Triple-negative breast cancer: an update.

Introduction

Breast cancer comprises a diverse collection of diseases rather than a single homogeneous disease. Both preclinical and clinical research now commonly target specific subgroups of breast cancer with the aim of identifying biological markers or genetic phenotypes, and to reveal subgroup-specific therapeutic targets or indicators of prognosis. Examples include the targeting of oestrogen receptor (ER)-driven breast cancers using tamoxifen, aromatase inhibitors and gonadotropin-releasing hormone agonists, and the subgroup of breast cancers driven by the receptor tyrosine kinase ErbB2 [or human epidermal growth factor receptor 2 (HER2)] which is targeted by the monoclonal antibody trastuzumab or the small molecule inhibitor lapatinib [1]. In each case, painstaking preclinical research followed by large, multicentre, randomised controlled trials have led to improved disease-free survival and overall survival (OS). Sadly these newer targeted agents are of no benefit to a significant group of women who have breast cancers that fail to express ERs and progesterone receptors (PRs) and overexpress HER2.

How do we define triple-negative breast cancer?

The term 'triple-negative' breast cancer refers to cancers that do not express ERs and PRs or overexpress HER2. This is an easily recognisable group for clinicians as it is currently not well served by any targeted therapy in routine practice. Approximately 20% of breast cancers have this triple-negative phenotype.

Transcriptional profiling of breast cancers has identified five distinct subtypes: luminal A, luminal B, normal breast-like, HER2 over-expressing and basal-like [2]. The basal-like group only infrequently expresses the ER or PR and rarely over-expresses HER2. As a group, basal-like cancers make up the majority (~80%) of the overall triple-negative subgroup [3].

There is, however, significant heterogeneity within and considerable overlap between the triple-negative and basal-like subgroups. There are some basal-like cancers that express ER or HER2, and triple-negative cancers can have expression profiles in the normal breast-like rather than the basal-like expression cluster.

In contrast to luminal breast cancers that are thought to originate from the inner layer of the breast duct lining, basal-like tumours are thought to arise from the outer (basal) layer of the duct. At present, there is controversy surrounding the definition of basal-like tumours. A plethora of different markers and definitions have been employed to identify cases in clinical data sets, most commonly by immunohistochemical (IHC) staining of proteins such as cytokeratin (CK) 5/6 that are expressed in normal cells in the basal epithelium of breast ducts (Figure 1).

Nielsen and colleagues have derived an IHC definition that closely correlates with the basal-like transcriptional profile [3]. This is based on negative ER and HER2 with positive CK5/6 and/or epidermal growth factor receptor (EGFR) expression. Even this definition does not show perfect correlation with microarray data. There is currently no accepted gold standard by which to define basal-like cancers and basal markers are not routinely reported in the breast cancer dataset in the UK. A number of studies have demonstrated the existence of considerable heterogeneity of outcome between different 'basal' markers within the triple-negative subgroup and this has highlighted a need to better characterise this subgroup in prospective clinical trials.

[FIGURE 1 OMITTED]

Who gets triple-negative breast cancer?

There are currently 8000 to 10,000 (15-20% of total) new cases of triple-negative breast cancer per year in the UK. Population-based studies have recently been published in North America. Bauer et al. published data from the California Cancer Registry [4]. Information on all three breast cancer markers (ER, PR and HER2 status) was available in over 50,000 women in this registry. Of these women, 12.5% were identified as having triple-negative breast cancer. Women with triple-negative disease were significantly more likely to be under age 40 [odds ratio (OR), 1.53], and non-Hispanic black (OR, 1.77) or Hispanic (OR, 1.23). Regardless of stage at diagnosis, women with triple-negative cancers had poorer survival than those with other breast cancers, and non-Hispanic black women with late-stage triple-negative cancer had the poorest survival, with a 5-year relative survival of only 14%.

The relationship between ethnicity and the triple-negative and basal-like subgroups has also been demonstrated by other groups. In the Carolina Breast Cancer study of 657 incident breast cancers [5], overall 26.2% of all breast cancers were triple negative. This phenotype was significantly more frequent in African American than non-African American women (33.9% versus 21.2%, P=0.0003), and premenopausal than postmenopausal women (30.3% versus 21.9%, P=0.02). The highest incidence of triple-negative breast cancer occurred among premenopausal African American women (44.3%) compared with postmenopausal African American women (24.6%, P=0.0008). In multivariate models combining all factors, the significant predictors of the triple-negative phenotype were high mitotic index (P<0.0001), high nuclear or histological grade (P<0.0001 for both) and race (P=0.03). A more detailed phenotypic characterisation of this study has confirmed the association between these features and the prevalence of the basal-like form of breast cancer [6]. In a study describing a cohort of 148 Nigerian patients with breast cancer [7], 66.9% were premenopausal with a mean age at diagnosis of 43.8 years. ER was expressed in only 22.3% and HER2 was over-expressed in 18.9% of patients. Overall, 87 of 148 (59%) patients were found to have triple-negative breast cancer.

Based on these data we might expect a higher incidence of triple-negative breast cancer in young women and women of African ancestry in urban areas of the UK.

Does triple-negative breast cancer have a different natural history?

There is a growing body of evidence to suggest that the clinical behaviour and metastatic pattern of dissemination of triple-negative breast cancers are different from those of comparable non-basal-like ductal carcinomas.

Triple-negative cancers have been shown to arise more frequently as interval cancers in women of screening age [8]. This is consistent with what is usually an aggressive and highly proliferative phenotype [6]. Several groups have shown that women with triple-negative breast cancer, when compared to those with non-triple-negative tumours, have poorer distant metastasis-free and cause-specific survival in the early years of follow-up [4,8-11]. Survival after the development of metastases was particularly poor in the triple-negative group [11,12]. There appears to be no difference in local control between the triple-negative and other subtypes [11].

Triple-negative breast cancers are nearly always high grade [8,9] and are ER negative by definition. Comparisons of clinical behaviour with all other breast cancers are often dominated by this difference in grade and ER status. Fulford et al. addressed this by looking exclusively at grade 3 invasive ductal carcinomas [13] and found that over the first 5 years, relapse-free survival and OS appeared similar between basal-like and other grade 3 tumours. There was, however, a significant difference in the hazard of death over time; this has recently been confirmed by others [8]. Fulford et al. found that patients with basal-like breast cancers had better subsequent survival after having already survived for 5 years than those in the non-basal-like group. In the basal-like group, perhaps as with many non-breast cancer epithelial malignancies, almost all the recurrences occurred in the first 5 years. This study also suggested the existence of two subgroups of basal carcinomas, one exhibiting early relapse and aggressive clinical course and a separate group that despite poor prognostic indicators, do not relapse. Thus even within a group defined by high grade and expression of basal markers there is considerable heterogeneity of outcome.

ER status has long been known to play a significant role in determining the natural history of breast cancer. ER-negative tumours are more likely to be poorly differentiated, of higher histological grade, and associated with a higher recurrence rate and with decreased OS and unresponsive to anti-oestrogens. As basal-like breast cancer is predominantly ER negative, and non-basal-like breast cancer is largely ER positive, the comparison between basal-like and non-basal-like breast cancer is at least in part a comparison of ER-positive with ER-negative breast cancer. Jumppanen et al. studied the clinical and biological features of the basal phenotype tumours determined by IHC and cDNA microarrays especially within the ER-negative subgroup [14]. They demonstrated that among ER-negative tumours, the clinical outcome of basal-like tumours is similar to that of non-basal-like tumours.

As well as differences in time course of recurrence, there appear to be differences in patterns of invasion or tropism of cells metastasising from basal-like primary cancers. Some groups have found that the basal-like and triple-negative subgroups are less likely than other groups to have positive axillary nodes [10,13] and that the relationship between tumour size and lymph node involvement is lost [8]. The sites of metastatic disease also seem to differ, with first metastases more common in lungs and a higher rate of central nervous system and leptomeningeal metastases [9,13,15].

It should be noted that not all triple-negative breast cancers are associated with a poor prognosis. For example, medullary-like breast cancer is a triple-negative breast cancer that has been reported in some series to have a better prognosis than expected [16]. This reinforces the notion that triple-negative breast cancers are a heterogenous group made up of subtypes with different clinical outcomes.

BRCA1 and basal-like breast cancer

Unlike sporadic cancers, where basal-like cancers represent 15-20% of invasive cancers, 80-90% of cancers arising in BRCA1 germ line mutation carriers are of the basal-like subtype [17]. Recent data suggest that 11% of unselected triple-negative cases occur in BRCA1 mutation carriers. In those patients under 40 years, this increases to 24% [18]. Strong similarities in gene expression have been seen in microarray analyses between BRCA1 and sporadic basal-like breast cancers [2]. This suggests functional deficiency of BRCA1 as a shared characteristic and indeed abnormalities have been noted in the expression of BRCA1 in sporadic breast cancers with a basal-like phenotype [19,20].

BRCA1 functional deficiency leads to a specific DNA repair defect [21] that sensitises cells to the DNA cross-links induced by cisplatin, carboplatin and mitomycin C [22,23]. The suggestion of a high prevalence of BRCA1 dysfunction in large but currently poorly defined groups within triple-negative breast cancer may provide a target that can be exploited using platinum-based drugs. The early preclinical data suggesting that functional deficiency in BRCA1 may lead to taxane resistance highlight the need to know more about the efficacy of taxanes within the triple-negative and basal-like subgroups.

Does triple-negative breast cancer respond differently to chemotherapy?

There have as yet been no clinical trials reported specifically within this subgroup. Some mature retrospective studies have suggested that the poor adverse early prognosis compared to other groups is not found in women treated with adjuvant chemotherapy [24]. While preclinical studies have shown a relationship between impaired BRCA1 function and platinum response [22], it has also been suggested that normal BRCA1 function may be required for response to spindle poisons (taxanes and vinorelbine) [25]. Some support for this has come from the poor response noted in a retrospective analysis of patients with BRCA1-positive breast cancer treated with neoadjuvant taxane-containing regimens [26]. So far there have only been poorly powered retrospective subgroup analyses addressing taxane sensitivity in triple-negative cancers. Harris et al. examined the relationship between ER, PR and HER2 expression and response to paclitaxel in advanced breast cancer [12], and concluded that HER2 status and hormone receptor status were all unable to predict response to treatment; however, they were found to have prognostic value with the triple-negative phenotype associated with reduced OS. Rouzier et al. assessed the response of basal-like breast cancer to pre-operative doxorubicin and cyclophosphamide (AC) followed by paclitaxel chemotherapy using needle biopsy and cDNA array analysis [27]. Those with basal-like and HER2-positive breast cancer had the highest rates of pathological complete response (CR) (45% in both groups). Luminal and normal-like breast cancer were associated with much lower rates of CR (6% and 0%, respectively). As all patients received both an anthracycline and a taxane before surgery, this study does not provide information on the response of subtypes to specific drugs.

To determine whether patients in the triple-negative and basal-like subgroups gain from addition of a taxane in the adjuvant setting, planned subgroup analyses must be conducted in very large trials such as the UK Taxotere as Adjuvant Chemotherapy (TACT) trial. Such analyses are currently under way.

Can we find better targets in triple-negative breast cancer?

Therapeutic advances have been hampered by the lack of understanding of the underlying biology of triple-negative breast cancer. Although there is still much to learn, a number of potential targets are emerging and early phase clinical trials of targeted therapies are under way (Table 1).

BRCA1 dysfunction: platinum salts and poly(ADP-ribose) polymerase inhibitors

BRCA1 dysfunction may be a useful target in a significant proportion of triple-negative breast cancers [28,29]. The Cancer Research UK and Breakthrough Breast Cancer's Triple Negative Trial (TNT) is testing this hypothesis within the UK National Cancer Research Network (NCRN) portfolio by examining whether carboplatin is more active than docetaxel in women with triple-negative and basal-like breast cancers, at first metastatic relapse. Parallel biological studies will help to better define the relationship between platinum-sensitive and BRCA1-deficient subgroups within triple-negative breast cancer. A non-randomised study using cisplatin has also begun in the USA (Table 1).

Other therapeutic methods have been developed for targeting the DNA repair defect in BRCA1-deficient cells such as focusing on the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) [30]. PARP inhibitors are currently in Phase II clinical trials in BRCA1 and BRCA2 carriers with advanced breast or ovarian cancer [31,32].

EGFR

Expression of EGFR is a common finding in basal-like breast cancer cell lines with as many as 66% expressing the receptor [3,9,10,33-35]. The therapeutic significance of expression and detection by IHC is unknown. Although activating mutations as found in lung cancer are remarkably rare [35,36], amplification may occur and is particularly common in subtypes such as metaplastic breast cancer [35]. The activity of anti-EGFR therapy either alone or in combination with chemotherapy, is currently being investigated in metastatic, triple-negative breast cancer (Table 2).

Dasatinib

Dasatinib is a kinase inhibitor targeting Bcr-Abl and Src family kinases. Molecular markers predictive of response to dasatinib have been identified in a panel of 23 breast cancer cell lines [37]. Transcriptional profiles with high correlation with in vitro sensitivity to dasatinib have been identified and validated in cell line models. The response signature was most prevalent in triple-negative cell lines and has led to a Phase II clinical trial which is now under way in advanced, anthracycline- and taxane-treated, triple-negative breast cancer (Table 2).

Bevacizumab

Bevacizumab targets the vascular endothelial growth factor (VEGF) angiogenesis pathway. Basal-like breast cancers have been shown to have frequent neovascularisation [38]. No trials have yet prospectively examined the activity of bevacizumab within the triple-negative or basal-like subgroups. The Eastern Cooperative Oncology Group (ECOG) 2100 study examined the addition of bevacizumab to weekly paclitaxel in women with first metastatic relapse, the majority of whom were HER2 negative. The trial showed a doubling of objective response rate (28% versus 14%, P<0.0001) and a 5-month improvement in progression-free survival in the bevacizumab arm. Although 60% of cases were ER positive, this trial has raised interest in investigating the role of bevacizumab in triple-negative breast cancer. The benefits of the addition of bevacizumab to adjuvant chemotherapy in triple-negative breast cancer are shortly to be assessed in the Bevacizumab Adjuvant Therapy in Triple Negative Breast Cancer (BEATRICE) trial.

Summary

Significant progress has been made in the understanding of the biology of ER-positive and HER2-positive breast cancers and this has led to the growth in targeted therapeutics for this group. However, few such developments have yet been made for ER/PR/HER2 triple-negative breast cancer despite its often early and aggressive pattern of relapse. There is currently great interest in unravelling the heterogeneity and underlying biological drivers of this group of breast cancers in order to develop therapies. Patient and clinician support for clinical trials with tissue-based biological studies will be vital for success.

References

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Kazumi Chia (1) and Andrew Tutt (2)

(1) National Institute for Health Research Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, UK and (2) Breakthrough Breast Cancer Unit at King's College London and Guy's and St Thomas' NHS Foundation Trust, London, UK

Correspondence to: Andrew Tutt, Guy's Hospital Breast Unit, 3rd Floor Thomas Guy House, Guy's Hospital, London SE1 9RT, UK (email: [e-mail])

Table 1: Clinical trials testing the efficacy of cisplatin/carboplatin
in the management of triple-negative breast cancer.

Trial                   Intervention      Primary
                                          endpoint

A Phase II              Cisplatin         Overall response
non-randomised                            rate of
study of cisplatin as                     triple-negative
first-line therapy for                    tumours to
triple-negative                           cisplatin as
metastatic breast                         first-line therapy
cancer
NCT00483223

Phase III, randomised   Carboplatin       Efficacy of
with crossover          versus            carboplatin
Negative Trial (TNT)    docetaxel         compared to
ISRCTN97330959                            docetaxel

Trial                    Number of           n       Start
                         arms

A Phase II               1 (single group    39   June 2007
non-randomised           assignment
study of cisplatin as    and historical
first-line therapy for   control)
triple-negative
metastatic breast
cancer
NCT00483223

Phase III, randomised    2 (parallel       350   September
with crossover           assignment,      -450        2007
Negative Trial (TNT)     uncontrolled)
ISRCTN97330959

Trial                    Disease           Secondary
                         setting           endpoint

A Phase II               Metastatic        PFS, clinical
non-randomised           breast cancer     benefit rate and
study of cisplatin as                      OS;
first-line therapy for                     Drug safety and
triple-negative                            toxicity
metastatic breast                          assessments
cancer
NCT00483223

Phase III, randomised    Metastatic or     Response
with crossover           locally           according to
Negative Trial (TNT)     advanced          RECIST criteria;
ISRCTN97330959           recurrent         PFS and OS
                         breast cancer

n, total number of patients to be enrolled; PFS, progression-free
survival; OS, overall survival; RECIST, Response Evaluation Criteria
in Solid Tumours.

Table 2: Targeted therapy trials for patients with advanced triple-
negative breast cancer.

Trial                                 Intervention

Cetuximab and cisplatin in the        Cetuximab and cisplatin or
Treatment of Triple-Negative          cisplatin alone
Metastatic Breast Cancer
(BALI-1)
NCT00463788

Phase II trial of cetuximab alone     Cetuximab alone or in
and in combination with               combination with carboplatin
carboplatin (LCCC 0403)
NCT00492375

Phase II trial evaluating the         EndoTAG-1 + paclitaxel or
efficacy and safety of                EndoTAG-1 monotherapy in
endoTAG-1 in                          comparison to paclitaxel
triple-receptor-negative breast       (control group)
cancer patients
NCT00448305

A study of dasatinib in patients      Dasatinib as second-line
with advanced triple-negative         therapy
breast cancer
NCT00371254 BMS-354825

Phase II study with Abraxane,         Abraxane, bevacizumab and
bevacizumab and carboplatin in        carboplatin
triple-negative metastatic breast
cancer
NCT00479674

A Phase II trial of bevacizumab       Bevacizumab and Abraxane
and ABI-007 (Abraxane) as
second-line therapy in HER-2
negative, HR-negative metastatic
breast cancer
NCT00472693

Study of SU011248 (sunitinib)         SU011248 versus standard of
versus chemotherapy for               care chemotherapy for
patients with previously treated      metastatic breast cancer
triple-receptor-negative breast
cancer
NCT00246571

Trial                                 Phase and study design

Cetuximab and cisplatin in the        Phase II
Treatment of Triple-Negative          Randomised, treatment and
Metastatic Breast Cancer              efficacy study
(BALI-1)
NCT00463788

Phase II trial of cetuximab alone     Phase II
and in combination with               Randomised
carboplatin (LCCC 0403)
NCT00492375

Phase II trial evaluating the         Phase II
efficacy and safety of                Randomised
endoTAG-1 in
triple-receptor-negative breast
cancer patients
NCT00448305

A study of dasatinib in patients      Phase II
with advanced triple-negative         Non-randomised, treatment
breast cancer                         and efficacy study
NCT00371254 BMS-354825

Phase II study with Abraxane,         Phase II
bevacizumab and carboplatin in        Non-randomised
triple-negative metastatic breast
cancer
NCT00479674

A Phase II trial of bevacizumab       Phase II
and ABI-007 (Abraxane) as             Non-randomised
second-line therapy in HER-2
negative, HR-negative metastatic
breast cancer
NCT00472693

Study of SU011248 (sunitinib)         Phase II
versus chemotherapy for               Randomised, open label,
patients with previously treated      active control, parallel
triple-receptor-negative breast       assignment, safety/efficacy
cancer                                study
NCT00246571

Trial                                 Primary endpoint

Cetuximab and cisplatin in the        Objective overall
Treatment of Triple-Negative          response
Metastatic Breast Cancer
(BALI-1)
NCT00463788

Phase II trial of cetuximab alone     Objective overall
and in combination with               response
carboplatin (LCCC 0403)
NCT00492375

Phase II trial evaluating the         4-month PFS
efficacy and safety of
endoTAG-1 in
triple-receptor-negative breast
cancer patients
NCT00448305

A study of dasatinib in patients      Objective overall
with advanced triple-negative         response
breast cancer
NCT00371254 BMS-354825

Phase II study with Abraxane,         Safety and
bevacizumab and carboplatin in        tolerability
triple-negative metastatic breast
cancer
NCT00479674

A Phase II trial of bevacizumab       Effect of addition
and ABI-007 (Abraxane) as             of bevacizumab to
second-line therapy in HER-2          Abraxane as
negative, HR-negative metastatic      second-line
breast cancer                         therapy
NCT00472693

Study of SU011248 (sunitinib)         PFS
versus chemotherapy for
patients with previously treated
triple-receptor-negative breast
cancer
NCT00246571

Trial                                 Number of arms

Cetuximab and cisplatin in the        2 (parallel
Treatment of Triple-Negative          assignment, active
Metastatic Breast Cancer              control)
(BALI-1)
NCT00463788

Phase II trial of cetuximab alone     2 (parallel
and in combination with               assignment, active
carboplatin (LCCC 0403)               control)
NCT00492375

Phase II trial evaluating the         3
efficacy and safety of
endoTAG-1 in
triple-receptor-negative breast
cancer patients
NCT00448305

A study of dasatinib in patients      1 (single group
with advanced triple-negative         assignment,
breast cancer                         uncontrolled)
NCT00371254 BMS-354825

Phase II study with Abraxane,         1 (single group
bevacizumab and carboplatin in        assignment and
triple-negative metastatic breast     historical control)
cancer
NCT00479674

A Phase II trial of bevacizumab       2 (single group
and ABI-007 (Abraxane) as             assignment and
second-line therapy in HER-2          active control)
negative, HR-negative metastatic
breast cancer
NCT00472693

Study of SU011248 (sunitinib)         2 (active control,
versus chemotherapy for               parallel assignment)
patients with previously treated
triple-receptor-negative breast
cancer
NCT00246571

Trial                                 n Start

Cetuximab and cisplatin in the        180 June 2007
Treatment of Triple-Negative
Metastatic Breast Cancer
(BALI-1)
NCT00463788

Phase II trial of cetuximab alone     100 NS
and in combination with
carboplatin (LCCC 0403)
NCT00492375

Phase II trial evaluating the         135 January
efficacy and safety of                2007
endoTAG-1 in
triple-receptor-negative breast
cancer patients
NCT00448305

A study of dasatinib in patients      45 December
with advanced triple-negative         2006
breast cancer
NCT00371254 BMS-354825

Phase II study with Abraxane,         70 May 2007
bevacizumab and carboplatin in
triple-negative metastatic breast
cancer
NCT00479674

A Phase II trial of bevacizumab       NS May 2007
and ABI-007 (Abraxane) as
second-line therapy in HER-2
negative, HR-negative metastatic
breast cancer
NCT00472693

Study of SU011248 (sunitinib)         200 November
versus chemotherapy for               2006
patients with previously treated
triple-receptor-negative breast
cancer
NCT00246571

Trial                                 Disease setting

Cetuximab and cisplatin in the        Metastatic breast
Treatment of Triple-Negative          cancer
Metastatic Breast Cancer
(BALI-1)
NCT00463788

Phase II trial of cetuximab alone     Metastatic breast
and in combination with               cancer
carboplatin (LCCC 0403)
NCT00492375

Phase II trial evaluating the         Metastatic or
efficacy and safety of                relapsed breast
endoTAG-1 in                          cancer
triple-receptor-negative breast
cancer patients
NCT00448305

A study of dasatinib in patients      Recurrent, locally
with advanced triple-negative         advanced or
breast cancer                         metastatic breast
NCT00371254 BMS-354825                cancer

Phase II study with Abraxane,         Metastatic breast
bevacizumab and carboplatin in        cancer
triple-negative metastatic breast
cancer
NCT00479674

A Phase II trial of bevacizumab       Metastatic breast
and ABI-007 (Abraxane) as             cancer
second-line therapy in HER-2
negative, HR-negative metastatic
breast cancer
NCT00472693

Study of SU011248 (sunitinib)         Metastatic breast
versus chemotherapy for               cancer
patients with previously treated
triple-receptor-negative breast
cancer
NCT00246571

Trial                                 Secondary endpoint

Cetuximab and cisplatin in the        PFS, OS and time to
Treatment of Triple-Negative          response
Metastatic Breast Cancer
(BALI-1)
NCT00463788

Phase II trial of cetuximab alone     PFS and OS;
and in combination with               Downstream effects of
carboplatin (LCCC 0403)               EGFR inhibitor
NCT00492375

Phase II trial evaluating the         Median PFS, tumour
efficacy and safety of                response, median OS (also,
endoTAG-1 in                          PFS, survival rate and
triple-receptor-negative breast       tumour response at 4
cancer patients                       months), pain assessment,
NCT00448305                           quality-of-life assessment

A study of dasatinib in patients      Disease control rate, PFS,
with advanced triple-negative         distribution of PFS and
breast cancer                         response duration
NCT00371254 BMS-354825

Phase II study with Abraxane,         PFS
bevacizumab and carboplatin in
triple-negative metastatic breast
cancer
NCT00479674

A Phase II trial of bevacizumab       NS
and ABI-007 (Abraxane) as
second-line therapy in HER-2
negative, HR-negative metastatic
breast cancer
NCT00472693

Study of SU011248 (sunitinib)         Objective response rate,
versus chemotherapy for               duration of response, OS,
patients with previously treated      1-year survival;
triple-receptor-negative breast       quality-of-life and
cancer                                symptoms assessment, PC R,
NCT00246571                           drug safety and toxicity

n, total number of patients to be enrolled; PFS, progression-free
survival, OS, overall survival, EGFR, epidermal growth factor receptor;
PCR, polymerase chain reaction; NS, not specified,' HR, hormone
receptor.