basal-like breast cancer

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Basal-Like Breast Cancer: A Critical Review Emad A. Rakha, Jorge S. Reis-Filho, and Ian O. Ellis

From the Department of Histopathol-ogy, Nottingham City Hospital NationalHealth Service (NHS) Trust; NottinghamUniversity, Nottingham; and the Break-through Breast Cancer ResearchCentre, Institute of Cancer Research,London, United Kingdom.

Submitted June 20, 2007; acceptedNovember 12, 2007.

Terms in blue are dened in the glos-sary, found at the end of this articleand online at www.jco.org.

Authors disclosures of potential con-icts of interest and author contribu-tions are found at the end of thisarticle.

Corresponding author: Ian O. Ellis,FRCPath, Molecular Medical Sciences,University of Nottingham, Departmentof Histopathology, Nottingham CityHospital NHS Trust, Hucknall Road,Nottingham, NG5 1PB, UK; e-mail:[email protected].

2008 by American Society of ClinicalOncology

0732-183X/08/2615-2568/$20.00

DOI: 10.1200/JCO.2007.13.1748

A B S T R A C T

Recent gene expression proling of breast cancer has identied specic subtypes with clinical,biologic, and therapeutic implications. The basal-like group of tumors is characterized by anexpression signature similar to that of the basal/myoepithelial cells of the breast and is reported tohave transcriptomic characteristics similar to those of tumors arising in BRCA1 germline mutationcarriers. They are associated with aggressive behavior and poor prognosis, and typically do notexpress hormone receptors or HER-2 ( triple-negative phenotype). Therefore, patients withbasal - like cancers are unlikely to benet from currently available targeted systemic therapy.Although basal-like tumors are characterized by distinctive morphologic, genetic, immunopheno-typic, and clinical features, neither an accepted consensus on routine clinical identication anddenition of this aggressive subtype of breast cancer nor a way of systematically classifying thiscomplex group of tumors has been described. Different denitions are, therefore, likely to producevariable and contradictory results that may hamper consistent identication and development oftreatment strategies for these tumors. In this review, we discuss denition, heterogeneity,morphologic spectrum, relation to BRCA1 , and clinical signicance of this important class ofbreast cancer.

J Clin Oncol 26:2568-2581. 2008 by American Society of Clinical Oncology

INTRODUCTION

Current clinical management of breast cancer stillrelies on the traditional prognostic and predictive

factors including histologic,clinical, and somewell-dened biologic factors (ie, hormone receptors andhumanepidermal growthfactorreceptor 2 [HER-2]expression). Despite the overall association of thesevariables with prognosis and outcome, 1 they arelimited in their ability to capture the nuances of thecomplex cascade of events that drive the clinicalbehaviorof breastcancer.Tumorsof apparentlyho-mogenous morphologic characters still vary in re-sponse to therapy andhave distinctoutcomes. 2 Theintroduction of high-throughput technologies thatsurvey hundreds to thousands of genes and theirproducts in a single assay, coupled with powerful

analytic tools, opened new avenues for classifyingbreast cancer intobiologically and clinically distinctgroups based on gene expression patterns 3-9 andDNA copy number alterations. 8,10

MOLECULAR PROFILING OF BREAST CANCER

In their seminal study, Perou et al 3 usedan intrinsicgene list obtained with cDNA expression microar-rays to classify breast cancers according to similari-ties ingeneexpressioncharacteristics. These authors

examined a series of 65paired andnonpaired breastspecimens that included 36 invasive ductal carcino-masandtwolobularcarcinomas. Although thesam-ples analyzed in that study were remarkably

heterogeneousin termsofclinicopathologic featuresand systemic therapy, the prognostic associationsoriginally identied in that study have been corrob-orated by other groups. 11 On the basis of unsuper-vised methods , breastcancercould be classied intoat least ve distinct molecular subtypes. Multipleindependent studies have conrmed and expandedthe original results. 3-5,12 Subsequent supervised andunsupervised clustering analyses have shown thatbreastcancer can be divided into twobroadgroups:estrogen-receptor (ER)-positive and ER-negativegroups, which can be further subdivided into addi-tional distinct biologically and clinically signicantsubgroups. TheER-positive tumorsexpressER,ER-responsive genes, andother genes that encode char-acteristic proteins of luminal epithelial cells andtherefore, are termed luminal group. Althoughsubclassication of luminal tumors is still conten-tious, there seem to be at least two groups of ER-positive breast cancers, commonly dened asluminal A and B tumors depending on the level of expressionof thecharacteristicgenes andexpressionof other genes either pertaining to the proliferationcluster and/or HER-2. 5,13,14 The second broadgroup (ER-negative tumors) was subdivided into

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three groups:HER-2positive,basal-liketumorsandso-called normalbreastlike tumors. HER-2positive tumors express high levels of genes located in the HER2 amplicon on 17q21, including HER-2 andgrowth factor receptor-bound protein 7 (GRB7), a high level of nu-clear factor (NF)- B activation, and the transcription factor GATA4,andlack expression of ER andGATA3. 15,16 Basal-like tumors lack ER and HER-2 and express genes characteristic of basal epithelial cells.Thenormal breastlikegroup resembles normal breast tissue sampleswithrelativelyhighexpressionof manygenes characteristicof adiposecells and other nonepithelial cell types, and low level of expression of luminalepithelialcell genes.Importantly, these breast cancersubtypesare associated with markedly different clinical outcomes, rangingfrom the best-prognosis luminal A tumors to the worst-prognosisHER-2 and basal-like tumors. 3-5,11,17 In addition, thismolecular clas-sication has also captured the attention of oncologists and scientistsalike because the molecular subtypes are potentially predictive of patternsof responseto specictherapeuticagents.For instance, lumi-nalA tumors areexpected to be sensitive to endocrine therapy, HER-2overexpressingtumorscan be targeted with monoclonalantibodiesagainst HER-2 or HER-2 tyrosine kinase inhibitors, and basal-like

cancers may respond to specic therapeutic regimens(discussed laterherein) and inhibitors of the poly(ADP-ribose) polymerase (PARP)enzyme.

MOLECULAR IDENTIFICATION OF BASAL-LIKE TUMORS

Given the importance of basal and luminal concepts in the genomicsignatures identied in the recent molecular classication and theheated debate about the origin of breast cancer stem cells and therelationship between features of different breast cancer classes andtype andfeaturesof thecells they might be derived from, 3,18,19 we willrst review thefeatures of thenormalparenchymal cells of the mam-

mary gland. In normal human breast, ducts and lobules are lined by two cell layers, an inner/luminal cell population and a distinct outercell layer, juxtaposed to the basement membrane. 20,21 These cells canbe distinguished by their immunophenotype, and several markershave been usedtodenethem. It isgenerally acceptedthatthe luminalepithelialcellsarecharacterized byexpressionof lowmolecularweightso-called luminalcytokeratins (CKs) including CK7, CK8, CK18, andCK19, in addition to other markers such as MUC1 alpha-6 integrin,BCL2, ER, progesterone receptor (PgR), GATA3, and epithelial celladhesionmolecules.Theouter cell layer is formed of morphologically and immunophenotypically heterogeneous cells depending on theirlocation and on the hormonal status of the tissue. These cells exhibitfeatures of both epithelial and smooth muscle (SM) cells, and they therefore are called myoepithelial (ME)cells. ME cells usuallyexpresshigh molecular weight basal CKs such as CK5, CK14 and CK17, inaddition to other markers including SM-specic markers (smoothmuscle actin [SMA] and SM myosin heavy chain), calponin, caldes-mon,p63, 4 integrin, laminin,maspin, CD10,P-cadherin,caveolin1,nerve growth factor receptor (NGFR), 14-3-3 , and S-100.22-30 MEcells are typically negativefor luminalCKs, epithelialmembraneanti-gen (EMA), desmin, ER, and PgR.31-41 ME cells are also called basalcells, which is a term used to refer to a cell population that is adjacentto the basementmembrane, in a basalpositionfrom theducts to theacini, and expresses basal CKs.39,42 However, in addition to ME cells,basal CKs are also expressed in a variable subpopulation of luminal

cells in both large ducts and the terminal duct lobular unit complex,although there is considerable variation in their expressionpattern. 21,42-44 Therefore, in the normal breast, the term basal hasconfusingly acquired two meanings: (i) it has become a synonym forME cells and (ii) it denes a specic subpopulation of basal CK-expressingcells that may befoundineithera luminalor basallocation.

Basal-like tumors express genes characteristic of basal/ME cells.In addition to structural roles, many of the basal-like gene productshavebeenimplicated in cellular proliferation, suppression of apopto-sis, cell migration and/or invasion, all hallmarks of cancer. 45,46 They underexpressER,ER-responsive genes, and other genes characteristicof luminal epithelial cells of the normal mammary gland, as well asgenes located in the HER2 amplicon on 17q21. 47 Collectively, thegene-expression prole of basal-like tumors provides myriad candi-date genes that might contribute to their aggressive phenotype and,arguably, maysuggesta lessdifferentiatedstem/progenitor cellphe-notypeor a stem cell origin for these tumors.Table 1 summarizes thegenesandfunctionalgroupscharacteristicallyoverexpressedordown-regulated in basal-like breast cancers.

GENOMIC DNA PROFILING OF BASAL-LIKE BREAST CANCER

Basal-like tumors have been characterized using microarray-basedcomparative genomic hybridization (array-CGH) in a number of studies. 7,8,48 Basal-like cancers are reported to have a greater geneticcomplexity compared with other breast cancer subtypes, suggesting agreaterdegreeofgeneticinstability. Bergamaschietal 7 andChinetal 11

have applied array-CGH to invasive breast cancers that were previ-ously characterized by expression arrays. They found that basal-liketumorsshowthe highestfrequencyof DNAlossesand gainscomparedwith other subtypes.However, it is unclear whether this is not related

to the fact that basal-like breast cancers are predominantly of highhistologic grade, whereas the other groups arecomposed of a mixtureoftumorsofdifferentgrades.Thesetwogroupshave alsoreportedthatdespite the highest prevalence of genomicaberrations, basal-like can-cers more frequently show low-level gains and deletions and lessfrequently show high-level gains/amplications 7,8 than do tumorspertaining to theother molecular subgroups. This pattern of genomicchanges may be suggestive of a defect in double-strand DNA break repairmechanisms. 49 A recentstudy hasalsodemonstrated thatbasal-likecancersfrequentlyharbor a dysfunctionalBRCA1 pathway.Inter-estingly, some of thefew recurrent amplicationsdescribed to date inbasal-like cancers include 7p11.2, involving the EGFR gene,50 7q31,affecting caveolin 1 51 and 12p13. 52

In a previous study, basal-like tumors, as dened by CK14 posi-tivity, showed a lower prevalenceof genomic changes compared withgrade-matched tumors. Interestingly, basal-like cancers showed arather distinctive CGH prole, with higher rates of loss at chromo-somes 16p, 17q, 19q, and Xp and lower rates of both loss at chromo-somes 4q, 9q, and 13q and gains at 17q and 20p. 53,54 In addition,genome-wide single nucleotidepolymorphismarrays haveshown thehighest overall rate of loss of heterozygosity (LOH) in the basal-likesubset of breast cancers that have been identied on the basis of mRNA expression array data. The fraction of LOH was two to threetimes higher than that of other subtypes of breast cancer. 55 Severalother characteristic cytogenetic changes have been reported. 7,53,54,56

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For example, the locus at 5q11, which has many checkpoint DNA-repair and tumor suppressor genes (including MSH3, RAD17, APC,RAD50,andXRCC4),was lost in100%of thebasal-likecancers, 7,55,57

but never in luminal or other subtypes. Basal-like tumors also show thelowestrateof LOHat 16q23-24and1p32-ter compared withotherclasses of breast cancer. 55

IMMUNOHISTOCHEMICAL IDENTIFICATION OFBASAL-LIKE TUMORS

To date, there is no internationally accepted denition for basal-likecancers. Although the majority of basal-like tumors have commonmorphologic features, 58,59 there areno specichallmarkmorphologicfeatures that can identify those tumors reliably in routine practice.Gene expression microarrays cannot be readily applied to clinically available formalin-xed,parafn-embeddedtissues,remainrelatively expensive, and are not established as a robust technology that can beusedin routinepatientmanagement.Given thatthe majorityof basal-like breast carcinomas lack ER, PR, and HER-2 expression, severalgroups have adopted a triple-negative(ER/PR/HER-2) denitionfor basal-like cancers.Although thisapproachis certainly convenient,given that this information is present in most pathology reports, itshould be emphasized that the overlap between triple-negative andbasal-likebreast cancers,as dened by expressionarray analysis, is notcomplete. 60,61 Itshouldbenoted thatalthoughmost basal-likecancersdo not express ER or HER-2, 15% to 45% are reported to express atleast one of these markers 4,13,60,62 ; on the other hand, not all triple-negative cancers are of basal-like prole. 4,60,63,64 One study demon-strated that ER and HER-2 were expressed in 14% of basal-likecancers 64 ; on the other hand, only approximately 85% of ER/HER-2 cancers are of basal-like phenotype by expression arrays. 60

Furthermore, inRNAexpression analysisexperiments,triple-negativetumors included not only basal-like cancers but also the so-callednormal breastlike class of breast cancer. 3,4,13,14,65 Although the lattergroupis stillpoorly characterized,theyarereportedto have a progno-sis which seems to be better than that of basal-likecancers, 4,62 and donotseemto respondtoneoadjuvantchemotherapy. 64,65 Infact,in one

study, 45%of patientswith basal-like cancer showed pathologiccom-plete responseafter receiving an anthracycline plustaxane-basedneo-adjuvant chemotherapy, whereas none of the normal breastlikecancersdidso. 64 Furthermore,ERexpression,as dened by immuno-histochemistry (IHC) analysis, has a documented technical false-negativerate, 66 andanydenition basedon allnegative results shouldbegenerally avoided.60,67 Therefore, itis important tonoticethatsomeclinical trials based on triple-negative denition (Table 2) are now underway. Such denitions may arguably lead to inaccurate conclu-sionsasaresultofthenoiseinsubtypedenitionintroducedbyrelyingon a triple-negativecriterion.

On thebasis of theforegoing, theonlyrealistic, potentiallyobjec-tive, andconvenient methodto identify these basal-likecarcinomas inclinical specimens would be through the positive detection of certainmarkers. In a more pragmatic approach, several IHC surrogates havebeen proposed for the routine identication of basal-like breast tu-mors. Nielsenet al 60 identied an IHC surrogate based on four mark-ers (ER, HER-2, epidermal growth factor receptor [EGFR], andCK5/6). They classied all HER-2positive tumors in the HER-2 subtype.Of the remaining cases, ER-positive tumors wereconsidered luminal,whereas ER-negative tumors were classied as either basal-like (ER and HER-2 negative, CK5/6 and/or EGFR positive) or undetermined(negative for all four markers;22%).In their study, this panelshoweda sensitivity of 76% and a specicity of 100% to identify breast carci-nomas with a basal-like phenotype as dened by expression proling

Table 1. Genes and Functional Groups Characteristically Overexpressed or Downregulated in Basal-Like Breast Cancers

References Functional GroupsUp- or

Downregulated Genes

3-5,11,14,47,51 Genes that are important structural elements ofbasal epithelial basal-like cells and frequentlydetected in basal-like tumors

Upregulated Metallothionein 1X , fatty acid binding protein7 , FOXC2 , activating transcription factor 3,KRT5 (CK5), KRT17 (CK17), and P-cadherin

3,4,47,145 Extracellular matrix receptors, and components ofhemidesmosomes that anchor basal epithelial

cells to the extracellular matrix via the basal CKlament network

Upregulated 6 4 integrin , several subunits of laminin-5 ,MMP14 , and collagen type XVII alpha-1

45,146 Proteins that act ivate s ignaling pathways, whichare commonly deregulated in cancer

Upregulated MEK , ERK and PI3 kinases , AKT kinases ,p38 , MRAS , CDCA7 and NF- B

3,4,11,103,147 Proliferation and mitotic checkpoint control genesand cell growth-related genes

Upregulated cyclin E1 , BUB1 , MYBL2 , TTK ,topoisomerase II , MCM2 , MAD2L1 ,STK6 , CDC2 , CDCA3 , CDCA5 , and PCNA

14,47 Tyrosine kinase receptors and genes involved insignal transduction and transcription factors

Upregulated c-KIT , EGFR , caveolin 1 and 2 , hepatocyte growth factor , Pleiotrophin , c-fos , and c-jun

3,14,148 Heat shock protein Upregulated B-crystallin and Hsp27 46,149,150 Cell migrat ion, invasion, extracellular remodeling Upregulated TGF 2 3,4,11,14,47,51,151 Hormone receptors, transcription factors,

oncogenes, and othersDownregulated ER alpha , PR , GATA transcription factors

(GATA3 ), basic transcription factor 3 ,FOXC1 , FOXA1 , TFF3 , X-box binding protein 1 , RAB

4,11,14,47 Oncogenes and others Downregulated HER-2 , GRB7 , GTPase binding effector protein 1 , bronectin-1 , and mucin-1

Genes up- or downregulated in relation to normal parenchymal cells of the breast.Genes encode proteins found in the extracellular compartment and extracellular protein receptors.Genes that encode characteristic proteins of luminal epithelial cells.

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analysis. These criteria for denition of basal-like tumors wereadopted by many otherauthors. 68-73 In a similar study, Livasy et al58

investigated 23 basal-like tumors identied by cDNA microarrays.They reported that the most consistent immunophenotyping of basal-like tumors was negativity for ER and HER-2, and positivity for vimentin, EGFR, CK8/18, and CK5/6. In addition, other crite-ria have been used in the denition of basal-like tumors such asER, P[g]R, HER-2negative [triple-negative], and CK5/6 and/orEGFR-positive,69 ER-negative, HER-2negative/positive and

[CK5 and/or P-cadherin and/or p63]-positive,74

and triple-negative.61 Table 3 summarizes the different denitions of basal-like cancer, their percentages, and control groups used in differentstudies with subsequent association with patients outcome. Othermarkers that have been included in the panel of basal biomarkersinclude vimentin and laminin, 58,68 c-KIT, 75 p63,76 nestin, 77 os-teonectin, 78 caveolin 1,51 and NGFR. 79

BASAL CKS AND BASAL-LIKE BREAST CANCER

Becausebasal CKsexpressionisoneof themain characteristic featuresofbasal-liketumors,mostbutnotallIHCstudies 53,63,76,80-82 haveused

themto denedbasal-liketumors (Table 3). 21,83,84 Ina previousstudy of a large series of unselected breast cancers, using different IHCmarkers, 67 we demonstrated thatbasal CKsare independently associ-atedwith pooroutcome. 4,60,63,84-87 Additionalmarkers usedto denebasal-liketumors,althoughassociatedwithbasalCKexpression,so farhave not helped improve the identication of cases with differingoutcomecomparedwith those identied using basal CKsalone.Theseadditional markers, if used to dene cases of basal-like cancer, wouldreduce considerably the proportion of cases allocated to this poor-

prognosis typeof breast cancer. Therefore, a suitable, pragmatic solu-tion would be to usebasalCKs expression to dene basal-like tumorsregardless of the expression of other markers. However, some au-thors may argue that although both basal CK-positive tumors andbasal-like breast cancers share several clinicopathologic and im-munohistochemical features, theyare not strictly the sameentity, 88

and basal CKs are not expressed in all tumors classied basal-likeby gene microarray analysis. 4 Although the prognosticsignicanceis theone of theaims of identifying newclasses of cancer, basal-liketumors identied by gene expression arrays also share a distinctmolecular prole, which may have therapeutic implications, inaddition to their prognostic signicance. For example, some of the

Table 2. Current Clinical Trials of Basal-Like Tumors

Trial Name Design Primary Aim No. of Arms Total Enrollment

Cetuximab and Cisplatin in theTreatment of TN MetastaticBC (BALI-1)

Phase II randomized, treatmentand efcacy study

To assess the overall response(PCR or PPR) during study

2 (parallel assignment, activecontrol)

180

Cetuximab and Carbo for ER/PR/ HER-2 Negative BC (LCCC0403)

Phase II randomized To assess overall response rateto cetuximab alone andcombination cetuximab plus

carboplatin

2 (parallel assignment,uncontrolled)

100 patients

Combined Treatment ofCetuximab and Paclitaxel inBasal Like BC

Phase I and II nonrandomized,treatment and efcacy study

To assess efcacy of combinedanti-EGFR cetuximab andweekly paclitaxel

1 (single group assignment,uncontrolled)

25

EndoTAG-1 in Triple ReceptorNegative Breast CancerPatients

Phase II randomized To assess the efcacy, safetyand tolerability of EndoTAG-1alone and in combination

3 135

A Study of Dasatinib (BMS-354825) in Patients WithAdvanced TN BC

Phase II nonrandomized,treatment and efcacy study

To estimate the objectiveresponse rate of dasatinib andobtain preliminarypharmacogenomics data

1 (single group assignment,uncontrolled)

45

Abraxane, Bevacizumab andCarboplatin in TN MetastaticBC (NCI CTCAE)

Phase II nonrandomized To assess the effect ofcombination of weeklypaclitaxel and carboplatin plusbiweekly bevacizumab

1 (single group assignment,and historical control)

70 patients

Bevacizumab and Abraxane asSecond-Line Therapy in TN

Metastatic BC

Phase II nonrandomized To determine the effect ofaddition of bevacizumab to

paclitaxel as second-linetherapy

2 (single group assignmentand active control)

NS

Erlotinib Plus Chemotherapy forTreatment of TN BC

Phase II nonrandomized,treatment and efcacy study

To assess PCR with of 4-6cycles of neoadjuvant CT andpulse erlotinib

1 (single group assignmentand active control)

30

Cisplatin as First Line Therapy forTN Metastatic BC

Phase II nonrandomized To assess overall response rateof TN tumors to cisplatin asrst-line therapy

1 (single group assignment,and historical control)

39

Carboplatin or Docetaxel CT forAdvanced Genetic BC(BRCA trial)

Phase II randomized To nd out if carboplatin isbetter than docetaxel forgenetic BC that has comeback after CT

2 (2:1 assignment,uncontrolled)

148 BRCA1 and74 BRCA2

Triple-Negative Trial Phase III randomized To determine whether there isgreater activity for carboplatinthan a taxane standard ofcare (docetaxel) in womenwith TN BC

2 (parallel assignment,uncontrolled)

350-450

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Table 3. Denitions and Prognostic Signicance of BLC in the Different Studies

StudySample

Size

BLC Controls

Follow-Up Association With OutcomeDenition No. % Description No.

Studies dened BLC based oncDNA expression microarrays

Sorlie et al, 2001 4 78 Intrinsic gene list 14 18 Other classes (luminal A/B/C, normalbreastlike and HER-2)

64 Up to 66months

BLC and HER-2 associated withpoorer outcome (shortest DFS andOS) in the 49 patients with follow-updata. The 2 deaths among the T1/T2tumors withdrawn from the data setfor the purpose of the survivalanalysis occurred in BLC

Perreard et al, 2006 147 117 Intrinsic gene list and a qRT-PCR

40 32 Other classes (luminal, normalbreast like and HER-2)

77 Up to 118months

BLC associated with poorer outcomecompared with luminal tumorsindependent of ER status (RFS, P .065; OS, P .002) and even whenadjusted for stage ( P .001). Nodifference between BLC and HER-2subtypes

Fan et al, 2006 62 295 Intrinsic gene list 53 18 Other classes (luminal A and B,normal breast like and HER-2)

242 Up to 210months

BLC associated with poorer outcomecompared with luminal tumors, buttheir outcome was not different fromHER-2 subtype

Hu et al, 2006 14 105 and311

Intrinsic gene list 26 Other classes (luminal A and B, INFand HER-2)

74 Up to 170months

BLC associated with poorer outcomecompared with luminal A tumors

independent of ER, grade, and LNstage ( P .03)

Langerod et al, 2007 103 80 Intrinsic gene list 12 15 Other classes (luminal A, highlyproliferating luminal, normal breastlike and HER-2)

68 Up to 16 years BLC, HER-2, and the highlyproliferating luminal groups are 6higher in breast cancer death ratesthan for the luminal A group; normalbreastlike are intermediate

Sotiriou et al, 2003 11 99 Intrinsic gene list 26 26 Other classes (Luminal 1, 2 and 3,HER-2)

73 Up to 140months

BLC associated with poorer outcomecompared with luminal tumors, buttheir outcome was similar to theHER-2 subtype

Calza et al, 2006 13 412 Intrinsic gene list 59 16 Other classes (luminal A and B,normal breast like and HER-2)

310 Average 6.1years

Among endocrine-treated patients(n 171), BLC did not differsignicantly from luminal A group.Among the untreated patients (n 130), BLC had a survival patternsimilar to HER-2 class. In all patients,HER-2 group had the worst DFS,whereas the luminal A and normal-like groups had the best prognosis

Studies dened BLC based on IHCdenition, using the same ordifferent panel of IHC markers

Nielsen et al, 2004 60 115 Intrinsic gene list 21 18 Other classes Average 17years

BLC associated with poorer outcomecompared with luminal subtype ( P .03). Outcomes of BLC were similar(P .045) to those of the HER-2group (these patients did notreceived antiHER-2 therapy)

930 ER/HER-2and CK5/6and/or EGFR

102 15 Luminal A and B, normal breast likeand HER-2

94

Luminal, HER-2, and undetermined 561

Garcia et al, 2007 152 930 CK5/6, caveolin 1,CAIX, p63 or CD117tumors

Tumors IHC negative for thesemarkers

Up to 10 years BLC associated with distantmetastasis and breast cancer deaths,particularly in node-negative patients

Rakha et al, 2006 91,98 1944 CK5/6 and/or CK14 347 18.6 Tumors IHC negative for these CKs(non-BLC)

1,525 Up to 206months

BLC associated with variables of poorprognosis and poorer patientsoutcome (DFS and OS) than non-

BLC, particularly among grade 3LN-negative tumors independentof all other variables

Jumppanen et al, 2007 88 445 CK5/14 48 1 3 CK5/14 negative tumors 327 Average 6years

BLC associated with shorter DFSduring the rst 3-5 years, but lostsignicance at 10 years. The sameresult was obtained when the BLCcases identied by geneexpression microarrays in thesame patients cohort

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Table 3. Denitions and Prognostic Signicance of BLC in the Different Studies (continued)

StudySample

Size

BLC Controls

Follow-Up Association With OutcomeDenition No. % Description No.

van de Rijn et al, 2002 87 600 CK5/6 and/or CK17 90 16 Tumors negat ive for both CKs 474 Average 66months

BLC associated with a poor clinicaloutcome. Multivariate analysis ofLN-negative tumors: Expression ofthese CKs was a prognostic factorindependent of tumor size and

gradeBanerjee et al, 2007 81 282 CK14/CK5/6/CK17

positivity49 17.4 Matched age, LN and grade, basal

CK-tumors49 Average 68

monthsBLC associated with recurrence,

shorter DFS and OS. (No. of eventswere 30 in BLC compared with 8 inthe control group)

Rodriguez-Pinilla et al, 2006 109 230 ER/HER-2and CK5/6and/or EGFR

27 12 Non-basal tumors 228 Average 101months

BLC associated with shorter OS butnot in multivariate analysis. BLCassociated with higher localrecurrence and distant (visceral)metastasis rates

Studies that did not nd adverseoutcome or even reportedbetter outcome for BLCpatients

Kim et al, 2006 75 776 ER/PR/HER-2andCK5/CK14/EGFR/c-KIT/p53

114 14.7 ER/PR/HER-2 positive or all basalmarker negative

662 Average 75months

BLC and HER-2 associated withvariables of poor prognosis morethan the HR-expressing group. HER-

2 subtype was prognostically theworst subgroup. On multivariateanalysis, HER-2 but not BLC wasassociated with poor prognosis

Potemski et al, 2005 63 195 CK5/6 and/or CK17 72 37 CK negative tumors 123 Average 62months

Basal CK-positive tumors associatedwith worse prognosis comparedwith basal CK-negative tumors in allcases but not in LN- or ER-negativesubgroups. In multivariate analysis,basal CK expression did not retainstatistical signicance

BLC ER/HER-2and CK5/6/CK17

48 25 Nonbasal tumors (luminal and HER-2)

144 BLC a ssociat ed wit h bet ter outcomethan luminal group. No differencebetween the BLC and HER-2groups

Fulford et al, 2007 82 470 CK14 grade IIItumors

88 20 Grade I II matched con trol s 382 Average 116months

BLC and non-BLC showed similar DFSand OS in the rst 5 years; then,BLC showed better outcome.However, survival after rstrecurrence was shorter for BLC

Studies that reported associationwith other prognosticvariables but did not reportpatients outcome (OS orDFS)

Matos et al, 2005 74 168 ER/HER-2tumors 12 7.6 Other classes (luminal A and B, andHER-2)

145 NS BLC assoc ia ted with var iables o f poorprognosis such as grade 3 tumorswith a high proliferation rate

Carey et al, 2006 69 496 ER/PR/HER-2andCK5/6/EGFR

100 20 Non-BLC (luminal A and B, HER-2and unclassied)

396 Up to 11 years BLC more frequent in AfricanAmerican premenopausal women,grade 3 tumors with highproliferative activity. BLC associatedwith worse outcome compared withluminal types

Pinilla et al, 2006 136 509 ER/HER-2, CK5/6

and/or EGFR

53 10.6 Non-basal tumors 445 NS BLC was associated with expression

of caveolin 1 and BRCA1-associatedtumors

Laakso et al, 2005 76 288 CK5/14 tumors 24 9 CK5/14-tumors 242 NS BLC were associated with grade 3,and HR negative and was inverselyassociated with HER-2 oncogeneamplication

NOTE. In almost all studies, HER-2positive patients did not receive specic antiHER-2 therapy with the subsequently expect poor prognosis of this group ascompared with the HER-2negative BLC.

Abbreviations: BLC, basal-like cancer; HR, hormone receptor; HER-2, human epidermal growth factor receptor 2; DFS, disease-free survival; OS, overall survial;qRT-PCR, quantitiative real-time polymerase chain reaction; ER, estrogen receptor; PR, progesterone receptor; RFS, relapse-free survival; LN, lymph node; CK,cytokeratin; IHC, immunohistochemistry; INF, interferon; NS, not stated.

Training set.Validation set.Tumors analyzed using cDNA microarrays.Tumors analyzed using IHC.This study used two denitions for BLC; basal CK positive and pure basal-like phenotype (ER/HER-2, and CK5/6 and/or CK17 ).






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MORPHOLOGIC FEATURES OF BASAL-LIKE TUMORS

By dening basal-like cancers either in terms of mRNA expressionprole or expression of basal IHC markers, studies are consistentin their morphologic description of this class of breast cancer.The basal-like group comprises 8% to 20% of all breast can-cers.3,4,53,54,63,75,82,87,98,100 The majority of these tumors are ductal

of no special type, but occasionally are tubular mixed,98

metaplas-tic,92 or medullary cancers 101 (Fig 1). They have common featuresincluding younger patient age, high histologic tumor grade,marked cellular pleomorphism, high nuclear-cytoplasmic ratio,lack of tubule formation, high mitotic index, frequent apoptoticcells, scant stromal content, a pushing border of invasion, centralgeographic or comedo-type necrosis. They are also characterizedby the presence of metaplastic elements such as spindle cells andsquamous cell metaplasia, presence of a central scar, glomeru-loid microvascular proliferation, and a stromal lymphocyticresponse. 13,54,59,80,81,98,102-104 In addition, some reports have sug-gested that basal-like tumors may achieve extraordinarily rapidclinical growth rates. 105 The high proliferative activity of basal-liketumors may probably explain why these tumors are overrepre-sented among the so-called interval breast cancers (eg, cancersarising between annual mammograms). 106

Although these features are strongly associated with basal-likecancerandcan help in theidentication of these tumors forexample,almostallmetaplasticand medullarycarcinomasarebasal-like, 92,98,101

they are generally not specic, and individual features can be seen inother high-grade tumors regardless of their immunophenotype, thusemphasizing the importance of IHC detection of specic (basal)markers as a realistic and simple method to identify these tumors inroutine practice.

CLINICAL CHARACTERISTICS OF BASAL-LIKE CANCERS

Despite differences in the denition and prevalence of basal-like tu-mors in various studies, the poor outcome of patients with basal-liketumors has been remarkably reproducible across many different pa-tient populations(Table3). 4,5,11,63,69,80,81,91 Basal-likecancer is associ-ated with an aggressive clinical history, development of locoregional

and distant metastasis (particularly in the rst 5 years82

), shortersurvival, and a relatively high mortality rate. 5,69,80,81,87,98 Previousstudies have demonstrated that basal-like phenotype is an indepen-dent marker ofpoor prognosis inbreastcancersas a whole, 1,9-11 inthelymph node (LN)-negative, 63,87 and LN-positive groups. 60,83 Basal-like phenotype was found to predict a particularly aggressive coursefor patients with grade 3, lymph node-negative tumors 91 and in pa-tients with metastatic disease. 82 In addition, basal-like tumors show aspecic pattern of distant metastasis with an increased propensity forvisceralmetastasesto brain andlungsitesknowto beassociatedwitha poorer prognosis 82,107,108 and less likely metastasize to bone andliver.81,82,102,109,110 Thesendingssuggest thatbasal-liketumors mightalso possess a distinct mechanism of metastatic spread.

However, it should be also noted that some reported lack of association between basal-like cancer and poor outcome (Table3).82 Others have also reported a negative association with out-come during the early few years of follow-up, which loses itssignicance after a long-termperiod(10years). 88,103 Furthermore,it has been reported that basal-like tumors either dened by thetriple-negative phenotype 111,112 or by basal CK expression98 arenot associated with increased risk for locoregional relapse afterconservative surgery. In fact, these ndings together with the fre-quently pushing well-dened border of invasion in these tumorsand absence of association with vascular invasion or lymph nodeinvolvement 13,58,80,82,91,95 do not appear to justify a more radical

Salivary gland-liketumors

Basal-like carcinomas

IDCBasal-like

MedullaryMetaplastic

BRCA1 downregulation(ID4 overexpression?) BRCA1 gene promoter methylation

Fig 1. Hypothetical spectrum of basal-like breast cancers. The hypothesized morphologic spectrum of basal-like breast cancers encompasses not only grade 3 invasiveductal carcinomas (IDCs) and carcinomas with medullary features, but also, at the lowed end of the spectrum, adenoid cystic carcinomas and, at the upper end of thespectrum, high-grade, malignant tumors with overt myoepithelial differentiation, such as malignant myoepitheliomas and metaplastic breast carcinomas. All of theselesions are consistently characterized by the lack of estrogen-receptor (ER) and human epidermal growth factor receptor 2 (HER-2) expression and the expression ofbasal/myoepithelial markers, including basal cytokeratins (CKs). Apart from adenomyoepithelioma, adenoid cystic carcinoma and low-grade adenosquamous(syringomatous) carcinoma, which have been shown to be lowmalignant potential tumors, the denition, natural history, and clinical behavior of other malignantmyoepithelial lesions of the breast are controversial to say the least. Fortunately, the identication of lesions in the low and upper end of the spectrum can be easilyachieved by means of morphologic analysis alone. Interestingly, it has recently been shown that BRCA1 pathway is dysfunctional in basal-like breast cancers, howeverthe mechanisms may differ in different subgroups: although in medullary and metaplastic breast cancers, BRCA1 is inactivated due to gene promoter methylation, ingrade 3 invasive ductal carcinomas with a basal-like phenotype, BRCA1 seems to be transcriptionally downregulated. The latter process is reported to be mediated viaID4 overexpression. 124






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approach to local or axillary surgery. The potentially aggressivebehavior of these tumors may be better approached by use of systemic therapy (described further later herein).

BASAL-LIKE BREAST CANCER AND BRCA1

There are several linesof evidence to suggest a link between basal-likebreast cancer and BRCA1deciency. 49 Many phenotypical, immuno-histochemical, and clinical characteristics and molecular features aresharedby basal-like breastcancers andtumors that arise in carriersof BRCA1 germline mutations. The majority of BRCA1-associated tu-mors are triple-negative and express basal CKs (in addition to othermarkerscommonly seenin basal-like tumorssuch as p53, P-cadherin,andEGFR 5,76,80,113-117 ),and,inmoststudies,bothpatientgroupshavea poor outcome. 80,118 In keeping with these similarities, clusteringanalyses of microarray expression proling data have shown thatfamilial BRCA1mutanttumorstendtofallintothebasal-likecategory,suggesting similar carcinogenic pathways or causes of these two sub-types.5 As withbasal-like tumors, cytogenetic abnormalities are com-mon in BRCA1 mutation-related breast cancers 119,120 and a set of characteristic cytogenetic changes in BRCA1-associated breast can-cers119,121 hasbeendescribed insporadic basal-likecancers. 7,54,56 Bothsporadic basal-like and BRCA1 breast tumors have frequent loss of X-chromosome inactivation. 122,123

Some studies have indicated that BRCA1mRNA expression waslower in basal-like sporadic cancers than in controls matched for ageand grade 124 andin approximately 30% of sporadic breast tumors. 125

BRCA1is rarelymutated in sporadic breast cancers 126 and, therefore,it isbelievedthatthismay bea resultof epigenetic mechanismssuchasacquired methylation of the BRCA1 gene promoter 127,128 or a dys-function in the upstream pathways that regulate BRCA1 expression,

suchas overexpressionof ID4.124

These sporadictumorswith reducedBRCA1expression tendto exhibittriple-negativephenotypesremark-ably similar to BRCA1-mutated and basal-like tumors. 49,117,124,129 Inaddition, theprofoundsimilaritiesbetweenhereditary BRCA1-relatedbreast tumorsandbasal-like tumorsstrongly implicatea fundamentaldefect in the BRCA1 or associated DNA-repair pathways in sporadicbasal-like tumors. 117 Although it is not clear whether in humansBRCA1 inactivation is the cause or a consequence of a basal-likephenotype, two hypotheses have been advanced for the similaritiesbetween basal-like cancers and tumors arising in BRCA1 mutationcarriers: (i) the precursors of basal-like cancers (likely to be basal-likeductal carcinoma in situ 19,130,131 ) and invasive basal-like breast carci-nomas may be more tolerant to loss of BRCA1function than those of other breastcancer subtypes, possibly because of the phenotypeof thecell of the initiating event or the concurrent inactivation of othertumor suppressor genes, such as TP53; and alternatively, (ii) BRCA1may be involved in the differentiation of breast epithelial cells and,therefore, BRCA1 inactivation would lead to tumors with a stemcelllike phenotype. 132,133 Furthermore, given the reported action of BRCA1 in regulating the ER pathway, 134 BRCA1 dysfunction may actively lead to the development of tumors with a basal-like pheno-type.135 Although theaforementioned hypotheses are attractive, thereis no denite answer at this moment. However, this is a eld that israpidly evolving, and evidence-based answers may emerge in thenear future.

Basal-likecancers andtumors arising in BRCA1germline muta-tion carriers are remarkably similar at the morphologic, immunohis-tochemical, transcriptome , and gene copy levels. In fact, there areincreasingly more coherent data to suggest that BRCA1 pathway dys-function may play an important role in the development of not only familial but also sporadic basal-like tumors. 49,135 Although BRCA1somatic gene mutations are unlikely to be commonly found in spo-radicbasal-likecancers,thesetumorshavebeenshowntohaveadysfunc-tional BRCA1 pathway because of BRCA1 gene promoter methylationand/or BRCA1 pathway transcriptional inactivation. 49,124 To empha-size the relationship between basal-like tumors and BRCA1, someauthors have demonstrated that the use of basal CK staining in com-bination withER andmorphologyprovidesa moreaccuratepredictorof BRCA1mutation status thanpreviouslyavailableandmaybeusefulin selecting patients for BRCA1mutation testing. 49,78,124

Interestingly, although several studies have demonstrated therelationship between BRCA1 and basal-like tumors, the availableevidence suggests that BRCA2 is not involved in the biology of basal-like carcinomas. 76,109,136

THERAPEUTIC IMPLICATIONS OF BASAL-LIKE TUMORS

Basal-like cancer often hasa triple-negative phenotype; as a result, themajority of these tumors cannot be managed effectively with existingtargetedtreatments (trastuzumab andhormonaltreatments).Despitetheir aggressivebehavior, current routinediagnostic practice doesnotspecicallyrecognize these tumors,andtheir managementisstillsameas that of other grade- and stage-matched breast cancers. This ismainly because the genes that are responsible for their aggressivephenotype are not well understood.

Several potential targets are now emerging, including EGFR,which isexpressed in 60%60,67 andampliedand/oraneusomic ina

subset of basal-like tumors,50

and itsdownstream signaling pathways.EGFR signaling has been inhibited in other cancer types with someclinical success, by using either EGFR-directed antibodies or the in-hibitors of receptor phosphorylation. 137,138 The growth factor recep-tor, c-KIT, which is expressed in a high proportion of basal-likecancers, 60,75,139 hasbeen successfully targeted in other tumor typesby imatinib that inhibits c-KITandplatelet-derivedgrowth factorrecep-tortyrosinekinases.These ndingsshouldbe interpretedwith cautionthough, as c- KIT positive breast tumors have been shown to lack activating KIT genemutations. 139 Dasatinib,an srcinhibitor,hasbeenshown in preclinical models to be most effective in triple-negative/basal-like breast cancers. 89,140 Although theactual target of this inhib-itor in basal-like cancers remains to be determined and no evidencebased onclinical experiencehasbeengathered todate, this compoundmay prove useful for future management of basal-like cancers. 89 Thefundamental biologic similarities between BRCA1-associated andbasal-like tumors suggest that strategies targeting potential BRCA1pathwaydysfunction in basal-like tumors might be effective. 141 Thereis increasing evidence that the DNA-repair defects characteristic of BRCA1-related cancers, especially defective homologous recombina-tion, confersensitivity to certain systemic agents, such as platinum saltsbasedchemotherapyagents andPARPinhibitors, 141-144 which,therefore,couldberelevant to thetreatmentof basal-like breastcancer.

The response of basal-like tumors to chemotherapy is currently under investigation (Table 4). However, most studies were either






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Table 4. Response of BLC to CT

References Study Cohort

BLC

Denition No. %

Rouzier et al, 2005 64 82 patients with stage I-III BC Intrinsic gene list applied to FNA samples 22 27

Rody et al, 2007 65 50 patients with stage II and III BC Intrinsic gene list applied to frozen preoperative corebiopsy from tumors

10 20

Diallo-Danebrock et al, 2007 104 236 patients with high-risk BC with more

than 9 affected axillary LNs

Expression of 24 proteins (IHC and TMA) and clustering

analysis; positive for CK5, CK17, vimentin, and p53

29 13

Carey et al, 2007 61 107 patients with stage II and III BC Triple-negative tumors (using IHC) 34 32

Banerjee et al, 2006 81 282 patients with grade III BC IHC expression (CK5/CK6, CK14 and/or CK17 tumors) 49 17

Rakha et al, 2006 91 1,872 patients with different tumorcharacteristics

IHC expression (CK5/6 and or CK14 tumors) 347 18.6

Rodriguez-Pinilla et al, 2006 109 230 patients with nonfamilial, LN-negative BC IHC expression (ER/HER-2 and CK5/6 and/or EGFRtumors)

27 12

Chappuis et al, 2002 153 38 patients with stage I-III disease BRCA1/2-associated cancers 7 BCRA1, 4 BCRA2, 27noncarriers

References Type of Study CT Clinical Events Response

Rouzier et al, 2005 64 Prospective, nonrandomized study ofpatients who received neoadjuvant CT(matched cohort study)

12 weeks of paclitaxel followed byuorouracil, doxorubicin, andcyclophosphamide 4 courses

10 cases (45%) showed PCRcompared with 7% in luminal, 0%in normal breast like and 45% inHER-2 tumors

BLC is more sensitive than theluminal and normal-likecancers

Rody et al, 2007 65 Retrospective, randomized study of tumorsfrom patients within the GEPARTRIOtrial who received neoadjuvant CT(matched cohort study)

All patients received 2 cycles of TACall on day 1, every 3 weeks).Then, patients with tumorresponse were assigned to 4 or 6further cycles of TAC, and thosewho did not show response werereceived either 4 further cycles ofTAC or 4 cycles of NX

10% of BLC showed PCR comparedwith 45% in HER-2 9% inluminal and 0% in normal breastlike. Relapse occur in 30% of BLCand normal breastlike, 13% inluminal and 0% in HER-2

BLC showed poor response toneoadjuvant CT comparedwith HER-2 and luminaltumors

Diallo-Danebrock et al, 2007 104 Retrospective study of patients who wererandomized to a trial (West GermanStudy Group AM01) comparing tandemHDCT (116 patients) with DDconventional CT (120 patients); casecontrol study

HDCT consisted of a short inductionwith 2 cycles of epirubicin andcyclophosphamide followed bytandem epirubicin,cyclophosphamide, and thiotepa.Control arm consisted of DDCT

BLC showed poor outcome in controlarm compared with luminal andnull subtypes but in HDCT, BLCshowed marked improvement ofoutcome that is not different fromluminal class

BLC showed better responseto HDCT than non-BLC

Carey et al, 2007 61 Retrospective, nonrandomized study ofpatients who received neoadjuvant CT(matched cohort)

All patients received doxorubicin andcyclophosphamide, atconventional doses for 4 cycles

10 cases (29%) of BLC showedPCR, 19 PPR, 5 stable diseasecompared with 7% of luminal and10% of HER-2 subtypes showedPCR

BLC has higher pathologicresponse rates than luminalsubtypes

Banerjee et al, 2006 81 Retrospective, nonrandomized study ofBLC compared with age-, LN-, andgrade-matched 49 non-BLC; casecontrol study

Adjuvant postoperative CT withanthracycline-based (uorouraciland cyclophosphamide plus eitherepirubicin or doxorubicin)

DFS and OS were shorter in BLCthan in non-BLC (both groupsreceived CT)

BLC associated with pooreroutcome than in controlgroup despite CT

Rakha et al, 2006 91 Retrospective, nonrandomized study of awell-characterized series of BC (250patients received adjuvant CT); matchedcohort

Adjuvant CT (Bonadonna CMF) In BLC, patients who received CTwas associated with betteroutcome than those who did notreceived CT. Among patients whoreceived CT, BLC showed betteroutcome than non-BLC in certainmatched subgroups

BLC patients who received CTwere associated with betteroutcome

Rodriguez-Pinilla et al, 2006 109 Retrospective, nonrandomized study (107patients received adjuvant CT; 71received CT and 43 received CT andtamoxifen); matched cohort

Adjuvant CT (CMF) 5 of 13 BLC who did not receive CTdied compared with 1 of 12 whoreceived CT who died duringfollow-up. When cases wereanalyzed with respect to CT, BLCwas the only factor associatedwith prognosis in untreatedpatients

BLC associated with poorprognosis among patientsnot receiving CT, whereasno such association wasfound in patients receiving it

Chappuis et al, 2002 153 Retrospective, nonrandomized study ofpatients who received neoadjuvant CTwho have BRCA1/2 results (26 patientswere from a clinical trial: NSABP-B18,-B26, and -B27, NCIC MA.10)

Anthracycline-based CT (usually 4cycles); doxorubicin andcyclophosphamide

10 carriers (93%) wih CCR comparedwith 8 (30%) noncarriers. PCR in44% of carriers compared with4% in noncarriers

BRCA1/2 carriers have a betterresponse to CT thannoncarriers; however, theeffect is less marked whenadjusted for TNM stages

Abbreviations: CT, chemotherapy; BLC, basal-like cancer; BC, breast cancer; FNA, ne-needle aspiration; PCR, pathologic complete response; HER-2, human epidermal growth factor receptor2; TAC, doxorubicin/cyclophosphamide/docetaxel; NX, vinorelbine/capecitabine; LN, lymph node; IHC, immunohistochemistry; TMA, tissue microarray; CK, cytokeratin; HD-, high dose; DD-,dose dense; PPR, pathologic partial response; CMF, cyclophosphamide/methotrexate/uorouracil; ER, estrogen receptor; NSABP, National Surgical Adjuvant Breast and Bowel Project; NCIC,National Cancer Institute of Canada; CCR, clinical complete response.

In this study, 10 cases were classied as BLC, eight cases (65%) were grade 2, and 20% were ER positive.Outcome was not considered in this table because most patients received subsequent taxane-based adjuvant CT after the neoadjuvant CT.In this study, 78% of the control group were hormone-receptor positive compared with 18% in BLC, and both BLC and non-BLC patients received CT.In the LN-positive grade 3 tumors with primary size 2 cm, for instance (n 120), there was no statistical difference between patients who received chemotherapy or not in the non-BLC

group, whereas in BLC group, patients who received chemotherapy showed better outcomes.






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retrospective, or failed to include a control group, or were not suf-ciently powered. Although it has been reportedthatbasal-like tumorsmay have a better response to chemotherapy, 61,104 basal-like pheno-type does not seem to be an independent predictor of chemotherapy response after accounting for the contribution of high grade, highproliferation rates, and hormone receptornegative status of thesetumors, 64 and a recent study has reported a low response rate of basal-like tumors to neoadjuvant therapy with docetaxel, doxorubi-cin, cyclophosphamide. 65 Whether moreaggressive treatment proce-dures can improve the outcome for these patients and which of theavailable options provide the greatestbenet are still under investiga-tion (Table 2). However, a caveat should be voiced, given that mostclinical trials have so far used a triple-negative denition for thesetumors (as described earlier herein). The answer these issues mightrequirecarefullydesignedprospectivestudiesto evaluate theimpactof thebasal-likephenotype andits individualgeneproducts on responseto specic therapy.

CONCLUSION

Basal-like breast cancer is a distinct group of tumors that show com-mon but heterogeneous morphologic, genetic, and immunopheno-typic features and is associated with poor clinical outcome, whichwould be best seen as a spectrum of lesions. The current denition of basal-like cancers varies widely. In terms of gene expression microar-rays, they aredened bya specic gene signature that is similarto thatof basal and/or myoepithelial cells of the breast. In terms of IHCidentication, they have been dened using either a panel of markersthat can dene those tumors identied in the microarray studies oraccording to basal CK expression. This later pragmatic denition is

supported by the association between basal CK and poor outcome;however, it seems likely that a consensus denition is far from beingachieved. Giventhelimited numberofemerging therapeutictargetsinthese tumors, routine IHC identication of basal-like subtype as apoor prognosticgroupof breastcancer, could bebasedon theexpres-sion of basal CKs. A more practical approach is to apply these basalCKs to tumors that are triple negative or show morphologic featuressuggestive of basal-like phenotype such as high-grade tumors. Al-though we do not advocate the inclusion of HER2 amplied, basalCKpositive breast cancers in the basal-like group, because of theobvious therapeutic implications (ie, HER-2positive cancers are al-ready managedina completelydifferentfashion), it isunclearwhetherER- and basal CKpositive breast cancers should be classied. Al-though the latter accounts for a small minority of breast cancers,further clarity on their response to endocrine therapy is required. Wealso recommendtheuseofa combination ofbasalCKsanda validandconsensus methodof interpretationof their resultssimilartothatusedfor assessment of HER-2. Basal-like tumors may require a more ag-gressive interventionand shouldraise thesuspicionofa BRCA1germ-line mutation, particularly if theyare hormone-receptor negative.

AUTHORS DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

The author(s) indicated no potential conicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Emad A. Rakha, Jorge S. Reis-Filho, Ian O. EllisManuscript writing: Emad A. Rakha, Jorge S. Reis-Filho, Ian O. Ellis

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Glossary Terms

Transcriptome: The complete expressed product of the en-tire genome in a particular cell, tissue, or biouid at a specicpoint in time.

Microarray: A miniature array of regularly spaced DNA oroligonucleotide sequences printed on a solid support at high den-sity that is used in a hybridization assay. The sequences may becDNAs or oligonucleotide sequences that are synthesized in situto make a DNA chip.

Unsupervised methods: Analysis done without using theknowledge of clinical end points of the study. Methods such ascluster analysis, which identify partitions in data sets by compar-ing pair-wise similarity measures of gene expression, are unsu-pervised methods. These methods are generally poorly suited foridentifying prognostic variables because they do not necessarily

create categories reecting distinct biological phenotypes and in mostcases the categories do not admit a straightforward interpretation.

Genomic signatures: The expression of a set of genes in a biologicsample (eg, blood, tissue) using microarray technology.

Immunophenotyping: A way to identify cells based on their sur-face antigens. This assay, applying a panel of different uorochrome-conjugated antibodies, is used to diagnose specic types of leukemiaand lymphoma.

Microarray-based comparative genomic hybridization(array-CGH): Array-based comparative genomic hybridization is amethod that uses microarrays to probe changes in chromosomal DNA,thereby identifying precise areas in which genetic changes occur in can-cer cells.


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basal-like breast cancer

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