Nevertheless, an additional benefit of single-agent
sequential chemotherapy is that this strategy allows efficacy
assessment of particular agents.
recommendation. Current experience indicates that sequential
use of single cytotoxic agents with proven efficacy in breast
cancer is a considerable alternative to standard multidrug
chemotherapy regimens, perhaps except for patients with
rapidly progressive visceral disease.
anthracyclines. Anthracyclines constitute the group of most
active cytotoxic agents in MBC. Anthracycline-naive patients
with MBC are typically applied single-agent anthracycline
treatment, be it doxorubicin (60–75 mg/m2 every 3 weeks or 20
mg/m2 weekly) or epirubicin (75–100 mg/m2 every 3 weeks or
20–30 mg/m2 weekly) or anthracycline-based combinations.
Patients relapsing >12 months after anthracycline-based
treatment may be reinduced with anthracycline-based
chemotherapy up to cumulative doxorubicin and epirubicin
dose levels of 450–550 and 800–1000 mg/m2, respectively. More
recently, liposomal doxorubicin formulations (pegylated or not
pegylated) have shown antitumor efficacy similar to that
observed with nonliposomal formulations in first-line
treatment of MBC, but with a low cardiac toxicity profile [40–
44]. Thus, liposomal doxorubicin may be considered in
patients with preexisting cardiac disease or in those who have
reached or near the cumulative cardiotoxicity threshold.
taxanes. Taxanes—paclitaxel, docetaxel and nanoparticle
albumin-bound paclitaxel (nab-paclitaxel)—have demonstrated
significant activity in MBC in terms of RR and PFS. Several
trials have explored the value of combining anthracyclines and
taxanes, given that these two classes of agents have different
mechanisms of action and no cross-resistance [45–50]. Most of
these studies showed that combined use of anthracyclines and
taxanes increased RR and time to progression (TTP), and two
studies also demonstrated improved OS [46, 47], however, at
the expense of higher treatment-related toxicity. A recent
meta-analysis showed increased RR and PFS, but not OS of
taxanes in combination with anthracyclines, compared with
standard nontaxane regimens [51]. Additionally, this
meta-analysis failed to identify a subset of patients who might
derive clear benefit from the addition of taxanes.
other agents. Increased use of anthracyclines and taxanes as
adjuvant and neoadjuvant treatments has restricted their use in
patients with relapse. Several new drugs including
antimetabolites (gemcitabine and capecitabine), vinca alkaloids
(vinorelbine) and epothilones (ixabepilone) have shown
activity in MBC. However, these compounds have typically
been used in salvage chemotherapy settings; therefore, their role
in first-line treatment is not well recognized.
Volume 20 | No. 11 | November 2009
Annals of Oncology review
Single-agent capecitabine was associated with RRs of 25% 150 mg/m2 on days 1, 8 and 15 every 4 weeks), compared with
[52, 53] and in the first-line treatment of MBC has provided docetaxel at 100 mg/m2 every 3 weeks [64]. It should be noted,
significantly longer OS than the classical cyclophosphamide– however, that neither docetaxel nor nab-paclitaxel has
fluorouracil–methotrexate regimen [54]. The Food and Drug demonstrated superiority over the weekly schedule of
Administration-approved capecitabine dose is 2500 mg/m2 on paclitaxel.
days 1–14 of a 21-day cycle; however, in clinical practice, a dose
taxane-based multidrug chemotherapy. Two randomized phase
of 2000 mg/m2 is commonly applied, particularly in elderly
III trials including anthracycline-pretreated MBC patients
patients [53].
demonstrated that two-drug taxane combinations (docetaxel
The efficacy of first-line vinorelbine seems to be modest [55],
and capecitabine, paclitaxel and gemcitabine) are associated
but a combination of vinorelbine and capecitabine in an elderly
with improved OS compared with taxane monotherapy [65,
population provided an RR of 43% [56]. Similarly, gemcitabine
66]. However, particularly in the case of docetaxel–capecitabine
as single agent showed limited efficacy in first-line treatment of
combination, multidrug therapy resulted in significantly
MBC. In a randomized study including elderly patients, this
increased hematologic and nonhematologic toxicity.
compound was found to be less effective than single-agent
Additionally, no cross-over to antimetabolites after the taxane
epirubicin (RR 16% versus 40%, TTP 3.4 versus 6.1 months
failure was mandated in these studies, and many patients did
and OS 11.8 versus 19.1 months, respectively) [57].
not receive subsequent therapy. A randomized phase III trial
Accumulating data demonstrate that ‘triple-negative’ or
comparing docetaxel plus gemcitabine versus docetaxel plus
‘basal’ phenotype of breast cancer may represent a biologically
capecitabine showed similar efficacy of both regimens, with
distinct entity, and preliminary results indicate its high
significantly lower nonhematologic toxicity of the former [67].
sensitivity to agents that bring about DNA interstrand
cross-links, such as mitomycin C or platinum salts [58]. recommendation. In patients with anthracycline resistance or
A randomized study comparing docetaxel to carboplatin in failure, taxane monotherapy (preferably docetaxel every 3
this subset of patients is currently ongoing among many other weeks, paclitaxel every week or nab-paclitaxel weekly) or
studies in clinical research. taxane-based combinations should be considered, taking into
account QoL, toxicity, characteristics of the disease and the ease
recommendation. No optimal first-line chemotherapy regimen
of administration.
can be defined in MBC, although anthracycline-based
combinations remain the most commonly used treatment
regimens. In patients who have received anthracyclines in the
chemotherapy after anthracycline and taxane
adjuvant or neoadjuvant setting, two main treatment options
pretreatment
include reintroduction of anthracyclines considering their
cumulative dose or application of taxanes. Patients with early There are few effective treatment options available to women
relapse after previous adjuvant anthracycline and taxane with MBC who failed to respond or relapsed after receiving
chemotherapy may be offered other regimens. both anthracyclines and taxanes. Several agents, including
capecitabine, vinorelbine, gemcitabine, epothilones and
platinum salts, as well as combinations thereof have been
chemotherapy after anthracycline pretreatment investigated [68]. Of those, capecitabine has been the most
frequently used agent, given its efficacy, safety and ease of
taxane monotherapy. The taxanes, applied as monotherapy or
administration [69]. Capecitabine has also become an attractive
in combination with other agents, are the most commonly used
partner for combination strategies with both cytotoxic and
compounds in MBC patients previously exposed to
targeted agents [70, 71].
anthracyclines. A Cochrane analysis demonstrated a modest
Gemcitabine and vinorelbine have been shown to be active in
survival advantage of taxane-based versus nontaxane regimens
some patients pretreated with anthracyclines and taxanes [72,
in this setting [59]. Paclitaxel has been traditionally used in
73]. A randomized study demonstrated that the combination of
doses ranging from 135 to 225 mg/m2 administered every 3
these two agents was associated with increased PFS, but not RR
weeks; however, its weekly administration (usually at a dose of
and OS, compared with vinorelbine alone [72].
80 mg/m2) provides superior RR, TTP and OS [21]. In contrast
More recently, ixabepilone (an analogue of epothilone B),
to paclitaxel, the efficacy of docetaxel does not appear to be
representing a new class of compounds suppressing
schedule dependent [60, 61].
microtubule activity, has emerged as an active agent in
A direct comparison of docetaxel (100 mg/m2) and paclitaxel
anthracycline and taxane-pretreated patients [74]. A recent
(175 mg/m2), both administered every 21 days, demonstrated
phase III study demonstrated that addition of ixabepilone to
longer TTP and OS of the former, albeit at the cost of
capecitabine is associated with increased RR and PFS compared
a significantly increased toxicity [62]. Another phase III trial
with capecitabine alone [71]. This benefit was achieved at the
showed higher RR and TTP of nab-paclitaxel compared with
expense of increased toxicity, particularly sensory neuropathy
paclitaxel (175 mg/m2 over 3 h every 21 days) [63].
and neutropenia.
Administration of nab-paclitaxel was associated with a lower
risk of hypersensitivity reactions, less grade 4 neutropenia, but recommendation. Based on the current experience,
increased grade 3 sensory neuropathy. Most recently, a phase II capecitabine, gemcitabine, liposomal doxorubicin, ixabepilone
randomized study showed longer PFS of nab-paclitaxel (used at or vinorelbine, all administered as either monotherapy or in
three different dosage levels: 300 mg/m2 every 3 weeks, 100 or combination with other cytotoxic agents may be beneficial after

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review
failure of anthracyclines and taxanes. Consecutive cytotoxic
chemotherapy is worth considering in women who have
responded to previous regimens, but no definitive guidance can
be given regarding the optimal agents or the order they should
be administered.
dose intensity
There are no new data demonstrating a benefit of increased
chemotherapy dose intensity in MBC [75]. Thus, this strategy
should not be attempted outside clinical trials.
treatment duration
Therapeutic options in MBC include continuation of
chemotherapy until disease progression or treatment
interruption at some point, with its reintroduction at the time
of progression. A series of randomized studies compared
shorter versus longer chemotherapy [76–81]. These studies
have generally shown that prolonged treatment is associated
with extended TTP but has little effect on OS. The impact of
prolonged therapy may be drug dependent, as some agents (e.g.
capecitabine) can be continued for longer periods than others
(e.g. anthracyclines and taxanes). A recent systematic review of
eight randomized trials including 1942 patients demonstrated
an insignificant reduction in the risk of death (hazard ratio
0.92; CI 0.84–1.00; P = 0.07) with prolonged therapy [82].
Thus, the benefit associated with longer chemotherapy duration
as first-line treatment in MBC seems to be at best marginal.
recommendation. There is no strong evidence to recommend
routinely continuing chemotherapy until disease progression or
significant side-effects arise. In patients with treatment
response or stable disease (as defined by a <50% reduction and
a <25% increase in the sum of the products of two
perpendicular diameters of all measured lesions and the
appearance of no new lesions), intermittent administration of
chemotherapy is a reasonable option. The decision on
treatment duration should take into account symptoms, side-
effects, QoL and patient preferences.
management of patients with
Her-2/neu-overexpressing MBC
trastuzumab
Trastuzumab represents an effective single agent in HER-2/neu-
overexpressing (3+ by IHC or FISH positive) MBC [83, 84]. In
a pivotal, randomized phase III trial carried out in patients with
HER-2/neu-overexpressing MBC, first-line treatment with the
combination of trastuzumab plus chemotherapy resulted in
significantly higher overall RR and significantly prolonged PFS
and OS as compared with chemotherapy alone [85]. This
clinical benefit was achieved with only minimal increase in the
subjective toxicity profile of the combination over single-agent
paclitaxel. A second randomized trial of docetaxel with or
without trastuzumab has also shown benefit in OS [86]. The
combination of an anthracycline and trastuzumab was also
highly effective in the pivotal trial, but accompanied by a high
risk of cardiotoxicity [85]. A series of other cytotoxic drugs
including vinorelbine, platinum compounds, capecitabine and
1776 | Beslija et al.
Annals of Oncology
gemcitabine administered in patients with HER-2/neu-
overexpressing MBC in combination with trastuzumab in the
first and up to fifth-line setting have produced RR between 24%
and 81% [87–97]. Selection of regimens is governed by the
patient’s prior treatment history and the side-effect profile of
concurrent therapy. Retrospective analyses and a randomized
trial comparing chemotherapy and trastuzumab to trastuzumab
alone followed by chemotherapy at progression demonstrated
a trend favoring survival for up-front use of concurrent therapy
[98, 99]. Given that, and owing to the survival advantage seen
in two trials of concurrent chemotherapy and trastuzumab, the
use of combination treatment is preferable to single-agent
therapy for most patients.
The benefit of adding more than one cytotoxic agent over
single-agent chemotherapy with trastuzumab is unclear.
Addition of carboplatin to trastuzumab and paclitaxel
increased RR and TTP in one randomized trial [100], whereas
a similar study using docetaxel instead of paclitaxel found no
benefit but reported an increased toxicity from adding the
platinum salt [101]. Similarly, preliminary results from a phase
II randomized trial adding capecitabine to docetaxel and
trastuzumab have demonstrated benefit in terms of PFS, and
not RR, the primary end point in this study [102].
Trastuzumab has also been studied in combination with
endocrine therapy for ER-positive, HER-2/neu-positive MBC.
In a randomized trial of anastrozole versus anastrozole and
trastuzumab, the addition of trastuzumab yielded modest
improvements in PFS and RR. OS, however, was found to be
prolonged only in a post hoc analysis comparing patients who
received trastuzumab in combination or sequential after
anastrozole failure to those who did not receive trastuzumab at
any time point [103, 104].
Treatment with trastuzumab may be complicated by
a modestly increased risk of congestive heart failure (CHF)
[105]. The risk for the development of CHF increases with
advanced age and concurrent therapy with trastuzumab and
anthracyclines [85]. Outside of research protocols, patients
should still not receive concurrent treatment with trastuzumab
and anthracyclines. However, the administration of
trastuzumab in combination with less cardiotoxic
anthracyclines like epirubicin or liposomal doxorubicin
formulations may be relatively safe and effective [106–110]. The
frequent pretreatment with anthracyclines in the adjuvant
setting, the concern over cardiotoxicity and the availability of
multiple nonanthracycline chemotherapy options that can be
safely paired with trastuzumab make the combination of
trastuzumab and anthracyclines less desirable. It was
recommended that patients undergo baseline measurement of
cardiac function before trastuzumab-based therapy and
continue cardiac surveillance while continuing treatment.
Echocardiography or radioisotope ventriculography are
commonly used to assess left ventricular function before and
during trastuzumab-based treatment. However, the optimal
cardiac surveillance strategy remains to be established.
Patients who have achieved optimal clinical response to
trastuzumab-based therapy may be considered for
maintenance treatment with single-agent trastuzumab,
though the clinical benefits of this practice are not
known.
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Annals of Oncology
dosage and treatment schedule. An initial loading dose of 4 mg/
kg trastuzumab, followed by 2 mg/kg weekly until disease
progression, is recommended. A higher loading dose of 8 mg/
kg followed by 6 mg/kg administered every 21 days has similar
pharmacokinetics to weekly administration regimen [94, 111],
although there are no data from randomized clinical trials to
prove that these two schedules are equally effective. However,
results from the HERA trial in the adjuvant setting indicate the
efficacy and safety of the latter dosing regimen also in MBC
[112].
progressive disease during trastuzumab treatment. Ongoing use
of trastuzumab beyond tumor progression as single agent or
after changing the concomitant chemotherapy has been widely
practiced but until recently was of unknown clinical value
[113]. Retrospective studies and feasibility analyses indicate
that such treatment was well tolerated by most patients [113–
115].
Two randomized trials have now evaluated the role of
continuing trastuzumab treatment beyond tumor progression.
Von Minckwitz et al. [116] compared capecitabine alone or
capecitabine plus trastuzumab among women with HER-2/neu-
positive MBC progressing under previous trastuzumab-based
treatment. The study demonstrated an improvement in RR and
TTP, but was underpowered to demonstrate an OS benefit.
Another clinical trial tested the efficacy of continuation of
trastuzumab after progression of Her-2/neu-positive MBC
under trastuzumab, anthracyclines and taxanes and
randomized between the addition of lapatinib to trastuzumab
and a switch to lapatinib only [117]. This study demonstrated
a significant improvement in clinical benefit rate and TTP and
a trend favoring OS among women who received
a combination of lapatinib and trastuzumab.
In early-phase clinical trials, the addition of pertuzumab, an
mAb targeting an epitope distinct from that bound by
trastuzumab on the Her-2/neu receptor, or the Hsp90 inhibitor
tanespimycin to trastuzumab have also demonstrated efficacy
and safety in patients with trastuzumab-refractory MBC [118,
119]. These findings indicate that continuing trastuzumab may
have clinical benefits in combination with other treatments,
despite tumor progression on prior trastuzumab treatment.
However, the evidence regarding the magnitude of such benefit
is unknown. Similarly, in a phase II clinical trial the antibody–
drug conjugate trastuzumab–DM1 exhibited single-agent
activity in patients progressing under prior Her-2/neu-targeted
therapy [120].
lapatinib
Several TKIs are being investigated in phase II trials in MBC.
Lapatinib, an orally available TKI directed against both the
erbB1 and the erbB2 (HER-2/neu) receptor, has activity in
trastuzumab-resistant, HER-2/neu-positive MBC [121–123]. As
a single agent, lapatinib has shown RRs between 5% [124]
among chemotherapy- and trastuzumab-refractory breast
cancer and 24% among trastuzumab-naive patients [125]. In
a pivotal trial in women with trastuzumab-resistant HER-2/
neu-positive MBC, the combination of capecitabine and
lapatinib was found to be significantly better than capecitabine
alone in terms of disease-free survival [70]. However, OS was
Volume 20 | No. 11 | November 2009
review
not significantly prolonged by the combined treatment with
extended follow-up [126].
In a recently published trial, evaluating the benefit of adding
lapatinib to first-line therapy with paclitaxel in patients with
unknown or negative Her-2/neu status, most clinical outcomes,
but not OS, were improved by addition of lapatinib to
paclitaxel only in the small subgroup of Her-2/neu-positive
patients [19]. When combined with letrozole in patients with
hormone-dependent MBC, lapatinib is active only in the Her-
2/neu-positive subgroup [127].
Patients with HER-2/neu-positive MBC have an increased
risk of developing brain metastases, likely owing to several
factors—a predilection for visceral sites of metastasis, a relative
sanctuary site in the CNS and prolonged OS owing to the
success of trastuzumab-based treatment [12]. Lapatinib has
shown hints of CNS activity (although modest in heavily
pretreated patients) as a single agent or in combination with
capecitabine [128]. Further, in the pivotal trial of capecitabine
with or without lapatinib, prevention or delay in the
development of CNS metastases with lapatinib was indicated
[126]. Nevertheless, treatment of CNS metastases remains
a clinical challenge. At present, there are no data on
prophylactic therapy or on the long-term clinical benefit of
surveillance in asymptomatic patients.
recommendation. The use of trastuzumab as first-line therapy
in combination with nonanthracycline-based chemotherapy is
strongly recommended in patients with HER-2/neu protein-
overexpressing (3+ by IHC) or Her-2/neu FISH-positive MBC
regardless of age or prior adjuvant chemotherapy. Treatment
with single-agent trastuzumab remains a viable alternative for
frail patients or patients with indolent disease. In these patients,
Her-2/neu-targeted therapies may also favorably combine with
endocrine therapy if tumors are both ER positive and Her-2/
neu positive.
Lapatinib as a single agent or in combination with
capecitabine should be considered in Her-2/neu-positive
patients with CNS metastases and those who progressed after
previous therapy including trastuzumab.
antiangiogenic treatment
bevacizumab
Bevacizumab is a humanized mAb directed against the vascular
endothelial growth factor (VEGF) and is the most mature
therapeutic agent specifically designed to disrupt angiogenesis.
Common side-effects include hypertension, nasal congestion/
discharge and slight exacerbation of chemotherapy-related side-
effects [129].
Three phase III trials have evaluated the efficacy of
chemotherapy alone or chemotherapy plus bevacizumab for
MBC. The first published study compared capecitabine alone or
capecitabine plus bevacizumab in patients with extensive
chemotherapy exposure including anthracyclines and taxanes
[130]. Although RRs increased substantially in the bevacizumab
arm, there was no prolonged PFS or OS. In contrast, a second
trial, ECOG2100, comparing weekly paclitaxel with or without
bevacizumab as first-line therapy for MBC, demonstrated
a significant improvement in RR and time to disease
doi:10.1093/annonc/mdp261 | 1777
review
progression with bevacizumab (5.5 versus 11.6 months) [131].
The third study [132], comparing docetaxel with or without
bevacizumab as first-line treatment, again demonstrated
improvement in TTP, though of far less absolute difference
than seen in ECOG2100. To date, none of the trials of
bevacizumab has shown a survival advantage. Thus, in first-line
treatment, bevacizumab in combination with taxanes appears
to improve upon results seen with chemotherapy alone, making
combination treatment an option for such patients. In contrast,
there are no data indicating a benefit of bevacizumab use in the
second-line chemotherapy.
bisphosphonates
bisphosphonate therapy for bone metastases
clodronate (oral). Several small placebo-controlled trials have
examined the efficacy of oral clodronate in patients with bone
metastases from breast cancer [133–135]. Overall, patients
who received oral clodronate had a significantly reduced
skeletal morbidity rate compared with patients who received
placebo.
ibandronate (oral and i.v.). The efficacy of oral and i.v.
ibandronate has been evaluated in randomized, placebo-
controlled trials in women with bone metastases from breast
cancer [136]. Two years of i.v. ibandronate therapy significantly
reduced the mean skeletal morbidity period rate and
lengthened the median time to first bone event compared with
placebo. A pooled analysis of two phase III studies of oral
ibandronate showed a significant reduction in the risk of bone
events compared with placebo [137].
zoledronic acid (i.v.). Intravenous zoledronic acid has been
shown to be superior to pamidronate in treatment of
hypercalcemia of malignancy (HCM) [138] and in reducing
the risk of skeletal-related events (SREs) in large randomized
trials in breast cancer patients with bone metastases [139, 140].
Overall, patients with MBC receiving zoledronic acid
experienced a higher reduction in the risk of developing an SRE
compared with patients receiving pamidronate [139].
Zoledronic acid also significantly prolonged the mean time to
first SRE and significantly reduced the annual skeletal
morbidity rate compared with pamidronate [139–141].
A subsequent study compared zoledronic acid with placebo in
patients with breast cancer and bone metastases. In this trial,
patients who received zoledronic acid had a significantly
longer median time to first SRE and a significantly reduced
risk of experiencing an SRE compared with placebo
[142].
pamidronate (i.v.). The efficacy of i.v. pamidronate for the
prevention of SREs has been demonstrated in two large
randomized phase III trials in patients with at least one
osteolytic bone lesion [143, 144]. In both trials, pamidronate
significantly lowered bone pain scores at the end of treatment
compared with placebo. A pooled analysis of these two trials
showed that pamidronate significantly increased the time to
first SRE, significantly reduced the proportion of patients who
experienced SREs and significantly reduced the skeletal
morbidity rate compared with placebo [145].
1778 | Beslija et al.
Annals of Oncology
recommendations. The strongest evidence for efficacy in
prevention of skeletal morbidity in patients with breast cancer
and bone metastases is available for i.v. bisphosphonate
preparations, but no trial has directly compared oral with i.v.
preparations. Evidence from randomized clinical trials in
patients with breast cancer and bone metastases indicates that
the use of bisphosphonates (oral clodronate 1600 mg/day, i.v.
ibandronate 6 mg every 21–28 days, oral ibandronate 50 mg/
day, i.v. pamidronate 90 mg every 21–28 days and i.v.
zoledronic acid 4 mg every 21–28 days) can reduce and delay
the incidence of skeletal morbidity [146]. Evidence supports the
use of bisphosphonates with or without other anticancer
treatment. Although most trials evaluated bisphosphonate
treatment administered for a maximum of 2 years, the optimal
duration of this treatment is unknown. The American Society
of Clinical Oncology guidelines on the use of bisphosphonates
in women with breast cancer recommend that bisphosphonate
therapy should be continued until there is a substantial decline
in patient performance status [147]. Currently, there are
insufficient data on the use of bisphosphonates in women
without metastatic bone involvement or without HCM.
safety considerations during bisphosphonate
therapy
Overall, bisphosphonate therapy is generally well tolerated in
patients with advanced breast cancer metastatic to bone and
can be safely combined with other anticancer therapies. Oral
bisphosphonates are associated with gastrointestinal side-effects
[148] and i.v. bisphosphonates are associated with transient
influenza-like symptoms and increased bone pain after the
initial infusions [148]. In addition, dose- and infusion rate-
dependent effects of bisphosphonates on renal function have
been reported [148]. Guidelines have been published which
recommend monitoring renal function in patients receiving
bisphosphonates and alternative dosing schedules for patients
with renal impairment [149]. Recently, an uncommon toxicity
consisting of osteonecrosis of the jaw (ONJ) has been reported
in patients accompanying prolonged use of bisphosphonates
[150]. Risk factors for ONJ may include poor oral hygiene and
dental surgery during bisphosphonate therapy. Therefore,
preventive dentistry recommendations have been published
[150–152]. Preliminary reports indicate that implementation of
preventative dentistry and monitoring recommendations can
substantially reduce the incidence of ONJ in patients with
cancer [153].
supportive care
symptomatic anemia
As mentioned previously [9], anemia constitutes a common
problem in patients with metastatic disease and may be caused
or aggravated by cytotoxic treatment resulting in fatigue. When
present, also other reasons for fatigue and associated symptoms
including nutritional status, treatment side-effects and
psychological and psychiatric disorders should be considered
and comprehensively investigated.
Symptomatic anemia (with a hemoglobin <10–11 g/dl)
should be diagnosed, investigated and corrected to maintain
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Annals of Oncology
QoL and avoid fatigue [154]. Under consideration of various
geographic approaches, erythropoiesis-stimulating proteins
(ESPs) and erythrocyte transfusions constitute reasonable
options to achieve this goal. However, the use of some ESPs has
shortened OS and/or increased the risk of serious
thrombovascular events or tumor progression/recurrence in
some clinical studies in patients with breast, non-small-cell
lung, head and neck, lymphoid and cervical cancers [155, 156].
To decrease these risks, it is recommended, therefore, to use the
lowest dose of ESP needed to avoid red blood cell transfusions
and use ESPs only for treatment of symptomatic anemia
associated with concomitant myelosuppressive chemotherapy.
The treatment should be discontinued when a hemoglobin level
of 11–12 g/dl has been reached. With adequate dosing and
schedule, there is no evidence of superiority of any ESP [157–
159]. In the case of nonresponsiveness to ESPs and for acute
symptoms, erythrocyte transfusions should be administered.
leukopenia
When using chemotherapy associated with a likelihood of
>20% of febrile leukopenia, a history of previous febrile
neutropenia under preceding chemotherapy or due to
individual risk factors, the use of myeloid colony-stimulating
factors can be considered [160–163].
psychological support
As recognized before [9], women with MBC may experience
psychological distress including depression, anxiety, stress–
response syndrome, difficulty in coping and social isolation.
Randomized trials of group psychosocial interventions in
patients with MBC identified psychological benefits specifically
including improvement in mood, pain control and coping.
Therefore, it was recommended that psychosocial support
should be available to patients with MBC. However, current
research does not allow for the recommendation of an optimal
type, timing or duration of psychological support
interventions. Moreover, the evidence of a survival advantage
due to psychological support interventions is not convincing.
menopausal symptoms, hormone replacement
therapy and topical estrogen
Menopausal symptoms crucially impair women’s QoL and are
frequently aggravated by endocrine therapy or cytotoxic
therapy in women with breast cancer. Based upon scientific
evidence causally linking the use of HRT to the development of
breast cancer [164, 165], the use of HRT in MBC is strongly
discouraged, as HRT may stimulate growth of hormone
receptor-positive cancers. In this vein, several reports about
a clinical benefit of HRT withdrawal in MBC have been
published [166, 167]. Likewise, in the absence of safety data on
the use of HRT in patients with ER- and PgR-negative tumors,
the panel strongly discouraged the use of HRT in all patients
with MBC. If topical estrogens need to be considered for QoL
reasons, preparations that result in the lowest possible systemic
absorption should be chosen. Vaginal estradiol tablets should
be used with caution in MBC patients, whereas estriol
suppositories may be less dangerous [168]. Whenever feasible,
nonhormonal treatment of menopausal symptoms should be
Volume 20 | No. 11 | November 2009
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sought, which may include pharmacological interventions,
mind–body and behavioral interventions [169–173].
surgical resection of the primary tumor
in metastatic disease
The benefit of surgical resection of the primary tumor in
patients presenting with metastatic (stage IV) breast cancer is
not established. However, recent retrospective reviews of
patient records have indicated that such intervention might
improve clinical outcomes. In two separate chart reviews
involving >800 patients, median OS was increased by 10–16
months in patients who underwent surgical resection (P <
0.0001 compared with patients who did not undergo surgery)
[174, 175]. However, another chart review of 147 patients
found the benefit of surgery only in patients who underwent
surgery before the diagnosis of metastatic disease [176].
Surgical removal of the primary tumor has been identified as an
independent predictor of improved outcome (OS or PFS) in
multivariate analyses among patients with stage IV disease and
intact primary tumors [177, 178]. It should, however, be noted
that these findings have not been validated to date in
prospective studies, and the real benefits of surgery in patients
with MBC remain to be elucidated.
emerging treatments and future
directions
A rapidly increasing number of molecular structures of
malignant cells can be targeted by various agents including
signal transduction inhibitors, mAbs, anticancer vaccines,
antisense strategies or antiangiogenic drugs. Because the mode
of action of the various available agents is distinct from
cytotoxic treatment, they represent ideal combination partners
for chemotherapeutic and endocrine treatment options. These
emerging approaches, however, will require additional efforts
for careful selection of patients most likely to benefit from
targeted therapies: Proper definition of targets and assessment
of target inhibition in tumors or indicative tissues,
determination of the mechanisms of drug sensitivity and
resistance and assessment of novel surrogate end points of
treatment effect may require assessment of an increasing
number of biological traits of patients and tumors alike,
functional imaging, repeated biopsies and storage of biological
material suitable for molecular and high-throughput analyses.
emerging treatments
antiangiogenic therapy. Following the encouraging results from
the use of bevacizumab in the first-line treatment of MBC,
results from additional randomized trials combining
bevacizumab with other targeted therapies [179] are eagerly
expected. In addition, there are numerous trials of other anti-
VEGF agents alone or in combination ongoing for advanced
breast cancer [180, 181]. As yet, no other drugs apart from
bevacizumab based upon the concept of antiangiogenesis are
approved for use. Another investigated strategy includes
continuous administration of low-dose cytotoxic drugs
(metronomic chemotherapy). This nontoxic and easily
doi:10.1093/annonc/mdp261 | 1779
review
deliverable scheduling is believed to induce anticancer effect at
least in part by virtue of antiangiogenic mechanisms. Two trials
using low-dose cyclophosphamide (50 mg daily) and
methotrexate (5 mg daily twice a week) have shown a RR in the
range of 20% [182, 183]. Metronomic therapy may be
potentially useful in pretreated or frail MBC patients, but it still
warrants clinical verification.
cetuximab. The monoclonal epidermal growth factor receptor
(EGFR) antibody cetuximab has shown little activity as single
agent in patients with mostly heavily pretreated MBC in
randomized phase II studies, but may add to the efficacy of
cytotoxic treatment [184, 185]. Inhibition of the EGFR is
presently investigated as a new treatment strategy specifically in
patients with triple-negative breast cancer.
future directions
targeting DNA repair mechanisms. A significant fraction of
breast cancer is hereditary and based on germline mutations in
the breast cancer early onset (BRCA) genes BRCA1 and BRCA2.
In addition, both genes are found inactivated in sporadic cases
by mutations and more often by epigenetic mechanisms. Both
BRCA1 and BRCA2 are at least partially necessary for DNA
repair by homologous recombination (HR). HR gets additional
importance in cells if another classical DNA recombination
pathway, namely the repair of single-stranded DNA (SSDNA) is
blocked. In normal cells, the inhibition of a crucial enzyme of
SSDNA repair, poly ADP-ribose polymerase (PARP1), does not
cause major effects. When SSDNA breaks are encountered
during DNA replication, the replication fork stalls and double-
stranded DNA (dsDNA) breaks accumulate. These dsDNA
breaks are then repaired via HR repair, an error-free repair
mechanism. In contrast, tumors lacking BRCA may be highly
sensitive to PARP1 inhibitors [186]. Thus, PARP1 inhibitors
alone or in combination may prove highly effective therapies
for cancers with lacking BRCA due to their high sensitivity to
the inhibitor and the lack of deleterious effects of these
compounds on the remaining healthy cells with functioning
BRCA HR pathway [187].
anticancer vaccines. The field of cancer vaccines is currently in
active preclinical and clinical investigations. Although no
therapeutic breast cancer vaccine has been approved to date, recent
preclinical and clinical findings have shown that the use of vaccine
therapies may well lead to an additional treatment choice,
ultimately being used for the therapy of advanced breast cancer.
One of the two structures mainly used as targets for an active
immune response, HER-2/neu, emerged from the dramatic
response to this receptor by passive immune therapy by
trastuzumab or pertuzumab [188]. The second commonly used
target structure Mucin 1 (MUC1), a transmembrane
glycoprotein was used in several vaccination trials [189]. All
those trials with varying vaccination strategies (i.e. peptide
based, dendritic cell based and others), with different adjuvants,
showed very limited toxic effects and consistent immunological
responses of the patients, but in general low or absent clinical
responses in patients with MBC. Patients with limited or
minimal tumor burden, however, may be a better target
population for therapeutic vaccine therapies.
1780 | Beslija et al.
Annals of Oncology
proteomics as a tool to define biomarkers. Biomarkers serve as
hallmarks for the status of tumor growth at a given time and
change during the disease process. In general, biomarkers can
guide us to define subgroups of patients whose tumors express
a specific target and thus may have a high probability of
response. Therefore, the identification of novel biomarkers that
are able to predict treatment response or resistance may allow
therapy to be tailored to individual patients. Cancer proteomics
is a rapidly developing field and is expected to accelerate the
discovery of new diagnostic, prognostic and therapy-related
biomarkers. The rationale for proteomic investigation is that
proteins are often expressed in quantities and physical forms
that cannot be predicted from DNA and messenger RNA
analysis, as for example due to post-translational modification
of proteins. Therefore, proteome analysis provides
a complementary approach to microarray gene expression
profiling [37, 190].
Application of protein microarray technology for the study
of ongoing signaling activity within breast tumor specimens
holds great potential for elucidating and profiling signaling
activity for patient-tailored therapy. Analysis of laser capture
microdissected primary human breast tumors and metastatic
lesions reveals pathway specific profiles and a new way to
classify cancer based on functional signaling portraits.
Moreover, the metastasis-specific changes that occur within
a new microenvironment can be revealed. Analysis of biopsy
material from clinical trials for targeted therapeutics
demonstrates the feasibility and utility of comprehensive signal
pathway activation profiling for molecular analysis [191, 192].
The possibility of detecting hundreds to thousands of proteins
at the same point of time is also a tool to define proteins
associated with response or resistance to therapy [193].
funding
Bristol Myers-Squibb; Eli Lilly; Roche.
acknowledgements
The panelists thank Ursula Fischer for the organization of the
infrastructure of this consensus. Pamela Goodwin (Samuel
Lunenfeld Research Institute, Mount Sinai Hospital, Toronto,
Canada) is a contributor to this work.
Organizing institution: CECOG, Headoffice: Schlagergasse 6,
Vienna, Austria (www.cecog.org).
Supporting institution: Clinical Division of Oncology,
Department of Medicine I/Cancer Center, General Hospital,
Medical University Vienna, Vienna, Austria
(www.meduniwien.ac.at/krebszentrum).
references
1. Smigal C, Jemal A, Ward E et al. Trends in breast cancer by race and ethnicity:
update 2006. CA Cancer J Clin 2006; 56: 168–183.
2. Brewster AM, Hortobagyi GN, Broglio KR et al. Residual risk of breast cancer
recurrence 5 years after adjuvant therapy. J Natl Cancer Inst 2008; 100:
1179–1183.
3. Carlson RW, Hudis CA, Pritchard KI. Adjuvant endocrine therapy in hormone
receptor-positive postmenopausal breast cancer: evolution of NCCN, ASCO,
and St Gallen recommendations. J Natl Compr Canc Netw 2006; 4: 971–979.
Volume 20 | No. 11 | November 2009
Annals of Oncology
4. Khatcheressian JL, Wolff AC, Smith TJ et al. American Society of Clinical
Oncology 2006 update of the breast cancer follow-up and management
guidelines in the adjuvant setting. J Clin Oncol 2006; 24: 5091–5097.
5. Rabaglio M, Aebi S, Castiglione-Gertsch M. Controversies of adjuvant endocrine
treatment for breast cancer and recommendations of the 2007 St Gallen
conference. Lancet Oncol 2007; 8: 940–949.
6. Goldhirsch A, Wood WC, Gelber RD et al. Progress and promise: highlights of
the international expert consensus on the primary therapy of early breast
cancer 2007. Ann Oncol 2007; 18: 1133–1144.
7. NCNN Breast Cancer Panel Members, version: v.1.2009 NCCN Clinical Practice
Guidelines in Oncology––Breast Cancer V.2.08; (http://www.nccn.org/
professionals/physician_gls/PDF/breast.pdf) (1 February 2009, date last
accessed).
8. Beslija S, Bonneterre J, Burstein HJ et al. Consensus on medical treatment of
metastatic breast cancer (statement for Central European Cooperative Oncology
Group). Breast Cancer Res Treat 2003; 81 (Suppl 1): S1–S7.
9. Beslija S, Bonneterre J, Burstein H et al. Second consensus on medical
treatment of metastatic breast cancer. Ann Oncol 2007; 18: 215–225.
10. Akehurst RL, Beinert T, Crawford J et al. Consensus on medical treatment of
non-small cell lung cancer. Lung Cancer 2002; 38 (Suppl 3): S3–S7.
11. Singletary SE, Greene FL. Revision of breast cancer staging: the 6th edition of
the TNM Classification. Semin Surg Oncol 2003; 21: 53–59.
12. Duchnowska R, Szczylik C. Central nervous system metastases in breast cancer
patients administered trastuzumab. Cancer Treat Rev 2005; 31: 312–318.
13. Diaz LK, Sneige N. Estrogen receptor analysis for breast cancer: current issues
and keys to increasing testing accuracy. Adv Anat Pathol 2005; 12: 10–19.
14. Wells CA, Sloane JP, Coleman D et al. Consistency of staining and reporting of
oestrogen receptor immunocytochemistry within the European Union––an inter-
laboratory study. Virchows Arch 2004; 445: 119–128.
15. Hauser-Kronberger C, Dandachi N. Comparison of chromogenic in situ
hybridization with other methodologies for HER2 status assessment in breast
cancer. J Mol Histol 2004; 35: 647–653.
16. Wixom CR, Albers EA, Weidner N. Her2 amplification: correlation of
chromogenic in situ hybridization with immunohistochemistry and fluorescence
in situ hybridization. Appl Immunohistochem Mol Morphol 2004; 12: 248–251.
17. Isola J, Tanner M, Forsyth A et al. Interlaboratory comparison of HER-2
oncogene amplification as detected by chromogenic and fluorescence in situ
hybridization. Clin Cancer Res 2004; 10: 4793–4798.
18. Wolff AC, Hammond ME, Schwartz JN et al. American Society of Clinical
Oncology/College of American Pathologists guideline recommendations for
human epidermal growth factor receptor 2 testing in breast cancer. J Clin
Oncol 2007; 25: 118–145.
19. Di Leo A, Gomez HL, Aziz Z et al. Phase III, double-blind, randomized study
comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line
treatment for metastatic breast cancer. J Clin Oncol 2008; 26: 5544–5552.
20. Tuma RS. Inconsistency of HER2 test raises questions. J Natl Cancer Inst 2007;
99: 1064–1065.
21. Seidman AD, Berry D, Cirrincione C et al. Randomized phase III trial of weekly
compared with every-3-weeks paclitaxel for metastatic breast cancer, with
trastuzumab for all HER-2 overexpressors and random assignment to
trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and
Leukemia Group B protocol 9840. J Clin Oncol 2008; 26: 1642–1649.
22. Wilcken N, Hornbuckle J, Ghersi D. Chemotherapy alone versus endocrine
therapy alone for metastatic breast cancer. Cochrane Database Syst Rev 2003;
Issue 2. Art. No.: CD002747. DOI: 10.1002/14651858.CD002747.
23. Thurlimann B, Paridaens R, Serin D et al. Third-line hormonal treatment with
exemestane in postmenopausal patients with advanced breast cancer
progressing on aminoglutethimide: a phase II multicentre multinational study.
Exemestane Study Group. Eur J Cancer 1997; 33: 1767–1773.
24. Lonning PE, Bajetta E, Murray R et al. Activity of exemestane in metastatic
breast cancer after failure of nonsteroidal aromatase inhibitors: a phase II trial.
J Clin Oncol 2000; 18: 2234–2244.
25. Bertelli G, Garrone O, Merlano M. Sequential use of aromatase inactivators
and inhibitors in advanced breast cancer. Proc Am Soc Clin Oncol 2002; 21:
60a.
Volume 20 | No. 11 | November 2009
review
26. Thurlimann B, Robertson JF, Nabholtz JM et al. Efficacy of tamoxifen following
anastrozole (‘Arimidex’) compared with anastrozole following tamoxifen as first-
line treatment for advanced breast cancer in postmenopausal women. Eur J
Cancer 2003; 39: 2310–2317.
27. Ellis M, Dehdahti F, Kommareddy A et al. A randomized phase 2 trial of low
dose (6 mg daily) versus high dose (30 mg daily) estradiol for patients with
estrogen receptor positive aromatase inhibitor resistant advanced breast
cancer. Cancer Res 2008; 69: 67s (Abstr 16).
28. Mahtani R, Stein A, Vogel C. High dose estrogen as a salvage hormonal
strategy for highly refractory metastatic breast cancer (MBC): back to the
future. Cancer Res 2008; 69: 386s (Abstr 6129).
29. Chia S, Piccart M, Gradishar W. Fulvestrant vs exemestane following non-
steroidal aromatase inhibitor failure: first overall survival data from the EFECT
trial. Breast Cancer Res Treat 2007; 109: (Abstr 2091).
30. Boccardo F, Rubagotti A, Perrotta A et al. Ovarian ablation versus goserelin
with or without tamoxifen in pre-perimenopausal patients with advanced
breast cancer: results of a multicentric Italian study. Ann Oncol 1994; 5:
337–342.
31. Jonat W, Kaufmann M, Blamey RW et al. A randomised study to compare the
effect of the luteinising hormone releasing hormone (LHRH) analogue goserelin
with or without tamoxifen in pre- and perimenopausal patients with advanced
breast cancer. Eur J Cancer 1995; 31A: 137–142.
32. Klijn JG, Beex LV, Mauriac L et al. Combined treatment with buserelin and
tamoxifen in premenopausal metastatic breast cancer: a randomized study. J
Natl Cancer Inst 2000; 92: 903–911.
33. Klijn JG, Blamey RW, Boccardo F et al. Combined tamoxifen and luteinizing
hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in
premenopausal advanced breast cancer: a meta-analysis of four randomized
trials. J Clin Oncol 2001; 19: 343–353.
34. Parton M, Smith IE. Controversies in the management of patients with breast
cancer: adjuvant endocrine therapy in premenopausal women. J Clin Oncol
2008; 26: 745–752.
35. Di Leo A, Isola J. Topoisomerase II alpha as a marker predicting the efficacy of
anthracyclines in breast cancer: are we at the end of the beginning? Clin Breast
Cancer 2003; 4: 179–186.
36. Kostler WJ, Zielinkski CC. Her-2/neu as predictive marker for endocrine therapy
and chemotherapy in patients with metastatic breast cancer. Breast Cancer Res
Treat 2003; 81: S73–S84.
37. Potti A, Dressman HK, Bild A et al. Genomic signatures to guide the use of
chemotherapeutics. Nat Med 2006; 12: 1294–1300.
38. Carrick S, Parker S, Wilcken N et al. Single agent versus combination
chemotherapy for metastatic breast cancer. Cochrane Database Syst Rev 2005;
Issue 2. Art. No.: CD003372. DOI: 10.1002/14651858.CD003372.pub3.
39. Sledge GW, Neuberg D, Bernardo P et al. Phase III trial of doxorubicin,
paclitaxel, and the combination of doxorubicin and paclitaxel as front-line
chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin
Oncol 2003; 21: 588–592.
40. Soto C, Torrecillas L, Reyes S et al. Capecitabine (X) and taxanes in patients
(pts) with anthracycline-pretreated metastatic breast cancer (MBC): sequential
vs. combined therapy results from a MOSG randomized phase III trial. J Clin
Oncol 2006; 24: (Abstr 570).
41. Tomova A, Brodowicz T, Tzekova V et al. Concomitant docetaxel plus
gemcitabine versus sequential docetaxel followed by gemcitabine. J Clin Oncol
2008; 26: (Abstr 1106).
42. Biganzoli L, Coleman R, Minisini A et al. A joined analysis of two European
Organization for the Research and Treatment of Cancer (EORTC) studies to
evaluate the role of pegylated liposomal doxorubicin (Caelyx) in the treatment of
elderly patients with metastatic breast cancer. Crit Rev Oncol Hematol 2007;
61: 84–89.
43. Batist G, Ramakrishnan G, Rao CS et al. Reduced cardiotoxicity and preserved
antitumor efficacy of liposome-encapsulated doxorubicin and
cyclophosphamide compared with conventional doxorubicin and
cyclophosphamide in a randomized, multicenter trial of metastatic breast
cancer. J Clin Oncol 2001; 19: 1444–1454.
44. Harris L, Batist G, Belt R et al. Liposome-encapsulated doxorubicin
compared with conventional doxorubicin in a randomized multicenter trial
doi:10.1093/annonc/mdp261 | 1781
review
as first-line therapy of metastatic breast carcinoma. Cancer 2002; 94:
25–36.
45. Biganzoli L, Cufer T, Bruning P et al. Doxorubicin and paclitaxel versus
doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic
breast cancer: the European Organization for Research and Treatment of
Cancer 10961 Multicenter Phase III Trial. J Clin Oncol 2002; 20: 3114–3121.
46. Bonneterre J, Dieras V, Tubiana-Hulin M et al. Phase II multicentre randomised
study of docetaxel plus epirubicin vs 5-fluorouracil plus epirubicin and
cyclophosphamide in metastatic breast cancer. Br J Cancer 2004; 91:
1466–1471.
47. Jassem J, Pienkowski T, Pluzanska A et al. Doxorubicin and paclitaxel versus
fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women
with metastatic breast cancer: final results of a randomized phase III
multicenter trial. J Clin Oncol 2001; 19: 1707–1715.
48. Lyman GH, Green SJ, Ravdin PM et al. A Southwest Oncology Group
Randomized Phase II Study of doxorubicin and paclitaxel as frontline
chemotherapy for women with metastatic breast cancer. Breast Cancer Res
Treat 2004; 85: 143–150.
49. Nabholtz JM, Falkson C, Campos D et al. Docetaxel and doxorubicin compared
with doxorubicin and cyclophosphamide as first-line chemotherapy for
metastatic breast cancer: results of a randomized, multicenter, phase III trial. J
Clin Oncol 2003; 21: 968–975.
50. Zielinski C, Beslija S, Mrsic-Krmpotic Z et al. Gemcitabine, epirubicin, and
paclitaxel versus fluorouracil, epirubicin, and cyclophosphamide as first-line
chemotherapy in metastatic breast cancer: a Central European Cooperative
Oncology Group International, multicenter, prospective, randomized phase III
trial. J Clin Oncol 2005; 23: 1401–1408.
51. Piccart-Gebhart MJ, Burzykowski T, Buyse M et al. Taxanes alone or in
combination with anthracyclines as first-line therapy of patients with metastatic
breast cancer. J Clin Oncol 2008; 26: 1980–1986.
52. Bajetta E, Procopio G, Celio L et al. Safety and efficacy of two different doses of
capecitabine in the treatment of advanced breast cancer in older women. J Clin
Oncol 2005; 23: 2155–2161.
53. Oshaughnessy JA, Blum J, Moiseyenko V et al. Randomized, open-label, phase
II trial of oral capecitabine (Xeloda) vs. a reference arm of intravenous CMF
(cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for
advanced/metastatic breast cancer. Ann Oncol 2001; 12: 1247–1254.
54. Stockler M, Sourjina T, Grimison P et al. A randomized trial of capecitabine (C)
given intermittently (IC) rather than continuously (CC) compared to classical
CMF as first-line chemotherapy for advanced breast cancer (ABC). J Clin Oncol
2007; 25: (Abstr 1031).
55. Langkjer ST, Ejlertsen B, Mouridsen H et al. Vinorelbine as first-line or second-
line therapy for advanced breast cancer: a phase I-II trial by the Danish Breast
Cancer Co-operative Group. Acta Oncol 2008; 47: 735–739.
56. Hess D, Koberle D, Thurlimann B et al. Capecitabine and vinorelbine as first-
line treatment in elderly patients (> or = 65 years) with metastatic breast
cancer. A phase II trial (SAKK 25/99). Oncology 2007; 73: 228–237.
57. Feher O, Vodvarka P, Jassem J et al. First-line gemcitabine versus epirubicin in
postmenopausal women aged 60 or older with metastatic breast cancer:
a multicenter, randomized, phase III study. Ann Oncol 2005; 16: 899–908.
58. Cleator S, Heller W, Coombes RC. Triple-negative breast cancer: therapeutic
options. Lancet Oncol 2007; 8: 235–244.
59. Ghersi D, Wilcken N, Simes RJ. A systematic review of taxane-containing
regimens for metastatic breast cancer. Br J Cancer 2005; 93: 293–301.
60. Tabernero J, Climent MA, Lluch A et al. A multicentre, randomised phase II
study of weekly or 3-weekly docetaxel in patients with metastatic breast
cancer. Ann Oncol 2004; 15: 1358–1365.
61. Willemse PH, Munck L, Creemers GJ et al. A phase III study on the efficacy
and safety of docetaxel, every three weeks or as a weekly regimen in patients
with metastatic breast cancer. Breast Cancer Res Treat 2007; 106: (Abstr 1083).
62. Jones SE, Erban J, Overmoyer B et al. Randomized phase III study of docetaxel
compared with paclitaxel in metastatic breast cancer. J Clin Oncol 2005; 23:
5542–5551.
63. Gradishar WJ, Tjulandin S, Davidson N et al. Phase III trial of nanoparticle
albumin-bound paclitaxel compared with polyethylated castor oil-based
1782 | Beslija et al.
Annals of Oncology
paclitaxel in women with breast cancer. J Clin Oncol 2005; 23:
7794–7803.
64. Gradishar W, Krasnojon D, Cheporov S et al. Randomized comparison of weekly
or every-3-week (q3w) nab-paclitaxel compared to q3w docetaxel as first-line
therapy in patients (pts) with metastatic breast cancer (MBC). J Clin Oncol
2007; 25: (Abstr 1032).
65. O’Shaughnessy J, Miles D, Vukelja S et al. Superior survival with capecitabine
plus docetaxel combination therapy in anthracycline-pretreated patients with
advanced breast cancer: phase III trial results. J Clin Oncol 2002; 20:
2812–2823.
66. Albain KS, Nag SM, Calderillo-Ruiz G et al. Gemcitabine plus paclitaxel versus
paclitaxel monotherapy in patients with metastatic breast cancer and prior
anthracycline treatment. J Clin Oncol 2008; 26: 3950–3957.
67. Chan S, Romieu G, Huober J et al. Gemcitabine plus docetaxel (GD) versus
capecitabine plus docetaxel (CD) for anthracycline-pretreated metastatic breast
cancer (MBC) patients (pts): results of a European phase III study. J Clin Oncol
2005; 23: 581.
68. Overmoyer B. Options for the treatment of patients with taxane-refractory
metastatic breast cancer. Clin Breast Cancer 2008; 8 (Suppl 2): S61–S70.
69. Ershler WB. Capecitabine monotherapy: safe and effective treatment for
metastatic breast cancer. Oncologist 2006; 11: 325–335.
70. Geyer CE, Forster J, Lindquist D et al. Lapatinib plus capecitabine for HER2-
positive advanced breast cancer. N Engl J Med 2006; 355: 2733–2743.
71. Thomas ES, Gomez HL, Li RK et al. Ixabepilone plus capecitabine for metastatic
breast cancer progressing after anthracycline and taxane treatment. J Clin
Oncol 2007; 25: 5210–5217.
72. Martin M, Ruiz A, Munoz M et al. Gemcitabine plus vinorelbine versus
vinorelbine monotherapy in patients with metastatic breast cancer previously
treated with anthracyclines and taxanes: final results of the phase III Spanish
Breast Cancer Research Group (GEICAM) trial. Lancet Oncol 2007; 8:
219–225.
73. Zelek L, Barthier S, Riofrio M et al. Weekly vinorelbine is an effective palliative
regimen after failure with anthracyclines and taxanes in metastatic breast
carcinoma. Cancer 2001; 92: 2267–2272.
74. Moulder SL. Ixabepilone for the treatment of taxane-refractory breast cancer.
Future Oncol 2008; 4: 333–340.
75. Stadtmauer EA. A dramatic story of hope and reality. J Clin Oncol 2008; 26:
11–12.
76. Muss HB, Case LD, Richards F II et al. Interrupted versus continuous
chemotherapy in patients with metastatic breast cancer. The Piedmont
Oncology Association. N Engl J Med 1991; 325: 1342–1348.
77. Falkson G, Gelman RS, Pandya KJ et al. Eastern Cooperative Oncology Group
randomized trials of observation versus maintenance therapy for patients with
metastatic breast cancer in complete remission following induction treatment. J
Clin Oncol 1998; 16: 1669–1676.
78. Nooij MA, de Haes JC, Beex LV et al. Continuing chemotherapy or not after the
induction treatment in advanced breast cancer patients. Clinical outcomes and
oncologists’ preferences. Eur J Cancer 2003; 39: 614–621.
79. Alba E, Ruiz-Borrego M, Martı́n M et al. Prolongation of TTP by maintenance
therapy with PLD in a multicenter phase III randomized trial following standard
chemotherapy for MBC: GEICAM 2001-01 study. J Clin Oncol 2007; 25: (Abstr
1007).
80. Gennari A, Conte P, Nanni O et al. Multicenter randomised trial of paclitaxel (P)
maintenance chemotherapy (CT) versus control in metastatic breast cancer
(MBC) patients achieving a response or stable disease to first-line CT including
anthracyclines and paclitaxel: final results from the Italian MANTA study. J Clin
Oncol 2005; 23: 522.
81. Gennari A, Amadori D, De Lena M et al. Lack of benefit of maintenance
paclitaxel in first-line chemotherapy in metastatic breast cancer. J Clin Oncol
2006; 24: 3912–3918.
82. Gennari A, Sormani M, Bruzzi P et al. A meta-analysis of chemotherapy
duration in metastatic breast cancer (MBC). J Clin Oncol 2008; 26: (Abstr 1067).
83. Vogel CL, Cobleigh MA, Tripathy D et al. Efficacy and safety of trastuzumab as
a single agent in first-line treatment of HER2-overexpressing metastatic breast
cancer. J Clin Oncol 2002; 20: 719–726.
Volume 20 | No. 11 | November 2009
Annals of Oncology
84. Cobleigh MA, Vogel CL, Tripathy D et al. Multinational study of the efficacy
and safety of humanized anti-HER2 monoclonal antibody in women who
have HER2-overexpressing metastatic breast cancer that has progressed
after chemotherapy for metastatic disease. J Clin Oncol 1999; 17:
2639–2648.
85. Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus
a monoclonal antibody against HER2 for metastatic breast cancer that
overexpresses HER2. N Engl J Med 2001; 344: 783–792.
86. Marty M, Cognetti F, Maraninchi D et al. Randomized phase II trial of the
efficacy and safety of trastuzumab combined with docetaxel in patients with
human epidermal growth factor receptor 2-positive metastatic breast cancer
administered as first-line treatment: the M77001 study group. J Clin Oncol
2005; 23: 4265–4274.
87. Burstein HJ, Keshaviah A, Baron AD et al. Trastuzumab plus vinorelbine or
taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the
trastuzumab and vinorelbine or taxane study. Cancer 2007; 110: 965–972.
88. Burstein HJ, Harris LN, Marcom PK et al. Trastuzumab and vinorelbine as first-
line therapy for HER2-overexpressing metastatic breast cancer: multicenter
phase II trial with clinical outcomes, analysis of serum tumor markers as
predictive factors, and cardiac surveillance algorithm. J Clin Oncol 2003; 21:
2889–2895.
89. Jahanzeb M, Mortimer JE, Yunus F et al. Phase II trial of weekly vinorelbine and
trastuzumab as first-line therapy in patients with HER2(+) metastatic breast
cancer. Oncologist 2002; 7: 410–417.
90. O’Shaughnessy JA, Vukelja S, Marsland T et al. Phase II study of trastuzumab
plus gemcitabine in chemotherapy-pretreated patients with metastatic breast
cancer. Clin Breast Cancer 2004; 5: 142–147.
91. Sledge GW Jr. Gemcitabine, paclitaxel, and trastuzumab in metastatic breast
cancer. Oncology (Williston Park) 2003; 17: 33–35.
92. Pegram MD, Slamon DJ. Combination therapy with trastuzumab (Herceptin) and
cisplatin for chemoresistant metastatic breast cancer: evidence for receptor-
enhanced chemosensitivity. Semin Oncol 1999; 26: 89–95.
93. Burris H III, Yardley D, Jones S et al. Phase II trial of trastuzumab followed by
weekly paclitaxel/carboplatin as first-line treatment for patients with metastatic
breast cancer. J Clin Oncol 2004; 22: 1621–1629.
94. Leyland-Jones B, Gelmon K, Ayoub JP et al. Pharmacokinetics, safety, and
efficacy of trastuzumab administered every three weeks in combination with
paclitaxel. J Clin Oncol 2003; 21: 3965–3971.
95. Bartsch R, Wenzel C, Altorjai G et al. Results from an observational trial with
oral vinorelbine and trastuzumab in advanced breast cancer. Breast Cancer Res
Treat 2007; 102: 375–381.
96. Bartsch R, Wenzel C, Altorjai G et al. Capecitabine and trastuzumab in heavily
pretreated metastatic breast cancer. J Clin Oncol 2007; 25: 3853–3858.
97. Bartsch R, Wenzel C, Gampenrieder SP et al. Trastuzumab and gemcitabine as
salvage therapy in heavily pre-treated patients with metastatic breast cancer.
Cancer Chemother Pharmacol 2008; 62: 903–910.
98. Ali SM, Carney WP, Esteva FJ et al. Serum HER-2/neu and relative resistance to
trastuzumab-based therapy in patients with metastatic breast cancer. Cancer
2008; 113: 1294–1301.
99. Hamberg P, Bontenbal M, Vernhout R et al. Combined trastuzumab (HER)/
docetaxel (TAX) versus sequential trastuzumab followed by docetaxel at
progression as first line chemotherapy for Her2-positive metastatic breast
cancer: preliminary results (multicenter BOOG-study; 2002-02). Breast Cancer
Res Treat 2007; 106: (Abstr 1077).
100. Robert N, Leyland-Jones B, Asmar L et al. Randomized phase III study of
trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and
paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J
Clin Oncol 2006; 24: 2786–2792.
101. Pegram M, Forbes J, Pienkowski T et al. BCIRG 007: first overall survival
analysis of randomized phase III trial of trastuzumab plus docetaxel with or
without carboplatin as first line therapy in HER2 amplified metastatic breast
cancer (MBC). J Clin Oncol 2007; 25: (Abstr LBA1008).
102. Wardley A, Antón-Torres A, Pivot X et al. Evaluation of trastuzumab,
docetaxel and capecitabine as first-line therapy for HER2-positive locally
advanced or metastatic breast cancer. Breast Cancer Res Treat 2007; 106:
(Abstr 309).
Volume 20 | No. 11 | November 2009
review
103. Mackey J, Kaufman B, Clemens M et al. Trastuzumab prolongs progression-
free survival in hormone-dependent and HER2-positive metastatic breast
cancer. Breast Cancer Res Treat 2006; 100: (Abstr 3).
104. Clemens M, Kaufman B, Mackey JR et al. Trastuzumab [Herceptin(R)] plus
anastrozole may prolong overall survival in post-menopausal women with
HER2-positive, hormone-dependent metastatic breast cancer: results of a post
hoc analysis from the TAnDEM study. ASCO Breast Cancer Symposium, San
Francisco, CA. 2007 (Abstr 231).
105. Safra T, Muggia F, Jeffers S et al. Pegylated liposomal doxorubicin (doxil):
reduced clinical cardiotoxicity in patients reaching or exceeding cumulative
doses of 500 mg/m2. Ann Oncol 2000; 11: 1029–1033.
106. Buzdar AU, Valero V, Ibrahim NK et al. Neoadjuvant therapy with paclitaxel
followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy
and concurrent trastuzumab in human epidermal growth factor receptor 2-
positive operable breast cancer: an update of the initial randomized study
population and data of additional patients treated with the same regimen. Clin
Cancer Res 2007; 13: 228–233.
107. Andreopoulou E, Gaiotti D, Kim E et al. Feasibility and cardiac safety of
pegylated liposomal doxorubicin plus trastuzumab in heavily pretreated patients
with recurrent HER2-overexpressing metastatic breast cancer. Clin Breast
Cancer 2007; 7: 690–696.
108. Chia S, Clemons M, Martin LA et al. Pegylated liposomal doxorubicin and
trastuzumab in HER-2 overexpressing metastatic breast cancer: a multicenter
phase II trial. J Clin Oncol 2006; 24: 2773–2778.
109. Wenzel C, Hussian D, Bartsch R et al. Preoperative therapy with epidoxorubicin
and docetaxel plus trastuzumab in patients with primary breast cancer: a pilot
study. J Cancer Res Clin Oncol 2004; 130: 400–404.
110. Venturini M, Bighin C, Monfardini S et al. Multicenter phase II study of
trastuzumab in combination with epirubicin and docetaxel as first-line treatment
for HER2-overexpressing metastatic breast cancer. Breast Cancer Res Treat
2006; 95: 45–53.
111. Baselga J, Carbonell X, Castaneda-Soto NJ et al. Phase II study of efficacy,
safety, and pharmacokinetics of trastuzumab monotherapy administered on
a 3-weekly schedule. J Clin Oncol 2005; 23: 2162–2171.
112. Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al. Trastuzumab after
adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;
353: 1659–1672.
113. Wong Y, Ottesen R, Niland J et al. Continued use of trastuzumab (TRZ) beyond
disease progression in the National Comprehensive Cancer Network (NCCN).
J Clin Oncol 2008; 26: (Abstr 6522).
114. Bartsch R, Wenzel C, Hussian D et al. Analysis of trastuzumab and
chemotherapy in advanced breast cancer after the failure of at least one
earlier combination: an observational study. BMC Cancer 2006; 6:
63.
115. Tripathy D, Slamon DJ, Cobleigh M et al. Safety of treatment of metastatic
breast cancer with trastuzumab beyond disease progression. J Clin Oncol
2004; 22: 1063–1070.
116. Von Minckwitz G, Zielinski C, Maarteense E et al. Capecitabine vs. capecitabine +
trastuzumab in patients with HER2-positive metastatic breast cancer
progressing during trastuzumab treatment: the TBP phase III study (GBG 26/BIG
3-05). J Clin Oncol 2008; 26: (Abstr 1025).
117. O’Shaughnessy J, Blackwell KL, Burstein H et al. A randomized study of
lapatinib alone or in combination with trastuzumab in heavily pretreated HER2+
metastatic breast cancer progressing on trastuzumab therapy. J Clin Oncol
2008; 26: (Abstr 1015).
118. Gelmon K, Fumoleau P, Verma S et al. Results of a phase II trial of trastuzumab
(H) and pertuzumab (P) in patients (pts) with HER2-positive metastatic breast
cancer (MBC) who had progressed during trastuzumab therapy. J Clin Oncol
2008; 26: (Abstr 1026).
119. Modi S, Stopeck AT, Gordon MS et al. Combination of trastuzumab and
tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory
HER-2 overexpressing breast cancer: a phase I dose-escalation study. J Clin
Oncol 2007; 25: 5410–5417.
120. Vukelja S, Rugo H, Vogel C et al. A phase II study of trastuzumab-DM1, a first-
in-class HER2 antibody-drug conjugate, in patients with HER2+ metastatic
breast cancer. Cancer Res 2008; 69: (Abstr 33).
doi:10.1093/annonc/mdp261 | 1783
review
121. Spector NL, Xia W, Burris H III et al. Study of the biologic effects of lapatinib,
a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and
survival pathways in patients with advanced malignancies. J Clin Oncol 2005;
23: 2502–2512.
122. Burris HA III, Hurwitz HI, Dees EC et al. Phase I safety, pharmacokinetics, and
clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of
epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients
with metastatic carcinomas. J Clin Oncol 2005; 23: 5305–5313.
123. Burris HA III. Dual kinase inhibition in the treatment of breast cancer: initial
experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist 2004; 9 (Suppl
3): 10–15.
124. Burstein HJ, Storniolo AM, Franco S et al. A phase II study of lapatinib
monotherapy in chemotherapy-refractory HER2-positive and HER2-negative
advanced or metastatic breast cancer. Ann Oncol 2008; 19: 1068–1074.
125. Gomez HL, Doval DC, Chavez MA et al. Efficacy and safety of lapatinib as first-
line therapy for ErbB2-amplified locally advanced or metastatic breast cancer.
J Clin Oncol 2008; 26: 2999–3005.
126. Cameron D, Casey M, Press M et al. A phase III randomized comparison of
lapatinib plus capecitabine versus capecitabine alone in women with advanced
breast cancer that has progressed on trastuzumab: updated efficacy and
biomarker analyses. Breast Cancer Res Treat 2008; 112: 533–543.
127. Johnston S, Pegram M, Press M et al. Lapatinib combined with letrozole vs.
letrozole alone for front line postmenopausal hormone receptor positive (HR+)
metastatic breast cancer (MBC): first results from the EGF30008 Trial. Cancer
Res 2008; 69: 74s (Abstr 46).
128. Lin NU, Carey LA, Liu MC et al. Phase II trial of lapatinib for brain metastases in
patients with human epidermal growth factor receptor 2-positive breast cancer.
J Clin Oncol 2008; 26: 1993–1999.
129. Schneider BP, Miller KD. Angiogenesis of breast cancer. J Clin Oncol 2005; 23:
1782–1790.
130. Miller KD, Chap LI, Holmes FA et al. Randomized phase III trial of
capecitabine compared with bevacizumab plus capecitabine in patients with
previously treated metastatic breast cancer. J Clin Oncol 2005; 23: 792–799.
131. Miller K, Wang M, Gralow J et al. Paclitaxel plus bevacizumab versus paclitaxel
alone for metastatic breast cancer. N Engl J Med 2007; 357: 2666–2676.
132. Miles D, Chan A, Romieu G et al. Randomized, double-blind, placebo-
controlled, phase III study of bevacizumab with docetaxel or docetaxel with
placebo as first-line therapy for patients with locally recurrent or metastatic
breast cancer (mBC): AVADO. J Clin Oncol 2008; 26: (Abstr LBA1011 ).
133. Paterson AH, Powles TJ, Kanis JA et al. Double-blind controlled trial of oral
clodronate in patients with bone metastases from breast cancer. J Clin Oncol
1993; 11: 59–65.
134. Kristensen B, Ejlertsen B, Groenvold M et al. Oral clodronate in breast cancer
patients with bone metastases: a randomized study. J Intern Med 1999; 246:
67–74.
135. Tubiana-Hulin M, Beuzeboc P, Mauriac L et al. [Double-blinded controlled study
comparing clodronate versus placebo in patients with breast cancer bone
metastases]. Bull Cancer 2001; 88: 701–707.
136. Body JJ, Diel IJ, Lichinitser MR et al. Intravenous ibandronate reduces the
incidence of skeletal complications in patients with breast cancer and bone
metastases. Ann Oncol 2003; 14: 1399–1405.
137. Body JJ, Diel IJ, Bell R et al. Oral ibandronate improves bone pain and
preserves quality of life in patients with skeletal metastases due to breast
cancer. Pain 2004; 111: 306–312.
138. Major P, Lortholary A, Hon J et al. Zoledronic acid is superior to pamidronate in
the treatment of hypercalcemia of malignancy: a pooled analysis of two
randomized, controlled clinical trials. J Clin Oncol 2001; 19: 558–567.
139. Rosen LS, Gordon D, Kaminski M et al. Long-term efficacy and safety of
zoledronic acid compared with pamidronate disodium in the treatment of
skeletal complications in patients with advanced multiple myeloma or breast
carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer
2003; 98: 1735–1744.
140. Rosen LS, Gordon DH, Dugan W Jr et al. Zoledronic acid is superior to
pamidronate for the treatment of bone metastases in breast carcinoma patients
with at least one osteolytic lesion. Cancer 2004; 100: 36–43.
1784 | Beslija et al.
Annals of Oncology
141. Lipton A, Chen YM. Continuing benefit of zoledronic acid for the prevention of
skeletal complications in breast cancer patients with bone metastases. Breast
Cancer Res Treat 2006; 100: (Abstr 1070).
142. Kohno N, Aogi K, Minami H et al. Zoledronic acid significantly reduces skeletal
complications compared with placebo in Japanese women with bone
metastases from breast cancer: a randomized, placebo-controlled trial. J Clin
Oncol 2005; 23: 3314–3321.
143. Hortobagyi GN, Theriault RL, Lipton A et al. Long-term prevention of skeletal
complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia
Breast Cancer Study Group. J Clin Oncol 1998; 16: 2038–2044.
144. Theriault RL, Lipton A, Hortobagyi GN et al. Pamidronate reduces skeletal
morbidity in women with advanced breast cancer and lytic bone lesions:
a randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study
Group. J Clin Oncol 1999; 17: 846–854.
145. Lipton A, Theriault RL, Hortobagyi GN et al. Pamidronate prevents skeletal
complications and is effective palliative treatment in women with breast
carcinoma and osteolytic bone metastases: long term follow-up of two
randomized, placebo-controlled trials. Cancer 2000; 88: 1082–1090.
146. Pavlakis N, Schmidt R, Stockler M. Bisphosphonates for breast cancer.
Cochrane Database Syst Rev 2005; Issue 3. Art. No.: CD003474.
DOI: 10.1002/14651858.CD003474.pub2.
147. Hillner BE, Ingle JN, Chlebowski RT et al. American Society of Clinical Oncology
2003 update on the role of bisphosphonates and bone health issues in women
with breast cancer. J Clin Oncol 2003; 21: 4042–4057.
148. Conte P, Guarneri V. Safety of intravenous and oral bisphosphonates and
compliance with dosing regimens. Oncologist 2004; 9 (Suppl 4): 28–37.
149. Aapro M, Abrahamsson PA, Body JJ et al. Guidance on the use of
bisphosphonates in solid tumours: recommendations of an international expert
panel. Ann Oncol 2008; 19: 420–432.
150. Mehrotra B, Ruggiero S. Bisphosphonate complications including osteonecrosis
of the jaw. Hematology Am Soc Hematol Educ Program 2006: 356–360, 515.
151. Weitzman R, Sauter N, Eriksen EF et al. Critical review: updated
recommendations for the prevention, diagnosis, and treatment of osteonecrosis
of the jaw in cancer patients––May 2006. Crit Rev Oncol Hematol 2007; 62:
148–152.
152. Edwards BJ, Hellstein JW, Jacobsen PL et al. Dental management of patients
receiving oral bisphosphonate therapy: expert panel recommendations. J Am
Dent Assoc 2006; 137: 1144–1150.
153. Ripamonti C, Maniezzo M, Cislaghi E et al. Application of preventive measures
minimizes the occurrence of the osteonecrosis of the jaw (ONJ) in solid tumors
patients (pts) with bone metastases treated with bisphosphonates (BPs):
a single institution series. Breast Cancer Res Treat 2007; 106: (Abstr 2056).
154. Rizzo JD, Somerfield MR, Hagerty KL et al. Use of epoetin and darbepoetin in
patients with cancer: 2007 American Society of Clinical Oncology/American
Society of Hematology clinical practice guideline update. J Clin Oncol 2008; 26:
132–149.
155. Bennett CL, Silver SM, Djulbegovic B et al. Venous thromboembolism and
mortality associated with recombinant erythropoietin and darbepoetin
administration for the treatment of cancer-associated anemia. JAMA 2008;
299: 914–924.
156. Leyland-Jones B, Semiglazov V, Pawlicki M et al. Maintaining normal
hemoglobin levels with epoetin alfa in mainly nonanemic patients with
metastatic breast cancer receiving first-line chemotherapy: a survival study.
J Clin Oncol 2005; 23: 5960–5972.
157. Schwartzberg LS, Yee LK, Senecal FM et al. A randomized comparison of
every-2-week darbepoetin alfa and weekly epoetin alfa for the treatment of
chemotherapy-induced anemia in patients with breast, lung, or gynecologic
cancer. Oncologist 2004; 9: 696–707.
158. Senecal FM, Yee L, Gabrail N et al. Treatment of chemotherapy-induced
anemia in breast cancer: results of a randomized controlled trial of darbepoetin
alfa 200 microg every 2 weeks versus epoetin alfa 40,000 U weekly. Clin
Breast Cancer 2005; 6: 446–454.
159. Glaspy J, Vadhan-Raj S, Patel R et al. Randomized comparison of every-2-week
darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-
induced anemia: the 20030125 Study Group Trial. J Clin Oncol 2006; 24:
2290–2297.
Volume 20 | No. 11 | November 2009
Annals of Oncology
160. Bennett CL, Weeks JA, Somerfield MR et al. Use of hematopoietic colony-
stimulating factors: comparison of the 1994 and 1997 American Society of
Clinical Oncology surveys regarding ASCO clinical practice guidelines. Health
Services Research Committee of the American Society of Clinical Oncology. J
Clin Oncol 1999; 17: 3676–3681.
161. Wade JC, Rubenstein EB. NCCN: fever and neutropenia. Cancer Control 2001;
8: 16–21.
162. Zielinski CC, Awada A, Cameron DA et al. The impact of new European
Organisation for Research and Treatment of Cancer guidelines on the use of
granulocyte colony-stimulating factor on the management of breast cancer
patients. Eur J Cancer 2008; 44: 353–365.
163. Aapro MS, Cameron DA, Pettengell R et al. EORTC guidelines for the use of
granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-
induced febrile neutropenia in adult patients with lymphomas and solid
tumours. Eur J Cancer 2006; 42: 2433–2453.
164. Beral V. Breast cancer and hormone-replacement therapy in the Million Women
Study. Lancet 2003; 362: 419–427.
165. Colditz GA, Hankinson SE, Hunter DJ et al. The use of estrogens and progestins
and the risk of breast cancer in postmenopausal women. N Engl J Med 1995;
332: 1589–1593.
166. Powles TJ, Hickish T. Breast cancer response to hormone replacement therapy
withdrawal. Lancet 1995; 345: 1442.
167. Dhodapkar MV, Ingle JN, Ahmann DL. Estrogen replacement therapy
withdrawal and regression of metastatic breast cancer. Cancer 1995; 75:
43–46.
168. Kendall A, Dowsett M, Folkerd E, Smith I. Caution: vaginal estradiol appears to
be contraindicated in postmenopausal women on adjuvant aromatase
inhibitors. Ann Oncol 2006; 17: 584–587.
169. Bruno D, Feeney KJ. Management of postmenopausal symptoms in breast
cancer survivors. Semin Oncol 2006; 33: 696–707.
170. Dalal S, Zhukovsky DS. Pathophysiology and management of hot flashes. J
Support Oncol 2006; 4: 315–320, 325.
171. Hickey M, Saunders CM, Stuckey BG. Management of menopausal symptoms
in patients with breast cancer: an evidence-based approach. Lancet Oncol
2005; 6: 687–695.
172. Elkins G, Marcus J, Stearns V et al. Randomized trial of a hypnosis intervention
for treatment of hot flashes among breast cancer survivors. J Clin Oncol 2008;
26: 5022–5026.
173. Avis NE. Breast cancer survivors and hot flashes: the search for nonhormonal
treatments. J Clin Oncol 2008; 26: 5008–5010.
174. Blanchard DK, Shetty PB, Hilsenbeck SG, Elledge RM. Association of surgery
with improved survival in stage IV breast cancer patients. Ann Surg 2008; 247:
732–738.
175. Fields RC, Jeffe DB, Trinkaus K et al. Surgical resection of the primary tumor is
associated with increased long-term survival in patients with stage IV breast
cancer after controlling for site of metastasis. Ann Surg Oncol 2007; 14:
3345–3351.
176. Bafford AC, Burstein HJ, Barkley CR et al. Breast surgery in stage IV breast
cancer: impact of staging and patient selection on overall survival. Breast
Cancer Res Treat 2009; 115: 7–12.
Volume 20 | No. 11 | November 2009
review
177. Babiera GV, Rao R, Feng L et al. Effect of primary tumor extirpation in breast
cancer patients who present with stage IV disease and an intact primary tumor.
Ann Surg Oncol 2006; 13: 776–782.
178. Rao R, Feng L, Kuerer HM et al. Timing of surgical intervention for the intact
primary in stage IV breast cancer patients. Ann Surg Oncol 2008; 15: 1696–1702.
179. Pegram M, Chan D, Dichmann R et al. Phase II combined biological therapy
targeting the HER2 proto-oncogene and the vascular endothelial growth factor
using trastuzumab (T) and bevacizumab (B) as first line treatment of HER2-
amplified breast cancer. Breast Cancer Res Treat 2006; 100: (Abstr 301).
180. Schneider BP, Sledge GW Jr. Drug insight: VEGF as a therapeutic target for
breast cancer. Nat Clin Pract Oncol 2007; 4: 181–189.
181. Burstein HJ, Elias AD, Rugo HS et al. Phase II study of sunitinib malate, an oral
multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer
previously treated with an anthracycline and a taxane. J Clin Oncol 2008; 26:
1810–1816.
182. Colleoni M, Orlando L, Sanna G et al. Metronomic low-dose oral cyclophosphamide
and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor
activity and biological effects. Ann Oncol 2006; 17: 232–238.
183. Colleoni M, Rocca A, Sandri MT et al. Low-dose oral methotrexate and
cyclophosphamide in metastatic breast cancer: antitumor activity and
correlation with vascular endothelial growth factor levels. Ann Oncol 2002; 13:
73–80.
184. O’Shaughnessy J, Weckstein D, Vukelja S et al. Preliminary results of
a randomized phase II study of weekly irinotecan/carboplatin with or without
cetuximab in patients with metastatic breast cancer. Breast Cancer Res Treat
2007; 106: (Abstr 308).
185. Carey L, Rugo H, Marcom P et al. TBCRC 001: EGFR inhibition with cetuximab
added to carboplatin in metastatic triple-negative (basal-like) breast cancer.
J Clin Oncol 2008; 26: (Abstr 1009).
186. Farmer H, McCabe N, Lord CJ et al. Targeting the DNA repair defect in BRCA
mutant cells as a therapeutic strategy. Nature 2005; 434: 917–921.
187. Fong PC, Boss DS, Carden CP et al. AZD2281 (KU-0059436), a PARP (poly
ADP-ribose polymerase) inhibitor with single agent anticancer activity in
patients with BRCA deficient ovarian cancer: results from a phase I study. J Clin
Oncol 2008; 26: (Abstr 5510).
188. Renard V, Leach DR. Perspectives on the development of a therapeutic HER-2
cancer vaccine. Vaccine 2007; 25 (Suppl 2): B17–B23.
189. Yang E, Hu XF, Xing PX. Advances of MUC1 as a target for breast cancer
immunotherapy. Histol Histopathol 2007; 22: 905–922.
190. Bild AH, Yao G, Chang JT et al. Oncogenic pathway signatures in human
cancers as a guide to targeted therapies. Nature 2006; 439: 353–357.
191. Sanders ME, Dias EC, Xu BJ et al. Differentiating proteomic biomarkers in
breast cancer by laser capture microdissection and MALDI MS. J Proteome Res
2008; 7: 1500–1507.
192. Wulfkuhle JD, Speer R, Pierobon M et al. Multiplexed cell signaling analysis of
human breast cancer applications for personalized therapy. J Proteome Res
2008; 7: 1508–1517.
193. Loeffler-Ragg J, Skvortsov S, Sarg B et al. Gefitinib-responsive EGFR-positive
colorectal cancers have different proteome profiles from non-responsive cell
lines. Eur J Cancer 2005; 41: 2338–2346.
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