Luminal B Breast Cancer: Molecular Characterization, Clinical ...news.medlive.cn/uploadfile/20140723/14060957108067.pdf · distinct proﬁle of response to hormone therapy and chemotherapy

Luminal B Breast Cancer: Molecular Characterization,Clinical Management, and Future PerspectivesFelipe Ades, Dimitrios Zardavas, Ivana Bozovic-Spasojevic, Lina Pugliano, Debora Fumagalli,Evandro de Azambuja, Giuseppe Viale, Christos Sotiriou, and Martine Piccart

Felipe Ades, Lina Pugliano, DeboraFumagalli, Evandro de Azambuja, Chris-tos Sotiriou, and Martine Piccart, Insti-tut Jules Bordet, Universite Libre deBruxelles; Dimitrios Zardavas, BreastInternational Group, Brussels, Belgium;Ivana Bozovic-Spasojevic, Institute forOncology and Radiology of Serbia,Belgrade, Serbia; and Giuseppe Viale,European Institute of Oncology, Univer-sity of Milan, Milan, Italy.

Published online ahead of print atwww.jco.org on July 21, 2014.

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

Corresponding author: Martine Piccart, MD,PhD, Institut Jules Bordet, 121 Boulevardde Waterloo, Bruxelles, Belgium 1000;e-mail: [email protected].

© 2014 by American Society of ClinicalOncology

0732-183X/14/3299-1/$20.00

DOI: 10.1200/JCO.2013.54.1870

A B S T R A C T

Gene expression profiling has reshaped our understanding of breast cancer by defining andcharacterizing four main intrinsic molecular subtypes: human epidermal growth factor receptor2–enriched, basal-like, luminal A, and luminal B subtypes. Luminal B breast cancer has beenreported to have lower expression of hormone receptors, higher expression of proliferationmarkers, and higher histologic grade than luminal A. It also exhibits worse prognosis and has adistinct profile of response to hormone therapy and chemotherapy. Although luminal cancersshare similarities, the studies conducted in recent years using next-generation sequencingtechnology show that luminal A and B breast cancers should be perceived as distinct entities,with specific oncogenic drivers, rather than more proliferative varieties of luminal tumors. Thisreview discusses the definition and molecular characterization of luminal B breast cancer andpresents the available clinical evidence for chemotherapy and endocrine therapy patterns ofresponse. It also provides an overview of ongoing research on molecularly targeted agents forthis disease.

J Clin Oncol 32. © 2014 by American Society of Clinical Oncology

INTRODUCTION

In the early 2000s, high-throughput technology en-abled the interrogation of the expression of thou-sands of genes in a single experiment. This led to thedetermination that breast cancer comprises at leastfour molecularly distinct diseases with different fea-tures, clinical behaviors, and treatment responseprofiles.1-4 These intrinsic molecular subtypes weredefined as: basal-like, human epidermal growth fac-tor receptor 2 (HER2) –enriched, and luminal Aand B subtypes.1

Additional studies separated luminal breastcancers into at least two subgroups: luminal A andluminal B.2 Luminal A tumors were characterized ashaving the highest expression of estrogen-relatedand low expression of proliferation-related genes,2

whereas luminal B cancers showed lower expressionof estrogen receptor (ER)2,3,5 as well as low ex-pression of progesterone receptor (PgR) genes6

and higher expression of proliferation clustergenes (MKI67) and cell cycle–associated genes(CCNB1 and MYBL2).7,8 Luminal B tumorsshowed increased expression of growth factor re-ceptor genes, with approximately 20% beingHER2 positive by mRNA levels and immunohis-tochemistry (IHC).9 Table 1 lists proposed surro-gate IHC definitions for the classification ofluminal B breast cancer.6,10-13

MOLECULAR CHARACTERIZATION OFLUMINAL B

Luminal B breast cancer is also unique with regard tothe profile of gene copy number alterations (CNAs),DNA methylation, and somatic point mutations.14

High-level DNA amplifications and chromosomalaberrations were more frequently detected in lumi-nal B cancer than in the other subtypes (Fig 1).15,16

Identifying recurrent genome CNAs in luminal Bbreast cancer led to the discovery of oncogenes thatfunction as the molecular drivers of this subtype (eg,ZNF703).17 This oncogene has been shown to in-duce cellular proliferation independently of estro-gen stimulation in cell lines17 and is associated withworse clinical outcome.18 It stimulates genes relatedto WNT and NOTCH signaling pathways, involvedin regulating the self-renewal of breast tumor–initiating cells (TICs).17 Similarly, when the SIX1oncogene is expressed, it promotes breast TICs andis related to negative prognosis.18,19

The METABRIC (Molecular Taxonomy ofBreast Cancer International Consortium) study, in-tegrating genomic and transcriptomic profiling of2,000 breast tumors, led to a refined breast cancermolecular taxonomy.20 Ten molecular subtypes(defined as integrative clusters and labeled IntClusts1 to 10) with different clinical behaviors were iden-tified. Luminal B breast cancers clustered in several

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IntClusts. IntClusts 1, 6, and 9 were enriched for luminal B cancerscharacterized by 17q23/20q cis-acting aberrations, 8p12 cis-acting ab-errations, and 8q cis-acting aberrations/20q amplifications, respec-tively. IntClust 2, which exhibited a high mortality rate, was enrichedin both luminal A and B cancers bearing cis-acting aberrations in the11q13/14 region, where several driver genes reside. Recurrent lossof transcript expression in PPP2R2A, a B-regulatory subunit of thePP2A mitotic exit holoenzyme complex, was observed in luminal Bcancers, a significant pathophysiologic molecular alteration forthis subtype.20

Next-generation sequencing (NGS) studies have helped toelucidate the molecular uniqueness of luminal B breast cancer. TheCancer Genome Atlas (TCGA) Network initiative characterized ahigh number of primary breast cancers using a wide variety of

platforms. This analysis provided an abundance of molecular char-acteristics distinguishing luminal B cancer from the other sub-types. Luminal A and luminal B breast cancers are distinct entities,albeit with overlap. An unsupervised clustering analysis of methyl-ation data showed that the group with a hypermethylated profilewas enriched for luminal B cancers. This group had also a lownumber of MAP3K1 and MAP2K4 mutations. It was shown thatluminal B cancers had lower frequency of PIK3CA mutations (29%v 45%) and higher frequency of TP53 mutations (29% v 12%) thanluminal A cancers (Fig 1).14 Another gene found to be mutated to asignificant degree in both luminal A and B cancers was GATA3,with a frequency of 14% and 15%, respectively. However, differenttypes of mutations were also identified for the two subtypes, withhotspot CA intron 4 deletions associated with luminal A cancerand exon 5 frame shifts associated with luminal B cancer.21 Of note,GATA3 mutations were shown to confer endocrine sensitivity inthe neoadjuvant setting and are positively correlated with Ki67decline on aromatase inhibition (P � .01).22

RUNX1 was identified through genome-wide analysis as a tran-scription factor involved in mediating ER genomic recruitment andregulating tethering genes.21-24 Loss-of-function mutations affectingthis gene, as well as its dimerization partner CBFB, could lead to aphenotype of endocrine resistance. RUNX1 deletion was associatedwith poorly differentiated breast cancer25; interestingly, pathway rep-resentation and analysis by direct reference on graphical models(PARADIGM) –inferred pathway analysis associated RUNX1 loss-of-function mutations with the luminal B subtype, as well as features ofendocrine resistance.22

A

B

Freq

uenc

y

90

80

70

60

50

40

20

30

10

0

Luminal ALuminal BHER2 enrichedBasal like

TP53 PIK3CA GATA3 MLL3 MAP3K1 CDH1 PTEN TBX3

Copy NumberAberrations

Luminal A Luminal B HER2 Enriched Basal Like

Increased copy number:

1q and 16p 1q, 8q, 17q, and 20q

1q, 7p, 8q, 16p, and 20q

3q, 8q, and 10p

Decreased copynumber:

16q 1p, 8p, 13q, 16q, 17p, and 22q

1p, 8p, 13q, and 18q

3p, 4p, 4q, 5q, 12q, 13q, 14q, and 15q

High-levelamplifications:

8p11-12, 11q13-14, 12q13-14, 17q11-12, 17q21-24, and 20q13

8p11-12, 8q, and 11q13-14

17q Rare Fig 1. Percentage of somatic mutationsand molecular alterations across differentintrinsic subtypes of breast cancer. (A)Reported copy number alteration acrossdifferent breast cancer intrinsic subtypes.(B) Frequencies of the most commonlymutated cancer-related genes across dif-ferent breast cancer intrinsic subtypes.HER2, human epidermal growth factorreceptor 2.

Table 1. Proposed Surrogate IHC Markers for Classification of Luminal BBreast Cancer

StudyER

StatusPgR

Status (%)HER2Status

Ki67Level (%)

Blows et al10� Positive Positive PositiveCheang et al11� Positive Positive Negative � 13.25Prat et al6 Positive � 20 Negative � 14Goldhirsch et al12� Positive Positive Negative � 14Harbeck et al13� Positive Positive Negative � 20 to 25

Abbreviations: ER, estrogen receptor; HER2, human epidermal growthfactor receptor 2; IHC, immunohistochemistry; PgR, progesteronereceptor.

�ER positive and/or PgR positive.

Ades et al

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LUMINAL B DEFINITION IN CLINICAL PRACTICE

Subtype Definition Using Gene Expression Classifiers

Several molecular signatures have been developed in an effort topredict the molecular subtype in clinical practice, but their perfor-mance is controversial, and their use in daily practice is limited be-cause of the relatively high cost and technical complexity. One of thesemolecular signatures, prediction of microarray (PAM) 50, is gener-ated from an expanded intrinsic set of 1,906 genes derived from fourmicroarray studies.2,3,8,26 After applying several minimization meth-ods, 50 genes involved in proliferation, or related to ER, HER2,myoepithelial, and basal characteristics, were selected. The PAMmethod was used to generate the algorithm. The original signature hasbeen implemented in a clinical assay (Prosigna) based on NanoString(Seattle, WA) technology. Because this technology allows the use ofmaterial extracted from formalin-fixed paraffin-embedded samples,the test can be widely applied in the clinical setting. This assay is able toidentify the same intrinsic subtypes as the original work,27 and itsprognostic value has been validated in two studies.28,29

Surrogate Histologic and IHC Markers

In clinical practice, luminal B cancers are differentiated fromluminal A cancers based on proliferation markers.9,11,30 ER and HER2expression show a bimodal distribution with clear cutoff points forassessment.31 However, proliferation is determined by several geneswith a continuous distribution; thus, its status cannot be identifieddichotomously. Therefore, establishing a cutoff to determine high andlow proliferative tumors in the clinical setting remains a challenge.

Proliferation status has been assessed in clinical practice by dif-ferent techniques, with tumor grade being the most widely used.30

Nonetheless, technical issues limit its use as a surrogate marker. In onestudy of 675 breast cancer samples, the concordance rate for gradeclassification among three different pathologists was as low as 43%.32

Ki67 is a nuclear marker expressed in all cell-cycle phases exceptG0.33 It is evaluated by IHC, with results expressed in a quantitativeway, meaning the percentage of stained cells. Important intratumorvariation occurs, depending on the tumor section analyzed and thepathologist evaluation.34 In a meta-analysis including 46 studies and12,155 patients, high Ki67 labeling was correlated with an increasedrisk of relapse and worse survival. The threshold for Ki67 in thesestudies varied between 3.5% and 35%, and the criteria to define thethreshold were diverse.35 In a study aimed at defining a Ki67 cutoff,tumors of 357 patients were profiled by PAM50 and compared withKi67 results; 101 breast cancers were classified as luminal A and 69 asluminal B. The optimal Ki67 level discriminating luminal A from Bwas 13.25%. This cutoff point was rounded up to 14%, and recom-mended as a surrogate marker for luminal cancer classification. Thehigh rate of misclassification, occurring in 25% of the cases,11 is worthnoting. The 14% level was endorsed by the 2011 St Gallen Early BreastCancer Conference consensus panel.12 In 2013, major disagreementsemerged among the panelists; the majority voted for a cutoff of� 20%, whereas others recommended a lower, local laboratory–specific cutoff or the use of multigene expression assay.13

PgR status has also been used to define luminal B cancer. PgRnegativity is a marker of worse prognosis in luminal cancers36,37; inbreast tumors assessed as ER positive and having Ki67 � 14%, loss ofPgR was identified as an adverse prognostic factor (relapse: hazard

ratio [HR], 1.96; 95% CI, 1.44 to 2.68).38 In another study, luminal Bcancers classified as ER positive, HER2 negative, Ki67 � 14%, andPgR � 20% had worse prognosis than tumors with PgR � 20%.6

Despite the multiple attempts to establish a clinically useful,IHC-based luminal B surrogate marker, efforts so far have failed toaccurately reproduce the PAM50 classification39 or to define a goldstandard, which in large part stems from the controversies about themost reliable way to quantify proliferation.

Prognostic Signatures Within Intrinsic Subtypes

Gene expression signatures are used to provide prognostic infor-mation beyond that provided by the clinicopathologic parameters andare particularly useful in the discrimination of luminal breast cancers.Most luminal A tumors are classified at low genomic risk, whereasluminal B cancers are often classified at high genomic risk40-42 (Table2). Several gene expression profiling (GEP) prognostic signatures havebeen developed with little overlap between their constituent genes.Despite this, a significant overlap in their performance is observed.40

In a meta-analysis of publicly available breast cancer gene expressionand clinical data, gene coexpression modules related to proliferation,ER, and HER2 were used to evaluate the role of constituent genes. Thestudy identified 524 genes associated with survival; of these, 71% werestrongly coexpressed with proliferation, 26% with ER, and 2.2% withHER2,9 revealing the importance of proliferation genes as a commondriving force behind signature performance.

Actually, these multigene prognosticators do not really identifydifferent risk groups within intrinsic subtypes; they rather dividebreast tumors according to their proliferation pattern. Because HER2-enriched and basal-like cancers are almost all high proliferative can-cers, GEP prognostic signatures add little information in thesesubtypes. However, in luminal breast cancers, the signatures are ableto identify low and high proliferative groups, roughly correlated withthe luminal A and luminal B subtypes.9,40,43

Table 2. Correlation Between Intrinsic Subtype Classification by PAM50 andOncotypeDX and MammaPrint Prognostic Signatures

PAM50Classification

TotalPatients

OncotypeDX MammaPrint

ClassificationNo. of

Patients ClassificationNo. of

Patients

Luminal A 121Low 68 Good 87Intermediate 13High 40 Poor 34

Luminal B 55Low 2 Good 9Intermediate 2High 51 Poor 46

HER2 positive/ER negative

18Low 1 Good 2Intermediate 0High 17 Poor 16

Basal like 7Low 1 Good 0Intermediate 1High 5 Poor 7

NOTE. Data adapted.40

Abbreviations: ER, estrogen receptor; HER2, human epidermal growth factorreceptor 2; PAM, prediction of microarray.

Luminal B Breast Cancer

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A revealing study compared 47 published breast cancer signa-tures with 1,000 randomly generated signatures composed of the samenumber of genes. Not only did � 90% of the random signaturespredict outcome, but 60% of the random signatures also performedbetter than the original ones.44 This strengthens the notion that prog-nostic signatures do not identify specific mechanisms of cancer aggres-siveness.9 Instead, because a large number of transcripts deregulated inbreast cancer correlate with proliferation genes, random signatures arealso proliferation related and able to discriminate prognosis.

CLINICAL BEHAVIOR

Luminal B breast cancer is recognized as having an aggressive clinicalbehavior, with prognosis similar to that of HER2-enriched and basal-like groups, whereas luminal A breast cancer is identified as having amore favorable clinical outcome.2-4,8 Luminal B cancers show in-creased relapse rates in the first 5 years after diagnosis, decreasing overtime, and a metastatic dissemination time pattern similar to basal-likeand HER2-enriched cancers.45 In a series of 831 untreated node-negative patients, the HR for early metastasis (� 5 years) was 2.86; forlate metastasis (� 5 years), it was 0.65 in comparison with luminalA.45,46 Moreover, luminal B cancers have a distinctive pattern of sitedissemination, with predilection for bone and to a lesser degree forlung. This is in contrast with luminal A breast cancer, for which boneis also the principal metastatic site, although it shows a low frequencyof metastasis to other sites.47

LUMINAL B AND BENEFIT OF CHEMOTHERAPY

Most luminal B cancers are classified as having a high OncotypeDXrecurrence score (RS).40 The NSABP (National Surgical AdjuvantBreast and Bowel Project) B-20 study assessed node-negative ER-positive patients randomly assigned to tamoxifen versus tamoxifen

plus chemotherapy. Patients with high RS (� 31) derived large benefitfrom chemotherapy (recurrence: HR, 0.26; 95% CI, 0.13 to 0.53), witha mean absolute decrease in distant recurrence rate of 27.6%.48 In theSWOG (Southwest Oncology Group) 8814 trial, which randomlyassigned node-positive ER-positive patients to tamoxifen versus ta-moxifen followed by chemotherapy, a chemotherapy benefit was alsoobserved in patients with high RS (� 31; disease-free survival [DFS]:HR, 0.59; 95% CI, 0.35 to 1.01), whereas no improvement was seen inpatients with low RS (� 18).49 However, patients with high expressionof ER did not benefit from addition of chemotherapy, irrespective ofOncotypeDX results. RS was also positively correlated with the likeli-hood of pathologic complete response (pCR; P � .005), indicatinggreater sensitivity to neoadjuvant chemotherapy.50

In neoadjuvant studies, luminal tumors exhibit lower pCR ratesthan HER2-enriched and triple-negative breast cancers51-58 (Table 3).When comparing the luminal tumors, results are conflicting; higherpCR rates in luminal B than in luminal A cancers were not homoge-neously observed.53,58 Nonetheless, neoadjuvant chemotherapyseems effective in reducing tumor volume in luminal B cancers (Table3). Tumors with high prognostic signature values, according to severalGEP classifiers, are associated with a higher probability of pCR.59

The latest update from the Early Breast Cancer Trialists’ Collab-orative Group (EBCTCG) was unable to ascertain chemosensitivity inluminal tumors or benefit from specific chemotherapies, because oflimited data to define luminal tumors. Poor differentiation, defined bylocal pathologists, was not predictive of chemosensitivity in patientswith ER-positive disease.60 The St Gallen consensus panel consideredthat both anthracyclines and taxanes should be included in the chem-otherapy regimens for luminal B breast cancer.12

Three prospective randomized trials—MINDACT (Microarray inNode-Negative Disease May Avoid Chemotherapy; NCT00433589),TAILORx (Trial Assigning Individualized Options for Treatment;NCT00310180), and RxPONDER (Treatment for Positive Node,

Table 3. pCR After Neoadjuvant Chemotherapy in Luminal B Breast Cancer

TrialNo. of

Patients ChemotherapyMethod of Luminal

B ClassificationTechnique Used for

Classification

pCR (%)

LuminalA

LuminalB

HER2Positive

BasalLike

Rouzier et al51 82 P-FAC Molecular Intrinsic gene set andhierarchic clustering

7� 7� 45 45

Carey et al52 107 AC plus taxane IHC ER or PgR positive, HER2positive

0 15 36 27

de Ronde et al53 191 Dose-dense AC or DX Molecular Intrinsic gene set andhierarchic clustering

1 4 54 67

Esserman et al54 144 AC-P Molecular Intrinsic gene set andhierarchic clustering

5 13 55 34

Bhargava et al55 359 Anthracycline or taxane IHC ER positive, PgR positive,HER2 negative

1.8 1.4 33.3 30.4

Lv et al56 104 FEC, DC, or DE IHC ER positive, PgR positive,HER2 negative, Ki67� 14%

0 8.7 22.2 24.4

Straver et al57 167 AC or AD IHC and molecular ER positive, HER2 negative,70-gene MammaPrint

3� 3� 32 34

Lips et al58 211 Dose-dense AC or DX Molecular PAM50 1.3 4.4 — —

Abbreviations: AC, doxorubicin plus cyclophosphamide; AC-P, doxorubicin, cyclophosphamide, and paclitaxel; AD, doxorubicin plus docetaxel; DC, docetaxel pluscarboplatin; DE, docetaxel plus epirubicin; DX, docetaxel plus capecitabine; ER, estrogen receptor; FEC, fluorouracil, epirubicin, and cyclophosphamide; HER2,human epidermal growth factor receptor 2; IHC, immunohistochemistry; PAM, prediction of microarray; pCR, pathologic complete response; P-FAC, paclitaxel,fluorouracil, doxorubicin, and cyclophosphamide; PgR, progesterone receptor.

�Luminal A and B not discriminated.

Ades et al




Endocrine Responsive Breast Cancer; NCT01272037)—are testingthe usefulness of gene signatures in predicting benefit from adju-vant chemotherapy in patients with ER-positive breast cancer.61-63

Results are expected between 2015 and 2017.

LUMINAL B AND BENEFIT OF ENDOCRINE THERAPY

The supporting evidence for the relatively lower benefit of endocrinetherapy in the luminal B subtype comes from few studies, which, aswas the case for chemotherapy, classify luminal tumors through sur-rogate markers. An EBCTCG meta-analysis evaluating patients en-rolled onto endocrine therapy trials showed small benefits withtamoxifen in patients with low ER levels.64 In the BIG (Breast Interna-tional Group) 1-98 trial, which assigned 8,010 patients to four treat-ment arms comparing different sequential administrations ofletrozole and tamoxifen, patients with lower ER levels had worse DFSthan those with high ER levels.65 Patients receiving tamoxifen or noadjuvant systemic treatment with an ER-positive/PgR-negative phe-notype had better outcomes than their ER-negative/PgR-negativecounterparts but worse outcomes than those with the ER-positive/PgR-positive phenotype.36 Nevertheless, this observation was notconfirmed in either in the NSABP B-14 study66 or in the IES (Inter-group Exemestane Study) comparing exemestane versus tamoxifen.67

The ATAC (Arimidex, Tamoxifen, Alone or in Combination)trial evaluated 5 years of anastrozole, tamoxifen, or their combinationin postmenopausal women; high OncotypeDX RS (� 31) was associ-ated with disease relapse when compared with low RS (� 18).68 A78-gene signature69 showed results similar to RS in evaluating thetreatment prognosis in tamoxifen-naive patients with metastaticbreast cancer.70 However, in the BCIRG (Breast Cancer InternationalResearch Group) study, comparing the combination of docetaxel orfluorouracil with doxorubicin and cyclophosphamide, both the lumi-nal A and luminal B subtypes showed significant responses to tamox-ifen (luminal B: HR, 0.44; 95% CI, 0.32 to 0.61; P � .001; luminal A:HR, 0.15; 95% CI, 0.07 to 0.33; P � .001).71

In contrast to the previously discussed markers that provide onlyprognostic information, dynamic changes in the expression of Ki67were able to predict outcome in luminal breast cancer treated withendocrine therapy. In the IMPACT (Immediate Preoperative Anas-trozole, Tamoxifen, or Combined With Tamoxifen) trial, patientswith higher Ki67 expression after 2 weeks of endocrine therapy hadlower recurrence-free survival (P � .004).72 In the P024 neoadjuvantendocrine therapy trial, baseline Ki67 was associated with higher riskof relapse (HR, 1.3; 95% CI, 1.05 to 1.50; P � .01).73 Luminal B and Atumors showed similar proportional falls in Ki67 in a neoadjuvant trialwith anastrozole; however, patients with luminal B cancers had apoorer outcome, explained by the higher baseline levels of Ki67.74

Using clinicopathologic (tumor size, node status, treatment re-sponse) and IHC information (ER status, Ki67, histologic grade), apreoperative endocrine prognostic index (PEPI) was developed froma cohort of patients in the P024 trial. This score was independentlyvalidated in the IMPACT trial, being able to correctly predict relapse-free survival.75 The PEPI score was also evaluated in the ACOSOG(American College of Surgeons Oncology Group) Z1031 trial check-ing for the effect of neoadjuvant anastrozole, letrozole, and exemes-tane in postmenopausal patients. Luminal B cancers had higher Ki67at baseline (P � .001), post–aromatase inhibitor treatment (P � .001),

and greater change in Ki67 (P � .001). No clinically relevant responsedifferences were found between treatment results among luminaltumors (HR, 1.67; 95% CI, 0.96 to 2.9; P � .07), nor in the rate ofbreast-conserving surgery, suggesting similar clinical efficacy (HR,0.75; 95% CI, 0.29 to 1.93; P � .54) despite the better PEPI scoreamong the luminal A group (27.1% v 10.7%; P � .004).76 In conclu-sion, both luminal A and B tumors derive benefit from endocrinetreatment, although the magnitude of benefit is larger in luminal A.

In the ATAC trial, ER-positive/PgR-negative patients obtainedlarger relative benefit from anastrozole than from tamoxifen (HR,0.42; 95% CI, 0.31 to 0.61), whereas ER-positive/PgR-positive patientsshowed no differences (HR, 0.84; 95% CI, 0.69 to 1.02).77 The relativereduction of risk was similar for anastrozole and tamoxifen amongpatients with different OncotypeDX RS values.68 In BIG 1-98, highKi67 predicted greater efficacy of letrozole over tamoxifen (HR, 0.53;95% CI, 0.39 to 0.72), whereas low Ki67 indicated no difference (HR,0.81; 95% CI, 0.56 to 1.15; P � .09).78 Nevertheless, using the surro-gate luminal B definition proposed by Cheang et al,11 no differencewas seen between tamoxifen and letrozole.78

In a neoadjuvant study randomly assigning postmenopausal ER-positive patients to letrozole or tamoxifen, letrozole was more effectivein tumors overexpressing epidermal growth factor receptor or HER2(clinical response, 88% v 21%; P � .001).79 In IMPACT, the responserate for tamoxifen was 22%, whereas for anastrozole, it was 58% inpatients presenting HER2 amplification or overexpression (HR, 4.9;95% CI, 0.53 to 63.22; P � .18).80 The same trend was observed in theBIG 1-98 trial; patients receiving letrozole had better DFS comparedwith those receiving sequential administrations of tamoxifen andletrozole or tamoxifen alone (P � .58 and .87, respectively).78 In ameta-analysis in patients with advanced ER-positive breast cancer,HER2-positive overexpression was identified as increasing the riskof disease recurrence (relative risk [RR], 1.42; 95% CI, 1.32 to 1.52;P � .001), independently from the type of hormone treatment(tamoxifen: RR, 1.33; 95% CI, 1.20 to 1.48; P � .001; other agents:RR, 1.49, 95% CI; 1.36 to 1.64), suggesting no additional benefitfrom aromatase inhibitors.81

Although some studies reported better outcomes with aromataseinhibitors over tamoxifen, these results were not homogeneously ob-served. These divergences do not allow the drawing of definitive con-clusions about the best endocrine agent in patients with luminal Bcancer; both choices are acceptable.

DRUG DEVELOPMENT IN LUMINAL B BREAST CANCER

Many of the mutated genes found in breast cancer occur at a lowfrequency, rendering their therapeutic exploitation difficult. This re-quests extensive molecular screening efforts to identify these pa-tients.82 In addition, functional characterization of these molecularevents is needed before they are pursued as therapeutic targets. Find-ings from high-dimension, clinically and molecularly annotatedbreast cancer data sets and functional genomic preclinical studies canlead to the development of solid hypotheses on predictive biomarkers,which can be tested prospectively through genotype-driven clinicaltrials.83 Figure 2 shows an overview of the signaling pathways underblockade with targeted compounds in luminal breast cancers.





Phosphatidylinositol-3-Kinase/AKT/Mammalian Target

of Rapamycin Signaling Pathway

In luminal breast cancer, phosphatidylinositol-3-kinase (PI3K)activation is implicated in de novo and acquired endocrineresistance.75,84-88 Despite lower frequency of PIK3CA mutations,14

luminal B cancers have higher PI3K activation than luminal A.89

PIK3CA mutations do not seem to be associated with PI3K pathwayactivation in early-stage ER-positive breast cancer; a PIK3CA muta-tion gene signature was identified as a positive prognosticator in thissetting.90 This gene signature indicates a phenotype of low mamma-lian target of rapamycin (mTOR) C1 signaling, suggesting thatPIK3CA mutations might act as weak PI3K pathway activators.PIK3CA mutations were associated with sensitivity to tamoxifen invitro,90 but it remains to be shown whether the strategy of combiningPI3K blocking with endocrine therapy will improve clinical outcome.

The most advanced compounds in clinical development arerapamycin analogs called mTOR inhibitors. The combination ofeverolimus and letrozole has been tested in the metastatic91 and neo-adjuvant settings,92 achieving positive results. The combination ofeverolimus with tamoxifen led to prolongation of progression-freesurvival (PFS; 8.6 v 4.5 months; P � .002) and overall survival (OS; notreached v 24.4 months; P � .01) in patients with aromatase inhibitor–pretreated metastatic disease.93 The BOLERO-2 (Breast Cancer Trialsfor Oral Everolimus) study randomly assigned patients with meta-static disease, pretreated with nonsteroidal aromatase inhibitors, toreceive everolimus combined with exemestane versus exemestane andplacebo.94 The study showed prolongation of PFS for the everolimusplus exemestane arm (PFS, 10.6 v 4.1 months; HR, 0.36; 95% CI, 0.27to 0.47; P � .001); OS data are still immature.94

No predictive biomarkers were identified to guide patient selec-tion for PI3K-blocking agents.95 In BOLERO-2, the four most fre-

quently mutated genes were PIK3CA (48%), CCND1 (31%), TP53(23%), and FGFR1 (18%), with the benefit of everolimus being similaracross these subgroups. Patients with zero or one genetic alteration inPI3K or fibroblast growth factor receptor (FGFR) pathways, or withCCND1 mutations, had increased benefit from treatment witheverolimus (HR, 0.27; 95% CI, 0.18 to 0.41). However, it should benoted that to date, no analysis has been conducted discriminatingbetween luminal A and B subtypes.

In a recent study, a PIK3CA mutation gene signature was foundto be predictive for Ki67 reduction in patients receiving letrozole witheverolimus in the neoadjuvant setting.96 In the TAMRAD (TamoxifenPlus Everolimus) study, low expression of LKB1, an inhibitor ofmTOR activation, was associated with improved clinical outcomeunder everolimus plus tamoxifen treatment.97

Despite positive results, rapalogs provide suboptimal PI3K path-way inhibition, because they block only mTORC1,98 causing down-regulation of inhibitory feedback mechanisms.99 Emphasis is nowbeing placed on the development of specific PI3K-targeted agents100

(Appendix Table A1, online only).

FGF Signaling Pathway

FGFR1 amplification101 was identified in 16% to 27% of luminalB breast cancers as a mechanism of endocrine resistance102 and asbeing associated with negative prognosis.103 The administration ofE-3810, a nonselective FGF-blocking agent, to 10 patients with meta-static breast cancer resulted in seven partial responses.104 A phase IIclinical trial assessed dovitinib, another nonselective inhibitor, inheavily pretreated patients with FGFR1-amplified luminal metastaticbreast cancer; it produced three partial responses and resulted in stabledisease in nine patients.105 Other studies are assessing the addition of

p85 p110IRS1

PIP3PIP2

S6K

rpS6

MDM2

p53 BAD FasL,Bim

p27Kip1p21

Cyclin D1

GSK3 TSC1/2

Akt mTOR-rictor

PTEN

FOXO

Src

PI3K

4E-BP1

eIF4E

Cell Survival Proliferation Metabolism Protein Synthesis

PDK1

RTKs: FGF-R, IGF-R

RAS

RAF

MEK

ERK

SOS

Grb2

PI3K Inhibitors FGF InhibitorsIGF Inhibitors CDK Inhibitors

Dalotuzumab,BMS-754807,MEDI-573

BKM120, GDC0941,GDC0032, GDC0980, XL765, BYL719, MK2206, AZD2014

PD0332991, LEE011,LY2835219

Dovitinib,AZD4547

mTOR-raptor

Fig 2. Signaling pathways under block-ade with target compounds in luminalbreast cancer. CDK, cycle-dependent ki-nase; FGF, fibroblast growth factor;FGF-R, fibroblast growth factor receptor;IGF, insulin-like growth factor; IGF-R,insulin-like growth factor receptor; mTOR,mammalian target of rapamycin; PI3K,phosphatidylinositol-3-kinase; RTK, recep-tor tyrosine kinase.

Ades et al




FGF-blocking agents to endocrine therapy (Appendix Table A1, on-line only).

Insulin-Like Growth Factor Signaling Pathway

The insulin-like growth factor (IGF) signaling pathway causesactivation of the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK path-ways.106 In luminal cancers, there is IGF-ER crosstalk; estrogen up-regulates IGF-1 and IGF-1 receptor (IGF-1R),107 and IGF-1 signalingboosts the proliferative effect of estrogen108 and is implicated in endo-crine resistance.109 Tamoxifen resistance has been suppressed with ananti–IGF-1R monoclonal antibody,110 and IGF blocking has synergis-tic effect with endocrine treatment in luminal breast cancers.111,112

A randomized phase II study testing ganitumab or placebo withexemestane or fulvestrant in postmenopausal women with metastatichormone receptor–positive disease was unable to demonstrate benefitfrom this strategy (PFS: HR, 1.17; 95% CI, 0.91 to 1.50; P � .44).113

However, a promising approach is the combination of mTOR andIGF inhibitors,114 acting synergistically through the downregulationof IGF-1R–mediated AKT activation induced by mTOR inhibition115

(Appendix Table A1, online only).

Cyclin-Dependent Kinases

Cycle-dependent kinase (CDK) deregulation confers a highlyproliferative cellular phenotype and is also linked to endocrine resis-tance.116 High expression of cyclin D1117,118 and E1119 is associatedwith poor clinical outcome in tamoxifen-treated women. Cyclin E2expression is characteristic of luminal B cancer and correlated withshorter distant metastasis–free survival.120 CCND1 (encoding gene forcyclin D1) amplification is found at higher frequencies in luminal Bcompared with luminal A cancer (58% v 29%).21 Furthermore, theMETABRIC study identified a bad prognosis molecular subtype ofluminal breast cancer, where CCND1 is located.20

PD-0332991, a highly specific CDK4 and CDK6 inhibitor, wasassessed in a phase II study randomly assigning patients with hormonereceptor–positive disease to the combination of PD-0332991 andletrozole versus letrozole alone.121 The combination caused significantprolongation of PFS (median PFS, 18.2 v 5.7 months; HR, 0.35; 95%CI, 0.17 to 0.72; P � .006). A phase III trial is ongoing. The patientpopulation in this trial consisted of two groups: a cohort of 66 patientsselected according to ER and HER2 status, and a cohort of 99 patientsselected according to CCND1 amplification and/or loss of p16. Thebenefit of the addition of PD-0332991 to letrozole occurred mainly inthe biomarker-negative population, in contrast with initial assump-tions (HR, 0.37 and 0.19, respectively). This is partially explained bythe excessively negative prognosis associated with CCND1 amplifica-tion.20 However, it indicates that patients with both luminal A and Bcancers will probably benefit from this strategy.

ADDITIONAL THERAPEUTIC TARGETS

TP53 is one of the most commonly mutated breast cancer genes.Luminal B cancers exhibit higher mutation rates than luminal Acancers (32% v 12%).21 Higher rates of MDM2 gene amplification, aTP53 antagonist, have been observed in luminal B (32%) than inluminal A cancers (14%).21 Thus, luminal B cancers exhibit increasedrates of TP53 pathway loss of function, which has been identified as amediator of endocrine resistance.22 Currently, a new class of targeted

agents functioning as MDM2 antagonists is under clinical assess-ment for patients with advanced solid tumors (NCT01462175,NCT01877382, and NCT01664000), aiming to restore wild-typeTP53 function.

The mixed-lineage leukemia gene MLL3 is also a frequentlymutated gene in luminal cancers.21,22,123 MLL is a family of histonetrimethyltransferases that can regulate gene transcription, includingregulation of ESR1 expression.124 Currently, there is a group of tar-geted agents under clinical development blocking epigenetic regula-tion, with histone deacetylase (HDAC) inhibitors being the mostadvanced class of compounds.125 At the preclinical level, HDAC in-hibitors reactivate gene expression of ESR1 and PGR, whereas whenthey were combined with DNA methyltranferase inhibitors, enhancedESR1 gene expression was induced.126,127 At the clinical level, theresults of a randomized phase II trial assessing exemestane with orwithout entinostat (HDAC inhibitor) in patients with ER-positivemetastatic breast cancer show that the combination significantly pro-longed median PFS (4.3 v 2.3 months; HR, 0.73; P � .055) and OS(28.1 v 19.8 months; HR, 0.59; P � .036).126

DISCUSSION

GEP has changed the way breast cancer is perceived. Rather than anaggressive variant of hormone receptor–positive tumors, the lumi-nal B subtype is a distinct entity. However, the application of GEPof luminal B disease in clinical practice has been limited, largelybecause this classification coincides with traditional characteriza-tion by IHC.

So far, the molecular definition of luminal B disease has also beenof limited use in tailoring breast cancer treatment. Despite the lowersensitivity of luminal B cancers to endocrine treatment, benefit is stillderived from these drugs, and the simple identification of hormonereceptor positivity by IHC is enough to justify its use. Therefore, themain clinical challenge relates to the selection of patients who willbenefit from adjuvant chemotherapy. Proliferation was identified as amain predictive marker for cytotoxic chemotherapy, because it is alsoa major discriminant between luminal B and luminal A subtypes.However, with proliferation being a continuous process, defining lowand high cutoffs poses an important research question. To date, nochemotherapy predictive biomarker has been validated. However, it ishoped that three ongoing prospective randomized trials testing prog-nostic gene signatures—MINDACT, TAILORx, and RxPONDER—will shed light on this issue.

Finally, after little more than a decade since the discovery ofbreast cancer intrinsic subtypes, the characterization of importantpathways and molecular alterations is leading to a new portfolio oftargeted agents for luminal tumors. Genotype-driven trials are alreadya reality in breast cancer research and will continue to contribute to theimprovement of treatments for patients with luminal B breast cancer.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

Although all authors completed the disclosure declaration, the followingauthor(s) and/or an author’s immediate family member(s) indicated afinancial or other interest that is relevant to the subject matter underconsideration in this article. Certain relationships marked with a “U” are





those for which no compensation was received; those relationships markedwith a “C” were compensated. For a detailed description of the disclosurecategories, or for more information about ASCO’s conflict of interest policy,please refer to the Author Disclosure Declaration and the Disclosures ofPotential Conflicts of Interest section in Information for Contributors.Employment or Leadership Position: None Consultant or AdvisoryRole: Martine Piccart, sanofi-aventis (C), Amgen (C), Roche (C),GlaxoSmithKline (C), PharmaMar (C) Stock Ownership: NoneHonoraria: Evandro de Azambuja, Roche, GlaxoSmithKline; MartinePiccart, sanofi-aventis, Amgen, Roche, GlaxoSmithKline, PharmaMarResearch Funding: None Expert Testimony: None Patents, Royalties,

and Licenses: Christos Sotiriou, Gene Expression Grade Index (GGI)Other Remuneration: Evandro de Azambuja, Roche, GlaxoSmithKline

AUTHOR CONTRIBUTIONS

Conception and design: All authorsCollection and assembly of data: All authorsData analysis and interpretation: All authorsManuscript writing: All authorsFinal approval of manuscript: All authors

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Appendix

Table A1. Ongoing Clinical Trials With Targeted Agents in Luminal Breast Cancers

Trial PhaseNo. of

Patients Subtype Setting Treatment Primary End Point Secondary End Points

Pan-PI3K inhibitorsBKM120

NCT01339442 I 22 ER positive Metastatic, HTpretreatment

BKM120 plus fulvestrant MTD, safety PR, CR, SD, PDs, TR

NCT01610284(BELLE-2)

III 1,060 HR positive Metastatic, AIpretreatment

Fulvestrant plus BKM120or placebo

PFS OS, ORR, CBR, AEs,PKs, QOL

NCT01633060(BELLE-3)

III 615 HR positive, HER2negative

Metastatic, mTORinhibitorpretreatment

Fulvestrant plus BKM120or placebo

PFS OS, ORR, CBR, AEs,PKs, QOL

GDC-0941NCT01437566 II 270 ER positive, HER2

negative,PIK3CAmutation

Metastatic, AIpretreatment

GDC-0941 or GDC-0980plus fulvestrant vfulvestrant

PFS, AEs ORR, CBR, durationof OR, PKs

NCT01740336 II 180 ER positive, HER2negative

Metastatic Paclitaxel plus GDC-0941or placebo

PFS Safety, ORR, CBR,duration of OR

Dual PI3K/mTOR inhibitorsBEZ235

NCT01248494 I 72 HR positive Metastatic BEZ235 or BKM120 plusletrozole

MTD PFS, ORR

XL765NCT01082068 I/II 72 HR positive, HER2

negativeMetastatic, AI

pretreatmentXL765 or XL147 plus

letrozoleMTD, safety, PFS at

3 monthsPKs, PDs

GDC-0980NCT01437566 II 270 ER positive, HER2

negative,PIK3CAmutation

Metastatic, AIpretreatment

GDC-0941 or GDC-0980plus fulvestrant vfulvestrant

PFS, AEs ORR, CBR, DOR, PKs

Isoform-selective PI3Kinhibitors

BYL719NCT01791478 I 30 HR positive, HER2

negativeMetastatic, HT

pretreatmentBYL719 plus letrozole MTD CBR, PFS, ORR,

safetyAKT inhibitors

MK2206NCT01344031 I 54 ER positive Metastatic, no

progressionwith AIs orfulvestrant

MK2206 plus anastrozole,fulvestrant, oranastrozole plusfulvestrant

MTD, RPTD Safety, CBR

NCT01776008 II 87 ER positive, HER2negative,PIK3CAmutation

Neoadjuvant MK2206 plus anastrozoleor anastrozole andgoserelin

pCR CRR, RRR, AEs

mTORC1/2 inhibitorsAZD2014

NCT01597388 I 30 ER positive Metastatic AZD2014 plus fulvestrant Safety PKsFGF inhibitors

DovitinibNCT01484041 I/II 36 HR positive, HER2

negativeMetastatic Dovitinib plus AI CBR RPTD, toxicities, PDs,

PFSNCT01528345 II 150 HR positive, HER2


pretreatmentFulvestrant plus dovitinib

or placeboPFS ORR, DOR, OS,

safety, ECOG PSAZD4547

NCT01202591 (GLOW) I/II 120 ER positive,FGFR1polysomy orgeneamplification

Metastatic, HTpretreatment

Fulvestrant plus AZD4547or placebo

Safety, PFS PKs, PDs, ORR, DOR,PFS at 12 weeks,QOL

NCT01791985(RADICAL)

I/II 99 ER positive Metastatic, HTpretreatment

AZD4547 plus anastrozoleor letrozole vexemestane

Safety, tumor changeat 12 weeks

NR

(continued on following page)





Table A1. Ongoing Clinical Trials With Targeted Agents in Luminal Breast Cancers (continued)

Trial PhaseNo. of

Patients Subtype Setting Treatment Primary End Point Secondary End Points

IGF inhibitorsDalotuzumab

NCT01605396 (MK-8669-064 AM3)

II 84 ER positive, Ki67� 15%

Metastatic Dalotuzumab,ridaforolimus, andexemestane vridaforolimus plusexemestane

PFS ORR, OS

NCT00903006 I/II 40 HR positive, HER2negative

Metastatic Fulvestrant v fulvestrant,dalotuzumab, anddasatinib

MTD, TTDP NR

BMS-754807NCT01225172 II 100 HR positive, HER2

negativeMetastatic, AI

pretreatmentBMS-754807 plus

letrozole v BMS-754807

PFS at 24 weeks ORR, DOR, safety,TFR, TR

MEDI-573NCT01446159 I 193 HR positive, HER2


pretreatmentMEDI-573 plus AI v AI Safety, PFS ORR, TTR, DOR, TTP,

change in tumorsize, OS, PKs, PDs,immunogenicity

CDK inhibitorsPD0332991


Neoadjuvant PD0332991 plus letrozole ORR AEs, PRR


Neoadjuvant PD0332991 plusanastrozole

pCR Safety, CRR, RRR,Ki67 at 2 weeks,PKs

NCT01740427 II/III 450 ER positive, HER2negative

Metastatic, firstline

PD0332991 plus letrozolev letrozole

PFS OS, ORR, DOR, DC,QTc interval, Cmin,QOL, TR

Abbreviations: AE, adverse event; BELLE, Buparlisib Breast Cancer Clinical Evaluation; CBR, clinical benefit rate; Cmin, minimum observed plasma troughconcentration; CR, complete response; CRR, clinical response rate; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status;ER, estrogen receptor; FGF, fibroblast growth factor; HER2, human epidermal growth factor receptor 2; HT, hormonal therapy; IGF, insulin growth factor; MTD,maximum-tolerated dose; mTOR, mammalian target of rapamycin; NR, not reported; OR, objective response; ORR, objective response rate; OS, overall survival;pCR, pathologic complete response; PD, pharmacodynamic; PI3K, phosphatidylinositol-3-kinase; PK, pharmacokinetic; PR, partial response; PRR, pathologicresponse rate; QOL, quality of life; RPTD, recommended phase II dose; RRR, radiologic response rate; SD, stable disease; TFR, treatment failure rate; TR,translational research; TTDP, time to disease progression; TTP, time to progression; TTR, time to response.

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