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. Kostler8, 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)
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, 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

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:

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

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(v) supportive care. to measure differences in quality-adjusted life years. Recommendations of the consensus panel represent statements that all members of the panel agreed upon. the San Antonio Breast Cancer Symposium. which was then repeatedly disseminated for review by the entire panel. (vii) high-dose therapy and (viii) future directions. differences in QoL were the primary outcome of interest for supportive care interventions. 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 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. In addition. 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 European Conference of Clinical Oncology.e. maximizing the QoL and prolongation of survival. In contrast. (ii) cytotoxic therapy. Europe and the United States. 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. Progression-free survival (PFS) and response rates (RRs) or disease stabilization were considered as secondary outcomes. Encouraged by previous considerations and recent data. M1 tumor of the breast. (iii) treatment of Her-2/neu-overexpressing MBC. Treatment choices for MBC are guided by  stage IV breast cancer. In analogy to our methods. like in previous reports [8. patient preferences. i. (vi) surgery. 9] and to put them into perspective with recent data. In doing so. HER-2/neu status. MBC was defined according to the tumor–node–metastasis system classification (6th edition) of the American Joint Committee on Cancer [11] as any T. medical oncology. with special emphasis upon their impact on clinical practice. 11 | November 2009 . All members of the panel participated in the preparation of a draft guideline document. by using the Allred score). Similar to previous publications.         hormone receptor [estrogen receptor (ER) and progesterone receptor (PgR)] status of the primary tumor or its metastases. the main goals of treatment in patients with MBC include prevention and palliation of symptoms. 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. As mentioned the-art treatment. (iv) bisphosphonates. the decision for the optimal timing of treatment initiation and the continuation of treatment has to be made on an individual basis. the panel agreed to hold up its previous statement [9] that the primary goals of treatment in MBC include    Annals of Oncology maximizing the quality of life (QoL). 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. the duration of the relapse-free interval since primary diagnosis and since completion of adjuvant therapy for breast cancer. the European Society of Medical Oncology and the European Breast Cancer Conference were used for identifying relevant literature. 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. Volume 20 | No. methods of consensus formation panel composition The CECOG has invited an expert panel consisting of experts in clinical medicine (i. considering available treatment options in relation to various clinical and biological variables. Diagnostic imaging workup should include assessment of frequent sites of metastases including the lung. electronic and manual searches including Medline and The Cochrane Library (search terms: breast cancer. Final text editing was completed by CCZ and WJK and accepted by all panelists. the panelists agreed that for consensus formation regarding therapies targeting the tumors. 9]. overall survival (OS) should be the primary outcome of interest and that significant differences in QoL or toxicity between interventions should be indicated. 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. 9]. liver and bone. The panel participants were from Australia. 1772 | Beslija et al. the present recommendations of the consensus panel concern patients with stage IV disease. Thus. the location and extent of metastases (visceral versus nonvisceral).e. previous treatment (including its effects and tolerance). Each subcommittee presented a consensus proposal. literature review and analysis In accordance with previous reports [8.g. 14]. patient symptoms. Data from phase II clinical trials or retrospective analyses were included only in case of lack of evidence from randomized phase III clinical trials. radiological imaging of the central nervous system (CNS) should be considered in Her-2/neu-positive patients [12]. Expression of ER and PgR should be reported in a semiquantified way (e. experts were asked to consider previous recommendations made by the group in preceding years [8. Each subcommittee was assigned a coordinator and independently reviewed publications addressing particular aspects relating to the medical management of MBC including (i) endocrine treatment. anticipated side-effects of treatment and the availability and access to treatment consensus formation The panel formed subcommittees of two to six participants. 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. However. any N.

However. aromatase inhibitors and fulvestrant should be considered in the choice of endocrine treatment in the individual patient. ovarian function suppression or a combination of Volume 20 | No. 11 | November 2009 doi:10. In tumors with 2+ protein overexpression by IHC. Only a limited amount of new important data has been generated in recent years. fulvestrant. Denmark) [18]. endocrine treatment In general and as recommended previously [9]. endocrine treatment should be offered as first option to most women with hormone-sensitive MBC. The different side-effect and toxicity profiles as well as the route of administration of tamoxifen. For 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. Following tamoxifen failure. but are clinically relevant for the choice of treatment and determining prognosis.Annals of Oncology review The panelists continued to acknowledge that this classification should not be regarded as rigid. a third-generation aromatase inhibitor or the selective ER downregulator fulvestrant is recommended for second-line treatment. tamoxifen. DAKO Inc. which would lead to a change in recommendations reached by the panel previously [9]. which enrolled patients after treatment failure on nonsteroidal aromatase inhibitors. Her-2/neu testing should be carried out by a standardized assay and scoring system according to the manufacturer’s recommendations (HercepTestÒ. no definitive recommendation for a treatment cascade can be given at present. When carried out in central laboratories with appropriate expertise. 19]. CNS. The panel repeated previous recommendations that efforts to standardize testing for Her-2/neu overexpression should be strongly encouraged. Based upon data from early breast cancer and MBC. Upon occurrence of MBC. a number of clinical and biological prognostic factors are associated with long-term clinical outcomes among women with MBC (Table 1). 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. Following failure of a third-generation nonsteroidal aromatase inhibitor. recommendations for the assessment of Her-2/neu protein overexpression and gene amplification Her-2/neu status should be assessed by IHC. Patients with hormone-sensitive MBC are typically characterized by     a long disease-free interval (>2 years). but may constitute the basis for treatment recommendations [9].g. progestins. estrogens or androgens may be considered [27. limited metastatic sites and disease-related symptoms and slow disease progression prognostic factors As stated in the previous consensus [9]. 28]. The panel declared that the determination of Her-2/neu status is obligatory in all breast cancer patients.. In the Evaluation of Faslodex versus Exemestane Clinical Trial trial. Prognostic factors in patients with metastatic breast cancer Prognostic factor Performance status Sites of disease No. Glostrup. CNS Multiple Negative Positive (significance less clear in Her-2/neu inhibitors era) <2 years Yes Yes  Disease-free interval Prior adjuvant therapy Prior therapy for MBC >2 years No No 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. PFS and OS were similar with exemestane and fulvestrant [29]. central nervous system. 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. surgical resection and radiation therapy) or watchful waiting may be considered. This recommendation is based upon lower toxicity of endocrine treatment and generally longer durations of response in this subset as compared with cytotoxic chemotherapy. Briefly. 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]. tamoxifen (or toremifen) [26]. although there are no data from randomized trials supporting or discouraging this practice. RR. the concurrent use of endocrine treatment and cytotoxic chemotherapy in MBC is discouraged [9]. a steroidal aromatase inhibitor [23–25]. local treatments (e. In premenopausal patients with endocrine-dependent MBC. the level of concordance between Her-2/neu 3+ overexpression assessed by IHC and FISH or CISH is high [15–17]. Since breast cancer is a very heterogeneous disease. FISH or chromogenic in situ hybridization (CISH). of sites of disease Hormone receptor status Her-2/neu status Favorable Good Bone. the following recommendations have been reconfirmed for the endocrine treatment of postmenopausal patients with hormone receptor-positive MBC:    Table 1. MBC.1093/annonc/mdp261 | 1773 . with no difference in OS [22]. In patients with very limited metastatic disease. no (or limited) visceral involvement. metastatic breast cancer. these criteria do not lend themselves to dichotomize risk strata. soft tissue Few Positive Negative Unfavorable Poor Viscera. 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].

Therefore. 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. To avoid continuing ineffective therapy. in contrast to endocrine therapy. other agents. liposomal doxorubicin may be considered in patients with preexisting cardiac disease or in those who have reached or near the cumulative cardiotoxicity threshold. However. at the expense of higher treatment-related toxicity. improvement in OS compared with sequential single-agent treatment administered at the maximum tolerated dose [38]. alleviate or prevent tumor-related symptoms and improve QoL. amelioration of cancer-related symptoms and treatment-related side-effects. sequential single-agent treatment. 11 | November 2009 . respectively. However. Several trials have explored the value of combining anthracyclines and taxanes. 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. therefore. liposomal doxorubicin formulations (pegylated or not pegylated) have shown antitumor efficacy similar to that observed with nonliposomal formulations in first-line treatment of MBC. When considering chemotherapy in MBC. However. At the onset of chemotherapy. compared with standard nontaxane regimens [51]. In this population of patients. Volume 20 | No. recommendation. while confirming higher RRs. longer PFS and a modest. which should be given only in conjunction with some form of adequate suppression of ovarian function [34]. chemotherapy is more likely associated with considerable and notorious sideeffects that have to be balanced against potential benefits. although the combination of luteinizing hormone–releasing hormone (LH–RH) agonist and tamoxifen may be superior to LH–RH agonist alone [33]. patient symptoms and performance status have to be recorded with each cycle. docetaxel and nanoparticle albumin-bound paclitaxel (nab-paclitaxel)—have demonstrated significant activity in MBC in terms of RR and PFS. Annals of Oncology cytotoxic chemotherapy general recommendations Chemotherapy remains the mainstay of treatment in MBC. Multidrug approach has been usually associated with increased toxicity. anthracyclines. probably due to higher chemotherapy dosages used in the former [41]. In contrast. however. if any. More recently. The candidates to chemotherapy are also patients with bulky visceral disease. Laboratory tests should be carried out before each chemotherapy administration to secure treatment safety. During therapy. First-line treatment Chemotherapy after anthracycline pretreatment Chemotherapy after anthracycline and taxane pretreatment first-line treatment sequential single-agent versus multidrug chemotherapy. an additional benefit of single-agent sequential chemotherapy is that this strategy allows efficacy assessment of particular agents. this meta-analysis failed to identify a subset of patients who might derive clear benefit from the addition of taxanes. Integrated assessment of chemotherapy benefits should include anticancer efficacy. in most instances further treatment with new agents should be considered. primary chemotherapy should generally be offered to patients whose tumors are not sensitive or are refractory to hormone therapy. Anthracycline-naive patients with MBC are typically applied single-agent anthracycline treatment. Most of these studies showed that combined use of anthracyclines and taxanes increased RR and time to progression (TTP). but with a low cardiac toxicity profile [40– 44]. The current line of chemotherapy should be stopped if prohibitive toxicity or overt progression arises. Additionally. taxanes. did not show improved survival [39–41]. Anthracyclines constitute the group of most active cytotoxic agents in MBC. tumor response should be assessed every two or three cycles. these compounds have typically been used in salvage chemotherapy settings. A recent meta-analysis showed increased RR and PFS. but not OS of taxanes in combination with anthracyclines. the following scenarios have to be considered:    that compared combination chemotherapy with specified. the randomized trials 1774 | Beslija et al. there are insufficient data on the use of aromatase inhibitors. 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. Taxanes—paclitaxel. The goals of chemotherapy in this setting are to prolong survival. is expected to resolve upon successful validation of genomic information on predictors of drug sensitivity and resistance in ongoing prospective clinical trials [37]. At progression. perhaps except for patients with rapidly progressive visceral disease. Thus. their role in first-line treatment is not well both continue to constitute suitable treatment options [30–32]. Nevertheless. 47]. 36]. severe tumor-related symptoms or rapid progression. given that these two classes of agents have different mechanisms of action and no cross-resistance [45–50]. vinca alkaloids (vinorelbine) and epothilones (ixabepilone) have shown activity in MBC. 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. an assessment of cancer-related symptoms and performance status should be carried out. and two studies also demonstrated improved OS [46. Several new drugs including antimetabolites (gemcitabine and capecitabine). 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. Initial disease staging should allow fair assessment of the baseline tumor burden. irrespective of hormonereceptor status. An overview of randomized trials indicates that first-line multidrug chemotherapy in MBC is associated with higher RRs. This shortcoming. Increased use of anthracyclines and taxanes as adjuvant and neoadjuvant treatments has restricted their use in patients with relapse. however.

compared with vinorelbine alone [72]. It should be noted. taxane monotherapy (preferably docetaxel every 3 weeks. 100 or chemotherapy after anthracycline and taxane pretreatment There are few effective treatment options available to women with MBC who failed to respond or relapsed after receiving both anthracyclines and taxanes. demonstrated longer TTP and OS of the former. Paclitaxel has been traditionally used in doses ranging from 135 to 225 mg/m2 administered every 3 weeks. A randomized phase III trial comparing docetaxel plus gemcitabine versus docetaxel plus capecitabine showed similar efficacy of both regimens. gemcitabine. recommendation. 66]. More recently. although anthracycline-based combinations remain the most commonly used treatment regimens. paclitaxel and gemcitabine) are associated with improved OS compared with taxane monotherapy [65. that neither docetaxel nor nab-paclitaxel has demonstrated superiority over the weekly schedule of paclitaxel. as well as combinations thereof have been investigated [68]. characteristics of the disease and the ease of administration. 53] and in the first-line treatment of MBC has provided significantly longer OS than the classical cyclophosphamide– fluorouracil–methotrexate regimen [54]. Capecitabine has also become an attractive partner for combination strategies with both cytotoxic and targeted agents [70. and preliminary results indicate its high sensitivity to agents that bring about DNA interstrand cross-links. are the most commonly used compounds in MBC patients previously exposed to anthracyclines. 73]. ixabepilone (an analogue of epothilone B). representing a new class of compounds suppressing microtubule activity. 11 | November 2009 doi:10.1 months and OS 11. including capecitabine. TTP 3.1093/annonc/mdp261 | 1775 . has emerged as an active agent in anthracycline and taxane-pretreated patients [74]. However. given its efficacy. safety and ease of administration [69]. this compound was found to be less effective than single-agent epirubicin (RR 16% versus 40%. Based on the current experience. however. Additionally. paclitaxel every week or nab-paclitaxel weekly) or taxane-based combinations should be considered. The Food and Drug Administration-approved capecitabine dose is 2500 mg/m2 on days 1–14 of a 21-day cycle. TTP and OS [21]. multidrug therapy resulted in significantly increased hematologic and nonhematologic toxicity. albeit at the cost of a significantly increased toxicity [62]. capecitabine has been the most frequently used agent. however. taxane-based multidrug chemotherapy. Gemcitabine and vinorelbine have been shown to be active in some patients pretreated with anthracyclines and taxanes [72. and many patients did not receive subsequent therapy. Similarly. taking into account QoL. ixabepilone or vinorelbine. Administration of nab-paclitaxel was associated with a lower risk of hypersensitivity reactions.4 versus 6. A direct comparison of docetaxel (100 mg/m2) and paclitaxel (175 mg/m2). recommendation. toxicity. in clinical practice. less grade 4 neutropenia. but not RR and OS. In patients who have received anthracyclines in the adjuvant or neoadjuvant setting. compared with docetaxel at 100 mg/m2 every 3 weeks [64]. chemotherapy after anthracycline pretreatment taxane monotherapy. Two randomized phase III trials including anthracycline-pretreated MBC patients demonstrated that two-drug taxane combinations (docetaxel and capecitabine.Annals of Oncology review 150 mg/m2 on days 1. A randomized study demonstrated that the combination of these two agents was associated with increased PFS. No optimal first-line chemotherapy regimen can be defined in MBC. In contrast to paclitaxel. but increased grade 3 sensory neuropathy. particularly in elderly patients [53]. gemcitabine as single agent showed limited efficacy in first-line treatment of MBC. Patients with early relapse after previous adjuvant anthracycline and taxane chemotherapy may be offered other regimens. In a randomized study including elderly patients. no cross-over to antimetabolites after the taxane failure was mandated in these studies. applied as monotherapy or in combination with other agents.1 months. In patients with anthracycline resistance or failure. vinorelbine. epothilones and platinum salts. The efficacy of first-line vinorelbine seems to be modest [55]. A Cochrane analysis demonstrated a modest survival advantage of taxane-based versus nontaxane regimens in this setting [59]. such as mitomycin C or platinum salts [58]. particularly in the case of docetaxel–capecitabine combination. This benefit was achieved at the expense of increased toxicity. particularly sensory neuropathy and neutropenia. Single-agent capecitabine was associated with RRs of 25% [52. The taxanes. respectively) [57]. Accumulating data demonstrate that ‘triple-negative’ or ‘basal’ phenotype of breast cancer may represent a biologically distinct entity. both administered every 21 days. Several agents. all administered as either monotherapy or in combination with other cytotoxic agents may be beneficial after Volume 20 | No. a phase II randomized study showed longer PFS of nab-paclitaxel (used at three different dosage levels: 300 mg/m2 every 3 weeks. A recent phase III study demonstrated that addition of ixabepilone to capecitabine is associated with increased RR and PFS compared with capecitabine alone [71]. Of those. 8 and 15 every 4 weeks). a dose of 2000 mg/m2 is commonly applied. recommendation. however. its weekly administration (usually at a dose of 80 mg/m2) provides superior RR. Most recently.8 versus 19. 61]. A randomized study comparing docetaxel to carboplatin in this subset of patients is currently ongoing among many other studies in clinical research. liposomal doxorubicin. gemcitabine. two main treatment options include reintroduction of anthracyclines considering their cumulative dose or application of taxanes. Another phase III trial showed higher RR and TTP of nab-paclitaxel compared with paclitaxel (175 mg/m2 over 3 h every 21 days) [63]. but a combination of vinorelbine and capecitabine in an elderly population provided an RR of 43% [56]. 71]. the efficacy of docetaxel does not appear to be schedule dependent [60. with significantly lower nonhematologic toxicity of the former [67]. capecitabine.

the use of combination treatment is preferable to single-agent therapy for most patients. QoL and patient preferences. The combination of an anthracycline and trastuzumab was also highly effective in the pivotal trial. Annals of Oncology dose intensity There are no new data demonstrating a benefit of increased chemotherapy dose intensity in MBC [75]. patients should still not receive concurrent treatment with trastuzumab and anthracyclines. the optimal cardiac surveillance strategy remains to be established. The impact of prolonged therapy may be drug dependent. whereas a similar study using docetaxel instead of paclitaxel found no benefit but reported an increased toxicity from adding the platinum salt [101]. Trastuzumab has also been studied in combination with endocrine therapy for ER-positive. A series of randomized studies compared shorter versus longer chemotherapy [76–81]. the administration of trastuzumab in combination with less cardiotoxic anthracyclines like epirubicin or liposomal doxorubicin formulations may be relatively safe and effective [106–110]. intermittent administration of chemotherapy is a reasonable option. 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.g. The benefit of adding more than one cytotoxic agent over single-agent chemotherapy with trastuzumab is unclear. 99]. Thus. Selection of regimens is governed by the patient’s prior treatment history and the side-effect profile of concurrent therapy. and not RR. Given that. the primary end point in this study [102]. P = 0. randomized phase III trial carried out in patients with HER-2/neu-overexpressing MBC. OS. 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]. However. management of patients with Her-2/neu-overexpressing MBC trastuzumab Trastuzumab represents an effective single agent in HER-2/neuoverexpressing (3+ by IHC or FISH positive) MBC [83. treatment duration Therapeutic options in MBC include continuation of chemotherapy until disease progression or treatment interruption at some point. Volume 20 | No. with its reintroduction at the time of progression. and owing to the survival advantage seen in two trials of concurrent chemotherapy and trastuzumab. Consecutive cytotoxic chemotherapy is worth considering in women who have responded to previous regimens.84–1. Similarly. but no definitive guidance can be given regarding the optimal agents or the order they should be administered. Echocardiography or radioisotope ventriculography are commonly used to assess left ventricular function before and during trastuzumab-based treatment. however. preliminary results from a phase II randomized trial adding capecitabine to docetaxel and trastuzumab have demonstrated benefit in terms of PFS. capecitabine and gemcitabine administered in patients with HER-2/neuoverexpressing MBC in combination with trastuzumab in the first and up to fifth-line setting have produced RR between 24% and 81% [87–97]. as some agents (e. 104]. Treatment with trastuzumab may be complicated by a modestly increased risk of congestive heart failure (CHF) [105]. There is no strong evidence to recommend routinely continuing chemotherapy until disease progression or significant side-effects arise. but accompanied by a high risk of cardiotoxicity [85]. 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. 1776 | Beslija et al. These studies have generally shown that prolonged treatment is associated with extended TTP but has little effect on OS.07) with prolonged therapy [82]. Patients who have achieved optimal clinical response to trastuzumab-based therapy may be considered for maintenance treatment with single-agent trastuzumab. anthracyclines and taxanes). A second randomized trial of docetaxel with or without trastuzumab has also shown benefit in OS [86]. Addition of carboplatin to trastuzumab and paclitaxel increased RR and TTP in one randomized trial [100]. However. This clinical benefit was achieved with only minimal increase in the subjective toxicity profile of the combination over single-agent paclitaxel. The frequent pretreatment with anthracyclines in the adjuvant failure of anthracyclines and taxanes. Thus. The risk for the development of CHF increases with advanced age and concurrent therapy with trastuzumab and anthracyclines [85]. In a randomized trial of anastrozole versus anastrozole and trastuzumab. 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). capecitabine) can be continued for longer periods than others (e. CI 0. the benefit associated with longer chemotherapy duration as first-line treatment in MBC seems to be at best marginal. A series of other cytotoxic drugs including vinorelbine. the addition of trastuzumab yielded modest improvements in PFS and RR. 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. HER-2/neu-positive MBC.00. this strategy should not be attempted outside clinical trials. In a pivotal. though the clinical benefits of this practice are not known. sideeffects.92. It was recommended that patients undergo baseline measurement of cardiac function before trastuzumab-based therapy and continue cardiac surveillance while continuing treatment. 84].g. recommendation. The decision on treatment duration should take into account symptoms. A recent systematic review of eight randomized trials including 1942 patients demonstrated an insignificant reduction in the risk of death (hazard ratio 0. 11 | November 2009 . platinum compounds. Outside of research protocols.

results from the HERA trial in the adjuvant setting indicate the efficacy and safety of the latter dosing regimen also in MBC [112]. there are no data on prophylactic therapy or on the long-term clinical benefit of surveillance in asymptomatic patients. Treatment with single-agent trastuzumab remains a viable alternative for frail patients or patients with indolent disease. but not OS. When combined with letrozole in patients with hormone-dependent MBC. Three phase III trials have evaluated the efficacy of chemotherapy alone or chemotherapy plus bevacizumab for MBC. In early-phase clinical trials. The study demonstrated an improvement in RR and TTP. The first published study compared capecitabine alone or capecitabine plus bevacizumab in patients with extensive chemotherapy exposure including anthracyclines and taxanes [130]. comparing weekly paclitaxel with or without bevacizumab as first-line therapy for MBC. 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. has activity in trastuzumab-resistant. despite tumor progression on prior trastuzumab treatment. treatment of CNS metastases remains a clinical challenge. although there are no data from randomized clinical trials to prove that these two schedules are equally effective. Common side-effects include hypertension. lapatinib is active only in the Her2/neu-positive subgroup [127]. 11 | November 2009 doi:10. or the Hsp90 inhibitor tanespimycin to trastuzumab have also demonstrated efficacy and safety in patients with trastuzumab-refractory MBC [118. there was no prolonged PFS or OS. 111]. 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]. [116] compared capecitabine alone or capecitabine plus trastuzumab among women with HER-2/neupositive MBC progressing under previous trastuzumab-based treatment. demonstrated a significant improvement in RR and time to disease lapatinib Several TKIs are being investigated in phase II trials in MBC. Similarly. In contrast.1093/annonc/mdp261 | 1777 . Further. 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. followed by 2 mg/kg weekly until disease progression. a second trial. recommendation. An initial loading dose of 4 mg/ kg trastuzumab.Annals of Oncology review not significantly prolonged by the combined treatment with extended follow-up [126]. OS was Volume 20 | No. progressive disease during trastuzumab treatment. anthracyclines and taxanes and randomized between the addition of lapatinib to trastuzumab and a switch to lapatinib only [117]. 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]. Patients with HER-2/neu-positive MBC have an increased risk of developing brain metastases.and trastuzumab-refractory breast cancer and 24% among trastuzumab-naive patients [125]. In these patients. prevention or delay in the development of CNS metastases with lapatinib was indicated [126]. However. the evidence regarding the magnitude of such benefit is unknown. Her-2/neu-targeted therapies may also favorably combine with endocrine therapy if tumors are both ER positive and Her-2/ neu positive. an mAb targeting an epitope distinct from that bound by trastuzumab on the Her-2/neu receptor. 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. is recommended. likely owing to several factors—a predilection for visceral sites of metastasis. ECOG2100. Retrospective studies and feasibility analyses indicate that such treatment was well tolerated by most patients [113– 115]. the addition of pertuzumab. Two randomized trials have now evaluated the role of continuing trastuzumab treatment beyond tumor progression. in the pivotal trial of capecitabine with or without lapatinib. evaluating the benefit of adding lapatinib to first-line therapy with paclitaxel in patients with unknown or negative Her-2/neu status. In a recently published trial. HER-2/neu-positive MBC [121–123]. most clinical outcomes. Another clinical trial tested the efficacy of continuation of trastuzumab after progression of Her-2/neu-positive MBC under trastuzumab. but was underpowered to demonstrate an OS benefit. Lapatinib. 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. Nevertheless. the combination of capecitabine and lapatinib was found to be significantly better than capecitabine alone in terms of disease-free survival [70]. 119]. were improved by addition of lapatinib to paclitaxel only in the small subgroup of Her-2/neu-positive patients [19]. In a pivotal trial in women with trastuzumab-resistant HER-2/ neu-positive MBC. an orally available TKI directed against both the erbB1 and the erbB2 (HER-2/neu) receptor. a relative sanctuary site in the CNS and prolonged OS owing to the success of trastuzumab-based treatment [12]. As a single agent. However. However. lapatinib has shown RRs between 5% [124] among chemotherapy. At present. Von Minckwitz et al. Lapatinib has shown hints of CNS activity (although modest in heavily pretreated patients) as a single agent or in combination with capecitabine [128]. nasal congestion/ discharge and slight exacerbation of chemotherapy-related sideeffects [129]. The use of trastuzumab as first-line therapy in combination with nonanthracycline-based chemotherapy is strongly recommended in patients with HER-2/neu proteinoverexpressing (3+ by IHC) or Her-2/neu FISH-positive MBC regardless of age or prior adjuvant chemotherapy. These findings indicate that continuing trastuzumab may have clinical benefits in combination with other treatments. Although RRs increased substantially in the bevacizumab arm. dosage and treatment schedule.

zoledronic acid (i. Zoledronic acid also significantly prolonged the mean time to first SRE and significantly reduced the annual skeletal morbidity rate compared with pamidronate [139–141]. none of the trials of bevacizumab has shown a survival advantage. there are no data indicating a benefit of bevacizumab use in the second-line chemotherapy. Volume 20 | No. bevacizumab in combination with taxanes appears to improve upon results seen with chemotherapy alone. 11 | November 2009 . pamidronate (i. preparations. The third study [132]. in first-line treatment. Currently. oral ibandronate 50 mg/ day. To date. 144]. i. zoledronic acid 4 mg every 21–28 days) can reduce and delay the incidence of skeletal morbidity [146]. treatment side-effects and psychological and psychiatric disorders should be considered and comprehensively investigated.v.v. supportive care symptomatic anemia As mentioned previously [9]. Evidence supports the use of bisphosphonates with or without other anticancer treatment. Symptomatic anemia (with a hemoglobin <10–11 g/dl) should be diagnosed. Annals of Oncology bisphosphonates bisphosphonate therapy for bone metastases clodronate (oral). The strongest evidence for efficacy in prevention of skeletal morbidity in patients with breast cancer and bone metastases is available for i. 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]. Thus.v. investigated and corrected to maintain 1778 | Beslija et al. In both trials. ibandronate has been evaluated in randomized. Overall. anemia constitutes a common problem in patients with metastatic disease and may be caused or aggravated by cytotoxic treatment resulting in fatigue. 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]. recommendations. preventive dentistry recommendations have been published [150–152].5 versus 11. A pooled analysis of these two trials showed that pamidronate significantly increased the time to first SRE. Risk factors for ONJ may include poor oral hygiene and dental surgery during bisphosphonate therapy. The efficacy of i.v.v.v. there are insufficient data on the use of bisphosphonates in women without metastatic bone involvement or without HCM.).review progression with bevacizumab (5. Oral bisphosphonates are associated with gastrointestinal side-effects [148] and i. The efficacy of oral and i.). significantly reduced the proportion of patients who experienced SREs and significantly reduced the skeletal morbidity rate compared with placebo [145].and infusion ratedependent effects of bisphosphonates on renal function have been reported [148]. safety considerations during bisphosphonate therapy Overall. Although most trials evaluated bisphosphonate treatment administered for a maximum of 2 years. When present. Evidence from randomized clinical trials in patients with breast cancer and bone metastases indicates that the use of bisphosphonates (oral clodronate 1600 mg/day.v. but no trial has directly compared oral with i. In addition.). bisphosphonate therapy is generally well tolerated in patients with advanced breast cancer metastatic to bone and can be safely combined with other anticancer therapies.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. though of far less absolute difference than seen in ECOG2100. 140]. ibandronate 6 mg every 21–28 days. comparing docetaxel with or without bevacizumab as first-line treatment. In contrast. making combination treatment an option for such patients. ibandronate (oral and i. also other reasons for fatigue and associated symptoms including nutritional status. Preliminary reports indicate that implementation of preventative dentistry and monitoring recommendations can substantially reduce the incidence of ONJ in patients with cancer [153].v. the optimal duration of this treatment is unknown. bisphosphonates are associated with transient influenza-like symptoms and increased bone pain after the initial infusions [148]. patients with MBC receiving zoledronic acid experienced a higher reduction in the risk of developing an SRE compared with patients receiving pamidronate [139]. patients who received oral clodronate had a significantly reduced skeletal morbidity rate compared with patients who received placebo. pamidronate significantly lowered bone pain scores at the end of treatment compared with placebo. A subsequent study compared zoledronic acid with placebo in patients with breast cancer and bone metastases.v. again demonstrated improvement in TTP.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. bisphosphonate preparations. dose. Two years of i. Guidelines have been published which recommend monitoring renal function in patients receiving bisphosphonates and alternative dosing schedules for patients with renal impairment [149]. placebocontrolled trials in women with bone metastases from breast cancer [136]. ibandronate therapy significantly reduced the mean skeletal morbidity period rate and lengthened the median time to first bone event compared with placebo. Therefore. i. pamidronate 90 mg every 21–28 days and i. an uncommon toxicity consisting of osteonecrosis of the jaw (ONJ) has been reported in patients accompanying prolonged use of bisphosphonates [150]. In this trial. Overall.6 months) [131]. Recently. Several small placebo-controlled trials have examined the efficacy of oral clodronate in patients with bone metastases from breast cancer [133–135]. 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].v.

the panel strongly discouraged the use of HRT in all patients with MBC. non-small-cell lung. In two separate chart reviews involving >800 patients. In addition. Randomized trials of group psychosocial interventions in patients with MBC identified psychological benefits specifically including improvement in mood. there is no evidence of superiority of any ESP [157– 159]. Because the mode of action of the various available agents is distinct from cytotoxic treatment. Another investigated strategy includes continuous administration of low-dose cytotoxic drugs (metronomic chemotherapy). repeated biopsies and storage of biological material suitable for molecular and high-throughput analyses. anxiety. These emerging approaches. With adequate dosing and schedule. mAbs. several reports about a clinical benefit of HRT withdrawal in MBC have been published [166. Whenever feasible. In this vein. no other drugs apart from bevacizumab based upon the concept of antiangiogenesis are approved for use. median OS was increased by 10–16 months in patients who underwent surgical resection (P < 0. therefore. Following the encouraging results from the use of bevacizumab in the first-line treatment of MBC. 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. menopausal symptoms. another chart review of 147 patients found the benefit of surgery only in patients who underwent surgery before the diagnosis of metastatic disease [176]. as HRT may stimulate growth of hormone receptor-positive cancers. a history of previous febrile neutropenia under preceding chemotherapy or due to individual risk factors. lymphoid and cervical cancers [155. leukopenia When using chemotherapy associated with a likelihood of >20% of febrile leukopenia. psychological support As recognized before [9]. To decrease these risks. be noted that these findings have not been validated to date in prospective studies. Likewise. Therefore. they represent ideal combination partners for chemotherapeutic and endocrine treatment options. stress– response syndrome. 175]. 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. current research does not allow for the recommendation of an optimal type. anticancer vaccines. However. whereas estriol suppositories may be less dangerous [168]. it was recommended that psychosocial support should be available to patients with MBC. However. 156]. As yet. 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. This nontoxic and easily Volume 20 | No. the use of HRT in MBC is strongly discouraged. it is recommended. women with MBC may experience psychological distress including depression. 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. 11 | November 2009 doi:10. 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. however. pain control and coping. emerging treatments antiangiogenic therapy.Annals of Oncology review sought. If topical estrogens need to be considered for QoL reasons. head and neck. the evidence of a survival advantage due to psychological support interventions is not convincing.and PgR-negative tumors. antisense strategies or antiangiogenic drugs. It should. 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. which may include pharmacological interventions. erythropoiesis-stimulating proteins (ESPs) and erythrocyte transfusions constitute reasonable options to achieve this goal. 167]. recent retrospective reviews of patient records have indicated that such intervention might improve clinical outcomes.1093/annonc/mdp261 | 1779 . there are numerous trials of other antiVEGF agents alone or in combination ongoing for advanced breast cancer [180. erythrocyte transfusions should be administered. 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. the use of myeloid colony-stimulating factors can be considered [160–163]. QoL and avoid fatigue [154]. However. Vaginal estradiol tablets should be used with caution in MBC patients.0001 compared with patients who did not undergo surgery) [174. nonhormonal treatment of menopausal symptoms should be 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. The treatment should be discontinued when a hemoglobin level of 11–12 g/dl has been reached. Based upon scientific evidence causally linking the use of HRT to the development of breast cancer [164. difficulty in coping and social isolation. 165]. However. Moreover. and the real benefits of surgery in patients with MBC remain to be elucidated. In the case of nonresponsiveness to ESPs and for acute symptoms. preparations that result in the lowest possible systemic absorption should be chosen. results from additional randomized trials combining bevacizumab with other targeted therapies [179] are eagerly expected. in the absence of safety data on the use of HRT in patients with ER. 178]. functional imaging. 181]. timing or duration of psychological support interventions. mind–body and behavioral interventions [169–173]. however. Under consideration of various geographic approaches.

11 | November 2009 . Both BRCA1 and BRCA2 are at least partially necessary for DNA repair by homologous recombination (HR). ultimately being used for the therapy of advanced breast cancer. 2. the identification of novel biomarkers that are able to predict treatment response or resistance may allow therapy to be tailored to individual patients.meduniwien. Residual risk of breast cancer recurrence 5 years after adjuvant therapy. emerged from the dramatic response to this receptor by passive immune therapy by trastuzumab or pertuzumab [188]. Eli Lilly. Roche. Pamela Goodwin (Samuel Lunenfeld Research Institute. prognostic and therapy-related biomarkers. Jemal A. and St Gallen recommendations. with different adjuvants. Trends in breast cancer by race and ethnicity: update 2006. namely the repair of single-stranded DNA (SSDNA) is blocked. may be a better target population for therapeutic vaccine therapies. 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]. ASCO. 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. Brewster AM. CA Cancer J Clin 2006. an error-free repair mechanism. cetuximab. 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].org). A significant fraction of breast cancer is hereditary and based on germline mutations in the breast cancer early onset (BRCA) genes BRCA1 and BRCA2. The field of cancer vaccines is currently in active preclinical and clinical investigations. a transmembrane glycoprotein was used in several vaccination trials [189]. Austria (www. Canada) is a contributor to this work. dendritic cell based and others). Hudis CA. but may add to the efficacy of cytotoxic treatment [184. does not cause major Vienna. 190]. 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. 192]. poly ADP-ribose polymerase (PARP1). 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. General Hospital. In contrast. Ward E et al. 100: 1179–1183. Adjuvant endocrine therapy in hormone receptor-positive postmenopausal breast cancer: evolution of NCCN. 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. Cancer proteomics is a rapidly developing field and is expected to accelerate the discovery of new diagnostic. 56: 168–183. 1780 | Beslija et al. In normal cells. references 1. Therefore. Patients with limited or minimal tumor deliverable scheduling is believed to induce anticancer effect at least in part by virtue of antiangiogenic Supporting institution: Clinical Division of Oncology. Medical University Vienna. The second commonly used target structure Mucin 1 (MUC1). 3. When SSDNA breaks are encountered during DNA replication. 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. In general. showed very limited toxic effects and consistent immunological responses of the patients. Austria (www. Organizing institution: CECOG. anticancer vaccines. Annals of Oncology future directions targeting DNA repair mechanisms. Inhibition of the EGFR is presently investigated as a new treatment strategy specifically in patients with triple-negative breast cancer. the replication fork stalls and doublestranded DNA (dsDNA) breaks accumulate. J Natl Compr Canc Netw 2006. proteomics as a tool to define biomarkers. 4: 971–979. but in general low or absent clinical responses in patients with MBC. Hortobagyi GN. recent preclinical and clinical findings have shown that the use of vaccine therapies may well lead to an additional treatment choice. HR gets additional importance in cells if another classical DNA recombination pathway.cecog. peptide based. In addition. however. HER-2/neu. Smigal C. both genes are found inactivated in sporadic cases by mutations and more often by epigenetic mechanisms. Department of Medicine I/Cancer Center. Metronomic therapy may be potentially useful in pretreated or frail MBC patients. but it still warrants clinical verification. One of the two structures mainly used as targets for an active immune response.e. 185]. Mount Sinai Hospital. tumors lacking BRCA may be highly sensitive to PARP1 inhibitors [186]. as for example due to post-translational modification of proteins. the inhibition of a crucial enzyme of SSDNA repair. Broglio KR et al. Headoffice: Schlagergasse 6. All those trials with varying vaccination strategies (i. Vienna. 183]. 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. Carlson RW. Pritchard KI. proteome analysis provides a complementary approach to microarray gene expression profiling [37. Thus. Volume 20 | No. Moreover. the metastasis-specific changes that occur within a new microenvironment can be revealed. Therefore. funding Bristol Myers-Squibb. Although no therapeutic breast cancer vaccine has been approved to date. acknowledgements The panelists thank Ursula Fischer for the organization of the infrastructure of this consensus. biomarkers can guide us to define subgroups of patients whose tumors express a specific target and thus may have a high probability of response. J Natl Cancer Inst 2008. Toronto. These dsDNA breaks are then repaired via HR repair. Biomarkers serve as hallmarks for the status of tumor growth at a given time and change during the disease process.

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