Cancer Treatment Reviews xxx (2014) xxx–xxx

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Cancer Treatment Reviews

journal homepage: www.elsevierheal th.com/ journals /c t rv

Anti-Tumour Treatment

Efficacy of biological agents in metastatic triple-negative breast cancer

http://dx.doi.org/10.1016/j.ctrv.2014.01.0030305-7372/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding author. Tel.: +39 02 6363 2223; fax: +39 02 6363 2216.E-mail addresses: annalisa.bramati@fbf.milano.it (A. Bramati), datamanager@

fbf.milano.it (S. Girelli), valter.torri@marionegri.it (V. Torri), gabriella.farina@fbf.milano.it (G. Farina), elena.galfrascoli@gmail.com (E. Galfrascoli), sheila.piva@fbf.milano.it (S. Piva), anna.moretti@fbf.milano.it (A. Moretti), chiara.dazzani@fbf.milano.it (M.C. Dazzani), paola.sburlati@fbf.milano.it (P. Sburlati), nicla.laverde@fbf.milano.it (N.M. La Verde).

1 Tel.: +39 02 6363 2223; fax: +39 02 6363 2216.2 Tel.: +39 02 39014528; fax: +39 02 39014522.

Please cite this article in press as: Bramati A et al. Efficacy of biological agents in metastatic triple-negative breast cancer. Cancer Treat Rev (2014),dx.doi.org/10.1016/j.ctrv.2014.01.003

Annalisa Bramati a,⇑, Serena Girelli a,1, Valter Torri b,2, Gabriella Farina a,1, Elena Galfrascoli a,1,Sheila Piva a,1, Anna Moretti a,1, Maria Chiara Dazzani a,1, Paola Sburlati a,1, Nicla Maria La Verde a,1

a Department of Oncology, Fatebenefratelli e Oftalmico, Corso di Porta Nuova, 23, 20121 Milan, Italyb IRCCS – Istituto di ricerche farmacologiche Mario Negri, Lab of Methodology of Biomedical research, Department of Oncology, via La Masa 19, 20156 Milan, Italy

a r t i c l e i n f o

Article history:Received 6 August 2013Received in revised form 21 January 2014Accepted 27 January 2014Available online xxxx

Keywords:Biological agents (BA)Metastatic triple-negativebreast cancer (mTNBC)Bevacizumab

a b s t r a c t

Metastatic triple-negative breast cancer (mTNBC) represents 15% of invasive breast cancers. Prognosis ispoor, and there is no specific target therapy but biological agents combined with chemotherapy may beeffective.

To assess the role of biological agents in metastatic triple-negative breast cancer we performed asystematic review of phase III randomized controlled trials published from January 2006 to February2013 and presentations at ESMO, ASCO, and SABCS congresses in 2010–2012. We consulted PubMedand ClinicalTrials.gov. Only studies comparing biological agents and chemotherapy versus chemotherapyalone were considered. Relevant statistical variables were log of the hazard ratio and relative variance forprogression-free survival (PFS) and overall survival (OS).

Of 353 PubMed publications and 229 studies registered on ClinicalTrials.gov, 10 trials were selectedand 5293 patients were analyzed: 1546 had mTNBC. Biological agents considered were bevacizumab,sunitinib, sorafenib, lapatinib, iniparib and cetuximab. In addition, a meta analysis of the four studiescontaining bevacizumab was performed and it showed a PFS improvement with a relative risk reductionof 35% (95% CI: 25–43%). No effect on OS was observed. No PFS and OS benefit was detected with theother agents.

No improvement of OS was detected in patients treated with biological agents plus chemotherapy,while a significant PFS improvement was observed only for bevacizumab and cetuximab. The overallimpact of these agents on patient survival was not as great as expected, probably because the molecularbasis of this illness needs to be better understood so that treatment can be more appropriately tailored.

� 2014 Elsevier Ltd. All rights reserved.

Introduction

‘‘Triple-negative’’ breast cancer (TNBC) has been identified forbiological characteristics and clinical outcome as a separate diseasein the last few years. It is characterized by the presence oftriple-negative immunohistochemistry for estrogen receptors(ER), progesterone receptors (PgR), and the HER-2 gene [1]. TNBCrepresents about 15% of all cases of breast cancer and occurs morefrequently in young and African American women; it is considered

to be a subtype of basal-like disease, which has great variability ofexpression [2–5]. Several studies have demonstrated that the prog-nosis in this setting is poor [6,7].

TNBC often occurs in patients carrying BRCA-1 and -2 mutations[8]. Although the majority of patients with immunohistologicallydefined TNBC do not have BRCA-1 and -2 mutations, it is possiblethat mutations in other DNA repair pathway genes could be in-volved in the development of cancer.

Cisplatin and its derivatives bind to and cause cross-linking ofDNA during replication, thus interfering with cell division. Withouteffective DNA repair mechanisms, these compounds cause celldeath by apoptosis. Neo-adjuvant studies have demonstrated theefficacy of cisplatin in vivo, although most studies of cisplatin ina metastatic setting have been retrospective [9,10]. Taxanes as wellas ixabepilone and anthracyclines, have also been shown to be ac-tive in this setting [11].

Molecular biology is a cornerstone in modern oncology, and cel-lular pathways are being explored to identify strategic checkpoints

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that can be targeted by new drugs. Among these pathways, theDNA repair system is now well defined. It is known that DNA repairmechanisms are based on gene redundancy; if one of the two cop-ies of the gene is damaged, the other copy will be activated to workinstead of the damaged one.

In many patients with breast cancer who have familial or spo-radic mutations of DNA repair genes (e.g., BRCA-1 and -2), thehomologous gene can be blocked by a specific agent, with subse-quent cell cycle arrest and cell death; the hypothesis behind thismechanism is known as ‘‘synthetic lethality.’’ Based on thishypothesis, the activity and efficacy of PARP inhibitors have beenstudied in patients with BRCA-1 and -2 mutations [12].

Angiogenesis is also a target of new biological drugs. Multipleangiogenic factors are commonly expressed by invasive breast can-cers; the 121-amino-acid isoform of vascular endothelial growthfactor (VEGF) predominates. VEGF stimulates endothelial prolifer-ation and migration, inhibits endothelial apoptosis, induces pro-teinases that remodel the extracellular matrix, increases vascularpermeability and vasodilatation, and inhibits antigen-presentingdendritic cells. Differences in function among the various VEGF iso-forms are not well defined, though VEGF-C has a predominant rolein lymphangiogenesis, whereas VEGF-A is more potent in inducingvasodilatation and pathologic angiogenesis [13].

Bevacizumab is a humanized monoclonal antibody directedagainst all isoforms of VEGF-A that leads to normalization of theblood supply to cancerous cells.

In addition, neoplastic cells have multiple growth patterns thatare regulated by the progressive activation of kinase enzymes. If ablockade in one of these pathways affects the cell, it can be over-come by a kinase associated with another pattern. In this setting,multikinase inhibitors, such as sunitinib and sorafenib, inhibitendothelial growth factors, PDGFR alfa and beta and protein ki-nases such as c-raf, b-raf, c-KIT, and flt-3 [14–16]. The discoverythat these pathways are activated in breast cancer led to clinicalstudies with sorafenib and sunitinib.

The efficacy of sorafenib has been demonstrated in advanced re-nal cell and hepatocellular carcinomas. Sorafenib demonstratedlimited activity as single-agent in metastatic breast cancer; so itwas postulated that greater activity might be achieved by combin-ing it with chemotherapy [17].

Sunitinib is an oral inhibitor of tyrosine kinase receptors impli-cated in breast cancer growth and metastasis, including vascularendothelial growth factor receptors, PDGFR, stem cell factor recep-tors, and colony-stimulating factor-1 receptors [18]. In preclinicalstudies involving the human breast cancer MX-1 xenograft model,sunitinib in combination with docetaxel, doxorubicin, or fluoroura-cil enhanced the antitumor activity of the chemotherapeuticagents, and the effect was accompanied by increased survival [19].

Epidermal growth factor receptor (EGFR) has been shown to behighly expressed in TNBC cell lines [20], which are inhibited by theanti-EGFR monoclonal antibody cetuximab.

At present, there are several ongoing studies to evaluate theefficacy of molecular targeting agents in patients with TNBC. Theaim of the present study was to perform a systematic review andmeta-analysis of the studies available to date in the literature, inorder to improve treatment strategies in this subgroup of patients.

Materials and methods

Literature search strategy

For this systematic review, we searched for published random-ized controlled clinical trials (RCTs) in the PubMed database fromJanuary 2006 to February 2013 that met the following inclusioncriteria: (1) Phase II and III randomized clinical trials, fully

Please cite this article in press as: Bramati A et al. Efficacy of biological agents idx.doi.org/10.1016/j.ctrv.2014.01.003

published in scientific journals. (2) Designed to compare chemo-therapy combined with a biological agent (BA) vs chemotherapyalone for the treatment of patients with metastatic breast canceras first or subsequent lines of therapy. (3) Inclusion of a populationof patients with TNBC or with the chance of extrapolating data tothe subgroup of patients with TNBC.

The following terms were used in the search: triple negativeAND breast cancer AND metastatic breast cancer ANDchemotherapy.

We also considered ongoing clinical trials registered in the Clin-icalTrials.gov database, as follows: (1) Phase II study AND breastcancer AND triple negative AND interventional study. (2) PhaseIII study AND breast cancer AND (bevacizumab OR sorafenib ORsunitinib OR erlotinib OR gefitinib OR iniparib OR olaparib ORcetuximab OR HDACI OR everolimus OR temsirolimus) AND inter-ventional study.

Selection criteria

The efficacy of chemotherapy combined with a BA was consid-ered. Outcome measures of interest included (1) progression-freesurvival (PFS), defined as the time from randomization until dis-ease progression or death without disease progression or the dateof the last follow-up for patients who were still alive without dis-ease progression and (2) overall survival (OS), defined as the timefrom randomization until death from any cause or the date of thelast follow-up for patients who were still alive.

For each study selected for the meta-analysis, we looked forpublished articles or abstracts. For unpublished articles, we lookedfor oral presentations at 2010–2012 conferences such as the Amer-ican Society of Clinical Oncology (ASCO), the San Antonio BreastCancer Symposium (SABCS), and the European Society for MedicalOncology (ESMO).

The RCTs selected for the meta-analysis had to fulfill both of thefollowing criteria: (1) Inclusion of patients with histologically con-firmed breast cancer with distant metastasis. (2) Reported resultsfor PFS and OS, both for the general population and for the tri-ple-negative subgroup, which was randomized to receive chemo-therapy alone or combined with the new drug.

Data extraction

Two oncologists from the Oncology Department of Fatebenefra-telli and Oftalmico Hospital independently reviewed the literature,and the data were discussed with a supervising statistician fromthe Oncology Department of Mario Negri Institute in Milan. Wecreated a database summarizing the number of patients in eacharm of the studies and the number of patients with TNBC. With re-gard to efficacy endpoints, we reported the number of events foreach arm with the respective hazard ratio value (HR), confidenceinterval (CI), and p value, with median PFS and OS.

Statistical analysis

For each trial, the HR and 95% CI for OS and PFS and the survivalratio of the group that received CT + BA vs the group without BAwere retrieved. Natural log transformation of HR was used, andthe standard error was calculated from the 95% CI if the HR wasnot provided in the original publication; natural log HR and itsstandard error were estimated by the indirect method, as de-scribed by Parmar et al. [21]. The heterogeneity among all trialsand among predefined treatment subsets was assessed with a c2test. If there was no heterogeneity among the studies, as confirmedby c2 test, these were selected for analyses. If the results of trialswere heterogeneous, the effects of possible explaining factors wereexplored. A fixed-effect model was used to estimate the treatment

n metastatic triple-negative breast cancer. Cancer Treat Rev (2014), http://

A. Bramati et al. / Cancer Treatment Reviews xxx (2014) xxx–xxx 3

effect across studies The I2 statistical test was used to measure thegrade of heterogeneity among the study results. Forest plots wereused for summarizing results. Analyses were conducted with Rev-man 5 software and the SAS statistical package.

Evaluation of the methodological quality of studies included in themeta-analysis

Two authors independently evaluated the quality of the pub-lished studies, and a third reviewer weighed in on any controver-sies until a consensus was reached. Data were extrapolated withan evaluation form that was designed specifically for the subjectof this review. The method used was taken from the CochraneHandbook [22], and it is called the ‘‘risk of bias table.’’ This methodenabled us to determine whether the different outcomes of thestudies (analyzed for each of the studies taken into consideration)had a risk of bias that could influence the results. This risk wasclassified into three groups: HIGH, if the risk of introducing a biaswas high; LOW, if the risk was low but not nonexistent; and UN-CLEAR, if there was insufficient information to classify the risk.Maybe an individual patient data meta-analysis could have givenus greater information about patient and tumour characteristics.In fact, in some publications TNBC cancers were not described inthis way, but we had to extrapolate them from the description ofbiological results. Anyway, the good quality of the trials we consid-ered makes this meta-analysis reliable.

Results

Selection of the studies

Our literature search produced a total of 354 studies included inthe PubMed database and 229 ongoing studies registered in theClinicalTrials.gov database. Among the studies published, we ex-cluded 342 studies because of lack of a chemotherapy or biologicalarm, absence of randomization, or absence of a metastatic TNBC(mTNBC) population. We analyzed the remaining 12 studies, whichare summarized in Tables 1 and 2. One study was excluded, be-cause it involved patients in a neo-adjuvant setting [23]. The stud-ies of Gray et al. [24] and Di Leo et al. [25] were considered only forassessment of quality, since Gray et al. study is an independent re-view of the study of Miller et al. [26], while the Di Leo et al. study isan independent analysis of the study of Finn et al. [27]. The studiesof Miles et al. [28], Robert et al. [29], Brufsky et al. [30], O’Shaugh-nessy et al. [31], Bergh et al. [32], and the two studies of Baselgaet al. [33,34] were considered for the systematic review (Fig. 1 con-tains a schematic of the search strategy that we used).

We found 229 studies in the ClinicalTrials.gov database; 98were phase III studies, while the remaining 131 were phase II stud-ies. We excluded all of the phase III studies, because they were

Table 1Description of the studies.

Author (type) Year Journal/congress Biological agent

Robert FP 2011 JCO (29) BevacizumabMiles FP 2010 JCO (28) BevacizumabGray/Miller FP 2009 JCO (24–26) BevacizumabBrufsky FP 2011 JCO (30) BevacizumabFinn/Di Leo FP 2009 JCO (27–25) LapatinibO’Shaughnessy FP 2011 NEJM (31) IniparibBaselga FP 2013 JCO (34) CetuximabBaselga FP 2012 JCO (33) SorafenibCurigliano AB/FP 2010 2013 SABCS (35) Breast (36) SunitinibBergh J. FP 2012 JCO (32) Sunitinib

FP full paper, AB abstract included in the metanalysis.

Please cite this article in press as: Bramati A et al. Efficacy of biological agents idx.doi.org/10.1016/j.ctrv.2014.01.003

either not randomized or were ongoing trials or because therewas an absence of data about the mTNBC population. For the samereasons, we also excluded 130 of the phase II studies.

We were able to find all of the necessary data for eligible studiesfrom oral communications or posters presented at the previouslylisted conferences (Figs. 2 and 3 describe the search strategy thatwe used).

The characteristics of the studies eligible for the meta-analysisare reported in detail in Tables 1 and 2. At the end of the evalua-tion, nine publications and one abstract/oral presentation were eli-gible. This enabled us to analyze a total of 5293 patients, of whom1546 had TNBC (Table 1). We included one study with an experi-mental arm that contained sunitinib not combined with chemo-therapy [35,36].

The 10 studies selected were grouped according to the BA usedas follows: bevacizumab (four studies), EGFR 1 and 2 inhibitors(one study with lapatinib), EGFR 1 inhibitors (one study withcetuximab), multikinase inhibitors (one study with sorafenib andtwo with sunitinib), and PARP inhibitors (one study with iniparib).Because the most homogeneous published studies were bev-acizumab based (four out of nine published studies), we decidedto perform the meta-analysis on the bevacizumab studies; thesewere also the only studies with peer-reviewed data available. Forall of the other studies, we found that it would be more appropriateto do a systematic review (Table 2 describes the efficacy data forthe studies selected for the systematic review).

Analysis of the quality of data

Four studies considering bevacizumab were selected for thismeta-analysis. The study of Robert et al. [29] compared standardchemotherapy (capecitabine or taxanes/anthracyclines) with orwithout bevacizumab for first line treatment of HER-2 negative lo-cally recurrent or metastatic breast cancer. Instead Brufsky et al.[30] tested bevacizumab in the second line setting. In these twostudies the allocation between the experimental arm and controlarm had a low risk of bias (due to the description of allocation con-cealment and the random sequence generation); however, theinvestigators chose which chemotherapy to treat the patient withbefore randomization, which could have led to a loss of balancein treatment assignment and a relevant shift in the direction andmagnitude of the effect.

The Miller et al. [26] study compared paclitaxel with or withoutbevacizumab; despite this study being published before the Grayet al. [24] one, it was taken into consideration since it presentedthe final analysis of the study.

Miles et al. [28] compared docetaxel with or without bev-acizumab at two different doses (7.5 and 15 mg/kg respectively).The design of this study might be biased, as the crossover allowedfrom the chemo-alone arm to the combination one could haveinfluenced the data on OS.We considered the studies of Finnet al. [27] and Di Leo et al. [25] in order to evaluate the qualityof the published data. The study of Di Leo evaluated paclitaxel pluslapatinib or placebo as first line treatment in metastatic breast can-cer. Data about TNBC population was extrapolated from the studyof Finn, a blinded, retrospective biomarker evaluation of molecularsubgroups. In this study the blinding of outcome assessment has ahigh risk of bias.

In the O’Shaughnessy et al. [31] study, in which iniparib pluschemotherapy was compared to chemotherapy alone, the modalityof evaluation of outcome could have caused bias.

Sunitinib was investigated in two studies. Curigliano et al.[35,36] compared sunitinib to best supportive care (BSC), whileBergh et al. [32] evaluated the efficacy of docetaxel with or withoutsunitinib.

n metastatic triple-negative breast cancer. Cancer Treat Rev (2014), http://

Table 2Efficacy data on the studies selected for the systematic review (bev7,5/10/15 = bevacizumab respectively 7,5/10/15 mg/kg).

Authors Treatment (arm1 vs arm2 vs control arm) N� PTStotal

N� PTSTNBC total

N� PTS TNBCExperimental Arm

N� PTS TNBCcontrol arm

PFS HR Exp. Arm Median PFS exp.Arm (months)

OS HR Exp. Arm Median OS Exp.Arm (months)

Miles bev7,5 + docetaxelvs bev15 + docetaxel⁄vs docetaxel

736 167 55 (60⁄) 52 HR 0.83 (0.68⁄)

Gray (ECOG) bev10 + paclitaxelvs paclitaxel

722 232 HR 0,45 (95% CI 0.33–0.61)

O’Shaughnessy iniparib + carboplatin + gemcitabineVS carboplatin + gemcitabine

123 123 61 62 HR 0.59 (95% CI 0.39–0.9) p = 0.01

5.9 vs 3.6 HR 0.57 (95% CI 0.36–0.9) p = 0.01

12.3 vs 7.7

Finn lapatinib + paclitaxelvs paclitaxel

579 131 71 60 HR 1.25 (95% CI 0.85–1.83)p = 0.22

4.6 vs 4.8

Robert NJ(RIBBON-1)

bevacizumab + capecitabinevs capecitabine

615 137 87 50 HR 0,72 (95%CI 0,49–1,06)

6,1 vs 4,2

Robert NJ(RIBBON-1)

bevacizumab + taxanes/anthracyclinesVS taxanes/anthracyclines

622 142 96 46 HR 0.78 (CI 0.53–1.15)

6.5 vs 6.2

Baselga sorafenib + capecitabinevs capecitabine

229 53 20 33 HR 0.6 (CI 0.31–1.14) 4.3 vs 2.5 HR 0.98 (95% CI 0.5–1.89)

17.5 vs 16.1

Baselga (BALI1)

cisplatin + cetuximabvs cisplatin

173 173 115 58 HR 0.67 (CI 0.47–0,97)p = 0.03

3.7 vs 1.5 HR 0.82 (95% CI 0.56–1.2)p = 0.31

12.9 vs 9.4

Curigliano sunitinibvs standard-of-care therapy

217 217 112 103 HR 1.2 (CI 0.89–1.63)p = 0.88

2 vs 2.7 HR 1.16 (95% CI 0.86–1.56) p = 0.83

9.4 vs 10.5

Brufsky A(RIBBON 2)

bevacizumab + CTvs CT

684 159 HR 0.49 (CI 0.33–0.74)

6 vs 2.7

Bergh J. Sunitinib + docetaxelvs docetaxel

593 127 58 69 HR 0.96 (CI 0.65–1.43)

PTS, patients; TNBC, triple-negative breast cancer; OS, overall survival; PFS, progression-free survival; HR, hazard ratio; Exp. Arm, experimental arm; CI, confidence interval.(60⁄) is the number of patients enrolled in bev15 + docetaxel⁄ arm of the study of Miles.

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Fig. 1. Selection process for the published randomized controlled trials (RCTs)included in the meta-analysis.

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Fig. 2. Selection process for the phase II studies registered in ClinicalTrials.govincluded in the meta-analysis.

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Fig. 3. Selection process for the phase III published randomized controlled trials(RCTs) included in the meta-analysis.

A. Bramati et al. / Cancer Treatment Reviews xxx (2014) xxx–xxx 5

Baselga et al. [33] evaluated sorafenib plus capecitabine versuscapecitabine and placebo.

The efficacy of cetuximab was considered in the study of Base-lga et al. [34] that compared cisplatin with cetuximab to cisplatinalone.

Table 3 describes the qualitative characteristics of the availabledata for each study. All studies conducted the analysis in ITT pop-ulation, but only five studies provided an adequate description toensure the control of bias due to allocation concealment; the riskof evaluation bias was low in three studies while bias due to attri-tion was reported to be controlled in four studies.

Progression-free survival and overall survival in the bevacizumabstudies

Bevacizumab improved PFS in all four of the studies that weanalyzed, with an HR of 0.65 (95% CI 0.57–0.75), as shown inFig. 4, which contains the forest plot for PFS calculated for the pop-ulation of patients with TNBC. In Fig. 5, PFS values are reported forthe general population; the data were obtained from studies thatrecruited patients with breast cancer regardless of the histotype.The advantage of the addition of bevacizumab to chemotherapywas confirmed, even for the general population. The forest plot

Please cite this article in press as: Bramati A et al. Efficacy of biological agents idx.doi.org/10.1016/j.ctrv.2014.01.003

did not show an advantage with regard to OS with the additionof bevacizumab to chemotherapy in the general population (Fig. 6).

The lack of an OS benefit lead to bevacizumab ‘‘withdrawal’’from the market in the USA, following FDA decision. In fact, in com-parative effectiveness research, which analizes the efficacy of a cer-tain drug in a population, focusing also on cost effectiveness interms of side effects and financial burden, bevacizumab did notmeet enough criteria. This decision has been criticized from manymembers of the oncological scientific community,

n metastatic triple-negative breast cancer. Cancer Treat Rev (2014), http://

Table 3Evaluation of the quality of the studies taken into consideration.

PAPER RandomSequenceGeneration

AllocationConcealment

Blinding OfOutcomeAssessment

Incomplete DataOutcome

ITTPopulation

SelectiveReporting Bias

OtherBias

Robert HIGH HIGH HIGH UNCLEAR LOW UNCLEAR HIGHFinn/Di Leo UNCLEAR UNCLEAR HIGH LOW HIGH UNCLEAR LOWGray/Miller UNCLEAR UNCLEAR UNCLEAR UNCLEAR LOW UNCLEAR HIGHMiles UNCLEAR LOW UNCLEAR UNCLEAR LOW UNCLEAR HIGHO’Shaughnessy UNCLEAR LOW HIGH UNCLEAR LOW UNCLEAR HIGHBrufsky HIGH HIGH HIGH UNCLEAR LOW UNCLEAR HIGHBaselga (cetuximab) LOW LOW HIGH LOW LOW LOW LOWCurigliano UNCLEAR LOW LOW LOW LOW LOW LOWBaselga (sorafenib) LOW LOW LOW LOW LOW LOW LOWBergh J. LOW UNCLEAR LOW LOW LOW LOW LOW

ITT intention to treat population.

Miles_15 extracted from Miles et al. 2010 arm with bevacizumab 15 mg/kg.

Miles_75 extracted from Miles et al. 2010 arm with bevacizumab 7.5 mg/kg.

Robert_c 2011 extracted from Robert et al. 2011 arm with capecitabine ±bevacizumab.

Robert_t 2011 extracted from Robert et al. 2011 arm with taxanes/anthracyclines±bevacizumab.

Fig. 4. Progression-free survival for patients with triple-negative breast cancer.

6 A. Bramati et al. / Cancer Treatment Reviews xxx (2014) xxx–xxx

Efficacy of other biological agents

The study by Baselga et al. [34] detected a PFS benefit for cetux-imab, with an HR of 0.67 (95% CI 0.47–0.97). Likewise, for PFS, thestudy by O’Shaughnessy et al. [31] reported an HR of 0.59 (95% CI0.39–0.9) in favor of iniparib.

All the other studies showed no benefit in terms of PFS. The useof lapatinib not only did not improve PFS, but it may have beendetrimental; this may be explained by its mechanism of action,as it requires a specific target (HER2) in order to be effective[25–27]. The study by Curigliano et al., presented at SABCS 2010[35] and recently published [36], with sunitinib in the experimen-tal arm was also negative with regard to PFS; the HR was 1.2 (95%CI 0.89–1.63). Even the study by Bergh et al. [32] showed no ben-efit with sunitinib; the HR was 0.96 (95% CI 0.65–1.43). Baselgaet al. [33] reported PFS data for sorafenib in the mTNBC population.They found that PFS was not increased, with an HR of 0.6 (95% CI0.31–1.14).

Please cite this article in press as: Bramati A et al. Efficacy of biological agents idx.doi.org/10.1016/j.ctrv.2014.01.003

In the studies that considered OS as an endpoint, no study, withthe exception of the O’Shaughnessy et al. [31] study, provided evi-dence of increased survival with the addition of a BA to chemother-apy (HR 0.57, 95% CI 0.36–0.90).

Discussion

mTNBC continues to represent a therapeutic challenge, as it hasa poor prognosis and, to date, there is no standard treatment avail-able. A general consensus has been reached on the importance ofchemotherapy; in particular, platinum derivatives seem to be themost effective choice, with a known biological rationale.

Combinations of chemotherapy and molecular-targeted BAscould potentially be effective therapies for mTNBC, which is whywe reviewed studies that employed the BAs bevacizumab, suniti-nib, sorafenib, cetuximab, iniparib, and lapatinib. In our opinion,a systematic review was necessary to summarize the current state

n metastatic triple-negative breast cancer. Cancer Treat Rev (2014), http://

Miles_15 extracted from Miles et al. 2010 arm with bevacizumab 15 mg/kg.

Miles_75 extracted from Miles et al. 2010 arm with bevacizumab 7.5 mg/kg.

Robert_c 2011 extracted from Robert et al. 2011 arm with capecitabine ±bevacizumab.

Robert_t 2011 extracted from Robert et al. 2011 arm with taxanes/anthracyclines±bevacizumab.

Fig. 5. Progression-free survival for the general population.

Miles_15 extracted from Miles et al. 2010 arm with bevacizumab 15 mg/kg.

Miles_75 extracted from Miles et al. 2010 arm with bevacizumab 7.5 mg/kg.

Robert_c 2011 extracted from Robert et al. 2011 arm with capecitabine ±bevacizumab.

Robert_t 2011 extracted from Robert et al. 2011 arm with taxanes/anthracyclines±bevacizumab.

Fig. 6. Overall survival for the general population.

A. Bramati et al. / Cancer Treatment Reviews xxx (2014) xxx–xxx 7

of the art. PFS and OS were the endpoints considered for efficacy.The first limit we had to deal with was that only studies designed

Please cite this article in press as: Bramati A et al. Efficacy of biological agents idx.doi.org/10.1016/j.ctrv.2014.01.003

for mTNBC report data on OS, while other studies report OS for thegeneral population without specifying the mTNBC one.

n metastatic triple-negative breast cancer. Cancer Treat Rev (2014), http://

8 A. Bramati et al. / Cancer Treatment Reviews xxx (2014) xxx–xxx

We performed a meta-analysis of studies that included bev-acizumab, because this was the only BA for which four studieshad complete data. Treatment with bevacizumab had a significantimpact on PFS for patients with TNBC (HR 0.65, 95% CI 0.57–0.74),but there was no benefit for OS, as was reported in the updatedstudies. In our opinion, improved PFS is an important goal for thissubgroup of patients in whom the disease is quite chemorespon-sive. For this reason, it is necessary to have drugs that can controldisease progression and delay the onset of symptoms. Recently, theuse of bevacizumab to treat metastatic breast cancer has been thesubject of a debate that has involved the entire oncology commu-nity. A meta-analysis has been published on the studies comparingbevacizumab + chemotherapy versus chemotherapy in Her2 nega-tive population and a benefit on PFS and response rate was ob-served, without benefit on OS [37]. Due to the lack of an OSbenefit, the FDA has withdrawn the licence for using bevacizumabin this setting. The reason for this decision was that drugs ap-proved as first-line treatment up to now have improved OS, notPFS.

We are currently learning that for clinical trials that show an in-crease in PFS, the lack of a statistically significant increase in OSdoes not necessarily indicate a lack of improvement in survival,especially for diseases with a long median survival post-progres-sion (SPP). OS is a reasonable primary endpoint when the medianSPP is short, as occurs in lung cancer, but it is too high a bar whenthe median SPP is long; for example, longer than 12 mo [38], e.g. inmetastatic breast cancer. When presented with this argument, theFDA countered that, if it was possible, the effect of SPP would haveto influence both the experimental and control groups. Discussionsregarding the use of PFS as a relevant clinical endpoint for the ap-proval of new drugs is ongoing, but if its use becomes the standardfor fast-track or definite approval of drugs in this setting, it will be-come more and more difficult, if not impossible, to obtain data onOS [39,40].

The studies analyzed in our review all contain data on mTNBCpatients, both as studies that focused only on this population andas subgroups of larger studies designed for HER2-negative patients.All of the drugs tested have a biological rationale, except for lapat-inib, which, in our opinion, requires its target HER2 in order to beeffective. In fact, the data obtained for the triple-negative popula-tion was positive in terms of PFS for all agents, except for lapatinib,which may even be detrimental, sunitinib and sorafenib. Unfortu-nately, iniparib activity, which in a phase II study seemed verypromising, was not confirmed in the phase III study [31,41].

TNBC patients do not have the option of using antiHER2 drugsor hormonal agents, so for this population, other BAs are urgentlyrequired. The only available therapy for this kind of disease is cyto-toxic chemotherapy and bevacizumab in combination with chemo-therapy in European countries, but the prognosis remains poor,especially for patients with metastases. In our opinion, BAs mayhave a role in the treatment of mTNBC, but their use seems to de-pend more on the lack of valid therapeutic options than on a phar-macological rationale. We must keep in mind that the term TNBCdoes not define a specific disease entity; instead, it describes onlywhat the disease lacks. We require a more in-depth knowledge ofthe molecular basis of TNBC.

First of all it is necessary to design clinical trials that allow us tobetter identify the different TNBC molecular subtypes throughgene expression profiling.

Lehmann et al. [42] identified six TNBC subtypes displaying un-ique gene expression profiles, including two basal-like, an immu-nomodulatory, a mesenchymal stem-like and a luminal androgenreceptor subtype. Every one of these patterns has a particular bio-marker to be targeted by new drugs. The more specific a drug is fora well defined target, the greater its activity; this is the story of antiHer-2 drugs and hormonal treatment.

Please cite this article in press as: Bramati A et al. Efficacy of biological agents idx.doi.org/10.1016/j.ctrv.2014.01.003

Only then we will be able to identify targets for effectivetherapies.

Conflict of interest statement

All authors have no financial or personal conflicts of interest todeclare.

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