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Consensus Metastatic Breast CC
Consensus Metastatic Breast CC
Consensus Metastatic Breast CC
doi:10.1093/annonc/mdp261
Published online 16 July 2009
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
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
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 Annals of Oncology
the-art treatment, considering available treatment options in stage IV breast cancer. Data from phase II clinical trials or retrospective
relation to various clinical and biological variables. analyses were included only in case of lack of evidence from randomized
Encouraged by previous considerations and recent data, the phase III clinical trials. As mentioned above, the main goals of treatment in
panel agreed to hold up its previous statement [9] that the patients with MBC include prevention and palliation of symptoms,
primary goals of treatment in MBC include maximizing the QoL and prolongation of survival. However, like in
previous reports [8, 9], the panel recognized that most randomized clinical
maximizing the quality of life (QoL), trials enrolling patients with MBC were not designed to provide
prevention and palliation of symptoms and a quantitative comparison of differences in survival adjusted by the
prolongation of survival concomitant changes in QoL, i.e. to measure differences in quality-adjusted
life years. Thus, the panelists agreed that for consensus formation regarding
Concordant with the previous recommendation [9] and due to therapies targeting the tumors, overall survival (OS) should be the primary
the biological variability of the patient and her disease, the outcome of interest and that significant differences in QoL or toxicity
decision for the optimal timing of treatment initiation and the between interventions should be indicated. In contrast, differences in QoL
continuation of treatment has to be made on an individual were the primary outcome of interest for supportive care interventions.
basis. Progression-free survival (PFS) and response rates (RRs) or disease
Treatment choices for MBC are guided by stabilization were considered as secondary outcomes.
As stated in the previous consensus [9], a number of clinical The use of a third-generation nonsteroidal (anastrozole and
and biological prognostic factors are associated with long-term letrozole) or steroidal (exemestane) aromatase inhibitor was
clinical outcomes among women with MBC (Table 1). Since recommended as first-line treatment with tamoxifen
breast cancer is a very heterogeneous disease, these criteria remaining to constitute a valuable option.
do not lend themselves to dichotomize risk strata, but are Following tamoxifen failure, a third-generation aromatase
clinically relevant for the choice of treatment and determining inhibitor or the selective ER downregulator fulvestrant is
prognosis. recommended for second-line treatment.
Following failure of a third-generation nonsteroidal
aromatase inhibitor, a steroidal aromatase inhibitor [23–25],
Table 1. Prognostic factors in patients with metastatic breast cancer tamoxifen (or toremifen) [26], fulvestrant, progestins,
estrogens or androgens may be considered [27, 28]. In the
Prognostic factor Favorable Unfavorable Evaluation of Faslodex versus Exemestane Clinical Trial trial,
which enrolled patients after treatment failure on
Performance status Good Poor
nonsteroidal aromatase inhibitors, RR, PFS and OS were
Sites of disease Bone, soft tissue Viscera, CNS
No. of sites of disease Few Multiple
similar with exemestane and fulvestrant [29]. However, no
Hormone receptor status Positive Negative
definitive recommendation for a treatment cascade can be
Her-2/neu status Negative Positive (significance given at present.
less clear in Her-2/neu
The different side-effect and toxicity profiles as well as the
inhibitors era) route of administration of tamoxifen, aromatase inhibitors
Disease-free interval >2 years <2 years and fulvestrant should be considered in the choice of
Prior adjuvant therapy No Yes endocrine treatment in the individual patient.
Prior therapy for MBC No Yes
In premenopausal patients with endocrine-dependent MBC,
CNS, central nervous system; MBC, metastatic breast cancer. tamoxifen, ovarian function suppression or a combination of
both continue to constitute suitable treatment options [30–32], that compared combination chemotherapy with specified,
although the combination of luteinizing hormone–releasing sequential single-agent treatment, while confirming higher RRs,
hormone (LH–RH) agonist and tamoxifen may be superior to did not show improved survival [39–41]. Multidrug approach
LH–RH agonist alone [33]. In this population of patients, there has been usually associated with increased toxicity. In contrast,
are insufficient data on the use of aromatase inhibitors, which a recently presented CECOG study has shown that sequential
should be given only in conjunction with some form of use of docetaxel and gemcitabine could result in unexpectedly
adequate suppression of ovarian function [34]. higher toxicity as compared with their combined application,
probably due to higher chemotherapy dosages used in the
cytotoxic chemotherapy former [41]. Nevertheless, an additional benefit of single-agent
sequential chemotherapy is that this strategy allows efficacy
general recommendations assessment of particular agents.
Chemotherapy remains the mainstay of treatment in MBC. The
goals of chemotherapy in this setting are to prolong survival, recommendation. Current experience indicates that sequential
alleviate or prevent tumor-related symptoms and improve QoL. use of single cytotoxic agents with proven efficacy in breast
However, in contrast to endocrine therapy, chemotherapy is cancer is a considerable alternative to standard multidrug
more likely associated with considerable and notorious side- chemotherapy regimens, perhaps except for patients with
effects that have to be balanced against potential benefits. rapidly progressive visceral disease.
Therefore, primary chemotherapy should generally be offered anthracyclines. Anthracyclines constitute the group of most
to patients whose tumors are not sensitive or are refractory to active cytotoxic agents in MBC. Anthracycline-naive patients
hormone therapy. The candidates to chemotherapy are also with MBC are typically applied single-agent anthracycline
patients with bulky visceral disease, severe tumor-related treatment, be it doxorubicin (60–75 mg/m2 every 3 weeks or 20
symptoms or rapid progression, irrespective of hormone- mg/m2 weekly) or epirubicin (75–100 mg/m2 every 3 weeks or
receptor status. At the onset of chemotherapy, an assessment of 20–30 mg/m2 weekly) or anthracycline-based combinations.
cancer-related symptoms and performance status should be Patients relapsing >12 months after anthracycline-based
carried out. Initial disease staging should allow fair assessment treatment may be reinduced with anthracycline-based
of the baseline tumor burden. During therapy, patient chemotherapy up to cumulative doxorubicin and epirubicin
symptoms and performance status have to be recorded with dose levels of 450–550 and 800–1000 mg/m2, respectively. More
each cycle. To avoid continuing ineffective therapy, tumor recently, liposomal doxorubicin formulations (pegylated or not
response should be assessed every two or three cycles. pegylated) have shown antitumor efficacy similar to that
Laboratory tests should be carried out before each observed with nonliposomal formulations in first-line
chemotherapy administration to secure treatment safety. treatment of MBC, but with a low cardiac toxicity profile [40–
Integrated assessment of chemotherapy benefits should include 44]. Thus, liposomal doxorubicin may be considered in
anticancer efficacy, amelioration of cancer-related symptoms patients with preexisting cardiac disease or in those who have
and treatment-related side-effects. The current line of reached or near the cumulative cardiotoxicity threshold.
chemotherapy should be stopped if prohibitive toxicity or overt
progression arises. At progression, in most instances further taxanes. Taxanes—paclitaxel, docetaxel and nanoparticle
treatment with new agents should be considered. albumin-bound paclitaxel (nab-paclitaxel)—have demonstrated
There is a paucity of data on prospectively evaluated significant activity in MBC in terms of RR and PFS. Several
molecular predictors that could govern the individualized trials have explored the value of combining anthracyclines and
choice of chemotherapeutic agents in patients with MBC [35, taxanes, given that these two classes of agents have different
36]. This shortcoming, however, is expected to resolve upon mechanisms of action and no cross-resistance [45–50]. Most of
successful validation of genomic information on predictors of these studies showed that combined use of anthracyclines and
drug sensitivity and resistance in ongoing prospective clinical taxanes increased RR and time to progression (TTP), and two
trials [37]. studies also demonstrated improved OS [46, 47], however, at
When considering chemotherapy in MBC, the following the expense of higher treatment-related toxicity. A recent
scenarios have to be considered: meta-analysis showed increased RR and PFS, but not OS of
taxanes in combination with anthracyclines, compared with
First-line treatment standard nontaxane regimens [51]. Additionally, this
Chemotherapy after anthracycline pretreatment meta-analysis failed to identify a subset of patients who might
Chemotherapy after anthracycline and taxane pretreatment derive clear benefit from the addition of taxanes.
failure of anthracyclines and taxanes. Consecutive cytotoxic gemcitabine administered in patients with HER-2/neu-
chemotherapy is worth considering in women who have overexpressing MBC in combination with trastuzumab in the
responded to previous regimens, but no definitive guidance can first and up to fifth-line setting have produced RR between 24%
be given regarding the optimal agents or the order they should and 81% [87–97]. Selection of regimens is governed by the
be administered. patient’s prior treatment history and the side-effect profile of
concurrent therapy. Retrospective analyses and a randomized
dose intensity trial comparing chemotherapy and trastuzumab to trastuzumab
There are no new data demonstrating a benefit of increased alone followed by chemotherapy at progression demonstrated
chemotherapy dose intensity in MBC [75]. Thus, this strategy a trend favoring survival for up-front use of concurrent therapy
should not be attempted outside clinical trials. [98, 99]. Given that, and owing to the survival advantage seen
in two trials of concurrent chemotherapy and trastuzumab, the
treatment duration use of combination treatment is preferable to single-agent
therapy for most patients.
Therapeutic options in MBC include continuation of The benefit of adding more than one cytotoxic agent over
chemotherapy until disease progression or treatment single-agent chemotherapy with trastuzumab is unclear.
interruption at some point, with its reintroduction at the time Addition of carboplatin to trastuzumab and paclitaxel
of progression. A series of randomized studies compared increased RR and TTP in one randomized trial [100], whereas
shorter versus longer chemotherapy [76–81]. These studies a similar study using docetaxel instead of paclitaxel found no
have generally shown that prolonged treatment is associated benefit but reported an increased toxicity from adding the
with extended TTP but has little effect on OS. The impact of platinum salt [101]. Similarly, preliminary results from a phase
prolonged therapy may be drug dependent, as some agents (e.g. II randomized trial adding capecitabine to docetaxel and
capecitabine) can be continued for longer periods than others trastuzumab have demonstrated benefit in terms of PFS, and
(e.g. anthracyclines and taxanes). A recent systematic review of not RR, the primary end point in this study [102].
eight randomized trials including 1942 patients demonstrated Trastuzumab has also been studied in combination with
an insignificant reduction in the risk of death (hazard ratio endocrine therapy for ER-positive, HER-2/neu-positive MBC.
0.92; CI 0.84–1.00; P = 0.07) with prolonged therapy [82]. In a randomized trial of anastrozole versus anastrozole and
Thus, the benefit associated with longer chemotherapy duration trastuzumab, the addition of trastuzumab yielded modest
as first-line treatment in MBC seems to be at best marginal. improvements in PFS and RR. OS, however, was found to be
recommendation. There is no strong evidence to recommend prolonged only in a post hoc analysis comparing patients who
routinely continuing chemotherapy until disease progression or received trastuzumab in combination or sequential after
significant side-effects arise. In patients with treatment anastrozole failure to those who did not receive trastuzumab at
response or stable disease (as defined by a <50% reduction and any time point [103, 104].
a <25% increase in the sum of the products of two Treatment with trastuzumab may be complicated by
perpendicular diameters of all measured lesions and the a modestly increased risk of congestive heart failure (CHF)
appearance of no new lesions), intermittent administration of [105]. The risk for the development of CHF increases with
chemotherapy is a reasonable option. The decision on advanced age and concurrent therapy with trastuzumab and
treatment duration should take into account symptoms, side- anthracyclines [85]. Outside of research protocols, patients
effects, QoL and patient preferences. should still not receive concurrent treatment with trastuzumab
and anthracyclines. However, the administration of
trastuzumab in combination with less cardiotoxic
management of patients with anthracyclines like epirubicin or liposomal doxorubicin
Her-2/neu-overexpressing MBC formulations may be relatively safe and effective [106–110]. The
frequent pretreatment with anthracyclines in the adjuvant
trastuzumab setting, the concern over cardiotoxicity and the availability of
Trastuzumab represents an effective single agent in HER-2/neu- multiple nonanthracycline chemotherapy options that can be
overexpressing (3+ by IHC or FISH positive) MBC [83, 84]. In safely paired with trastuzumab make the combination of
a pivotal, randomized phase III trial carried out in patients with trastuzumab and anthracyclines less desirable. It was
HER-2/neu-overexpressing MBC, first-line treatment with the recommended that patients undergo baseline measurement of
combination of trastuzumab plus chemotherapy resulted in cardiac function before trastuzumab-based therapy and
significantly higher overall RR and significantly prolonged PFS continue cardiac surveillance while continuing treatment.
and OS as compared with chemotherapy alone [85]. This Echocardiography or radioisotope ventriculography are
clinical benefit was achieved with only minimal increase in the commonly used to assess left ventricular function before and
subjective toxicity profile of the combination over single-agent during trastuzumab-based treatment. However, the optimal
paclitaxel. A second randomized trial of docetaxel with or cardiac surveillance strategy remains to be established.
without trastuzumab has also shown benefit in OS [86]. The Patients who have achieved optimal clinical response to
combination of an anthracycline and trastuzumab was also trastuzumab-based therapy may be considered for
highly effective in the pivotal trial, but accompanied by a high maintenance treatment with single-agent trastuzumab,
risk of cardiotoxicity [85]. A series of other cytotoxic drugs though the clinical benefits of this practice are not
including vinorelbine, platinum compounds, capecitabine and known.
progression with bevacizumab (5.5 versus 11.6 months) [131]. recommendations. The strongest evidence for efficacy in
The third study [132], comparing docetaxel with or without prevention of skeletal morbidity in patients with breast cancer
bevacizumab as first-line treatment, again demonstrated and bone metastases is available for i.v. bisphosphonate
improvement in TTP, though of far less absolute difference preparations, but no trial has directly compared oral with i.v.
than seen in ECOG2100. To date, none of the trials of preparations. Evidence from randomized clinical trials in
bevacizumab has shown a survival advantage. Thus, in first-line patients with breast cancer and bone metastases indicates that
treatment, bevacizumab in combination with taxanes appears the use of bisphosphonates (oral clodronate 1600 mg/day, i.v.
to improve upon results seen with chemotherapy alone, making ibandronate 6 mg every 21–28 days, oral ibandronate 50 mg/
combination treatment an option for such patients. In contrast, day, i.v. pamidronate 90 mg every 21–28 days and i.v.
there are no data indicating a benefit of bevacizumab use in the zoledronic acid 4 mg every 21–28 days) can reduce and delay
second-line chemotherapy. the incidence of skeletal morbidity [146]. Evidence supports the
use of bisphosphonates with or without other anticancer
treatment. Although most trials evaluated bisphosphonate
bisphosphonates treatment administered for a maximum of 2 years, the optimal
bisphosphonate therapy for bone metastases duration of this treatment is unknown. The American Society
of Clinical Oncology guidelines on the use of bisphosphonates
clodronate (oral). Several small placebo-controlled trials have
in women with breast cancer recommend that bisphosphonate
examined the efficacy of oral clodronate in patients with bone
therapy should be continued until there is a substantial decline
metastases from breast cancer [133–135]. Overall, patients
in patient performance status [147]. Currently, there are
who received oral clodronate had a significantly reduced
insufficient data on the use of bisphosphonates in women
skeletal morbidity rate compared with patients who received
without metastatic bone involvement or without HCM.
placebo.
ibandronate (oral and i.v.). The efficacy of oral and i.v. safety considerations during bisphosphonate
ibandronate has been evaluated in randomized, placebo- therapy
controlled trials in women with bone metastases from breast Overall, bisphosphonate therapy is generally well tolerated in
cancer [136]. Two years of i.v. ibandronate therapy significantly patients with advanced breast cancer metastatic to bone and
reduced the mean skeletal morbidity period rate and can be safely combined with other anticancer therapies. Oral
lengthened the median time to first bone event compared with bisphosphonates are associated with gastrointestinal side-effects
placebo. A pooled analysis of two phase III studies of oral [148] and i.v. bisphosphonates are associated with transient
ibandronate showed a significant reduction in the risk of bone influenza-like symptoms and increased bone pain after the
events compared with placebo [137]. initial infusions [148]. In addition, dose- and infusion rate-
zoledronic acid (i.v.). Intravenous zoledronic acid has been dependent effects of bisphosphonates on renal function have
shown to be superior to pamidronate in treatment of been reported [148]. Guidelines have been published which
hypercalcemia of malignancy (HCM) [138] and in reducing recommend monitoring renal function in patients receiving
the risk of skeletal-related events (SREs) in large randomized bisphosphonates and alternative dosing schedules for patients
trials in breast cancer patients with bone metastases [139, 140]. with renal impairment [149]. Recently, an uncommon toxicity
Overall, patients with MBC receiving zoledronic acid consisting of osteonecrosis of the jaw (ONJ) has been reported
experienced a higher reduction in the risk of developing an SRE in patients accompanying prolonged use of bisphosphonates
compared with patients receiving pamidronate [139]. [150]. Risk factors for ONJ may include poor oral hygiene and
Zoledronic acid also significantly prolonged the mean time to dental surgery during bisphosphonate therapy. Therefore,
first SRE and significantly reduced the annual skeletal preventive dentistry recommendations have been published
morbidity rate compared with pamidronate [139–141]. [150–152]. Preliminary reports indicate that implementation of
A subsequent study compared zoledronic acid with placebo in preventative dentistry and monitoring recommendations can
patients with breast cancer and bone metastases. In this trial, substantially reduce the incidence of ONJ in patients with
patients who received zoledronic acid had a significantly cancer [153].
longer median time to first SRE and a significantly reduced
risk of experiencing an SRE compared with placebo
[142]. supportive care
pamidronate (i.v.). The efficacy of i.v. pamidronate for the symptomatic anemia
prevention of SREs has been demonstrated in two large As mentioned previously [9], anemia constitutes a common
randomized phase III trials in patients with at least one problem in patients with metastatic disease and may be caused
osteolytic bone lesion [143, 144]. In both trials, pamidronate or aggravated by cytotoxic treatment resulting in fatigue. When
significantly lowered bone pain scores at the end of treatment present, also other reasons for fatigue and associated symptoms
compared with placebo. A pooled analysis of these two trials including nutritional status, treatment side-effects and
showed that pamidronate significantly increased the time to psychological and psychiatric disorders should be considered
first SRE, significantly reduced the proportion of patients who and comprehensively investigated.
experienced SREs and significantly reduced the skeletal Symptomatic anemia (with a hemoglobin <10–11 g/dl)
morbidity rate compared with placebo [145]. should be diagnosed, investigated and corrected to maintain
psychological support
emerging treatments and future
As recognized before [9], women with MBC may experience
psychological distress including depression, anxiety, stress– directions
response syndrome, difficulty in coping and social isolation. A rapidly increasing number of molecular structures of
Randomized trials of group psychosocial interventions in malignant cells can be targeted by various agents including
patients with MBC identified psychological benefits specifically signal transduction inhibitors, mAbs, anticancer vaccines,
including improvement in mood, pain control and coping. antisense strategies or antiangiogenic drugs. Because the mode
Therefore, it was recommended that psychosocial support of action of the various available agents is distinct from
should be available to patients with MBC. However, current cytotoxic treatment, they represent ideal combination partners
research does not allow for the recommendation of an optimal for chemotherapeutic and endocrine treatment options. These
type, timing or duration of psychological support emerging approaches, however, will require additional efforts
interventions. Moreover, the evidence of a survival advantage for careful selection of patients most likely to benefit from
due to psychological support interventions is not convincing. targeted therapies: Proper definition of targets and assessment
of target inhibition in tumors or indicative tissues,
menopausal symptoms, hormone replacement determination of the mechanisms of drug sensitivity and
therapy and topical estrogen resistance and assessment of novel surrogate end points of
Menopausal symptoms crucially impair women’s QoL and are treatment effect may require assessment of an increasing
frequently aggravated by endocrine therapy or cytotoxic number of biological traits of patients and tumors alike,
therapy in women with breast cancer. Based upon scientific functional imaging, repeated biopsies and storage of biological
evidence causally linking the use of HRT to the development of material suitable for molecular and high-throughput analyses.
breast cancer [164, 165], the use of HRT in MBC is strongly
discouraged, as HRT may stimulate growth of hormone emerging treatments
receptor-positive cancers. In this vein, several reports about antiangiogenic therapy. Following the encouraging results from
a clinical benefit of HRT withdrawal in MBC have been the use of bevacizumab in the first-line treatment of MBC,
published [166, 167]. Likewise, in the absence of safety data on results from additional randomized trials combining
the use of HRT in patients with ER- and PgR-negative tumors, bevacizumab with other targeted therapies [179] are eagerly
the panel strongly discouraged the use of HRT in all patients expected. In addition, there are numerous trials of other anti-
with MBC. If topical estrogens need to be considered for QoL VEGF agents alone or in combination ongoing for advanced
reasons, preparations that result in the lowest possible systemic breast cancer [180, 181]. As yet, no other drugs apart from
absorption should be chosen. Vaginal estradiol tablets should bevacizumab based upon the concept of antiangiogenesis are
be used with caution in MBC patients, whereas estriol approved for use. Another investigated strategy includes
suppositories may be less dangerous [168]. Whenever feasible, continuous administration of low-dose cytotoxic drugs
nonhormonal treatment of menopausal symptoms should be (metronomic chemotherapy). This nontoxic and easily
deliverable scheduling is believed to induce anticancer effect at proteomics as a tool to define biomarkers. Biomarkers serve as
least in part by virtue of antiangiogenic mechanisms. Two trials hallmarks for the status of tumor growth at a given time and
using low-dose cyclophosphamide (50 mg daily) and change during the disease process. In general, biomarkers can
methotrexate (5 mg daily twice a week) have shown a RR in the guide us to define subgroups of patients whose tumors express
range of 20% [182, 183]. Metronomic therapy may be a specific target and thus may have a high probability of
potentially useful in pretreated or frail MBC patients, but it still response. Therefore, the identification of novel biomarkers that
warrants clinical verification. are able to predict treatment response or resistance may allow
therapy to be tailored to individual patients. Cancer proteomics
cetuximab. The monoclonal epidermal growth factor receptor is a rapidly developing field and is expected to accelerate the
(EGFR) antibody cetuximab has shown little activity as single discovery of new diagnostic, prognostic and therapy-related
agent in patients with mostly heavily pretreated MBC in biomarkers. The rationale for proteomic investigation is that
randomized phase II studies, but may add to the efficacy of proteins are often expressed in quantities and physical forms
cytotoxic treatment [184, 185]. Inhibition of the EGFR is that cannot be predicted from DNA and messenger RNA
presently investigated as a new treatment strategy specifically in analysis, as for example due to post-translational modification
patients with triple-negative breast cancer. of proteins. Therefore, proteome analysis provides
a complementary approach to microarray gene expression
future directions profiling [37, 190].
Application of protein microarray technology for the study
targeting DNA repair mechanisms. A significant fraction of
of ongoing signaling activity within breast tumor specimens
breast cancer is hereditary and based on germline mutations in
holds great potential for elucidating and profiling signaling
the breast cancer early onset (BRCA) genes BRCA1 and BRCA2.
activity for patient-tailored therapy. Analysis of laser capture
In addition, both genes are found inactivated in sporadic cases
microdissected primary human breast tumors and metastatic
by mutations and more often by epigenetic mechanisms. Both
lesions reveals pathway specific profiles and a new way to
BRCA1 and BRCA2 are at least partially necessary for DNA
classify cancer based on functional signaling portraits.
repair by homologous recombination (HR). HR gets additional
Moreover, the metastasis-specific changes that occur within
importance in cells if another classical DNA recombination
a new microenvironment can be revealed. Analysis of biopsy
pathway, namely the repair of single-stranded DNA (SSDNA) is
material from clinical trials for targeted therapeutics
blocked. In normal cells, the inhibition of a crucial enzyme of
demonstrates the feasibility and utility of comprehensive signal
SSDNA repair, poly ADP-ribose polymerase (PARP1), does not
pathway activation profiling for molecular analysis [191, 192].
cause major effects. When SSDNA breaks are encountered
The possibility of detecting hundreds to thousands of proteins
during DNA replication, the replication fork stalls and double-
at the same point of time is also a tool to define proteins
stranded DNA (dsDNA) breaks accumulate. These dsDNA
associated with response or resistance to therapy [193].
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 funding
alone or in combination may prove highly effective therapies
Bristol Myers-Squibb; Eli Lilly; Roche.
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 acknowledgements
BRCA HR pathway [187].
The panelists thank Ursula Fischer for the organization of the
anticancer vaccines. The field of cancer vaccines is currently in infrastructure of this consensus. Pamela Goodwin (Samuel
active preclinical and clinical investigations. Although no Lunenfeld Research Institute, Mount Sinai Hospital, Toronto,
therapeutic breast cancer vaccine has been approved to date, recent Canada) is a contributor to this work.
preclinical and clinical findings have shown that the use of vaccine Organizing institution: CECOG, Headoffice: Schlagergasse 6,
therapies may well lead to an additional treatment choice, Vienna, Austria (www.cecog.org).
ultimately being used for the therapy of advanced breast cancer. Supporting institution: Clinical Division of Oncology,
One of the two structures mainly used as targets for an active Department of Medicine I/Cancer Center, General Hospital,
immune response, HER-2/neu, emerged from the dramatic Medical University Vienna, Vienna, Austria
response to this receptor by passive immune therapy by (www.meduniwien.ac.at/krebszentrum).
trastuzumab or pertuzumab [188]. The second commonly used
target structure Mucin 1 (MUC1), a transmembrane references
glycoprotein was used in several vaccination trials [189]. All
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