The value of platinum agents as neoadjuvant chemotherapy

关于三阴性乳腺癌

BreastCancerResTreat(2014)144:223–232DOI10.1007/s10549-014-2876-z

REVIEW

Thevalueofplatinumagentsasneoadjuvantchemotherapyintriple-negativebreastcancers:asystematicreviewandmeta-analysis

FaustoPetrelli?AndreaCoinu?KarenBorgonovo?MaryCabiddu?MaraGhilardi?VeronicaLonati?SandroBarni

Received:12January2014/Accepted:7February2014/Publishedonline:21February2014ÓSpringerScience+BusinessMediaNewYork2014

AbstractPlatinumagentssuchascisplatinandcarbo-platinareDNA-damagingagentswithactivityinbreastcancer(BC),particularlyinthetriplenegative(TN)sub-group.Theutilityofplatinumagents,inadditiontostan-dardneoadjuvantchemotherapy(NAC),iscontroversial.ToassesstheactivityofplatinumagentsinpatientswithTNBCtreatedwithNAC,weperformedasystematicreviewandmeta-analysisofallpublishedstudies.AsearchofPubMed,EMBASE,theWebofScience,SCOPUS,andtheCochraneCentralRegisterofControlledTrialswasperformedtoidentifystudiesthatinvestigatedplatinum-basedNACinpatientswithTNBC.Randomeffectmodelswereadoptedtoestimatethesummaryriskratio(RR),andthepublicationbiaswasevaluatedusingafunnelplotandEgger’sregressionasymmetrytest.Theprimaryendpointswerethepooledrateofthepathologiccompleteresponse(pCR)andtheRRtoobtainapCRinpatientstreatedversusnottreatedwithNACcontainingplatinumagents.28studieswereincluded(sixrandomizedcontrolledtrialsand22retrospectiveorprospectivestudies)foratotalof1,598TNBCpatients.Overall,thepooledrateofpCRinpatientstreatedwithplatinum-basedNACwas45%.Inrandom-izedtrials,NACcontainingcisplatinorcarboplatinsig-ni?cantlyincreasedtherateofpCRcomparedwithnonplatinumagents(RR=1.45,95%CI1.25–1.68;P\http://wendang.chazidian.comparedwithnon-TN,TNBCswereasso-ciatedwithathreefoldincreaseinthepCRratewhentreatedwithplatinum-basedNAC(RR3.32,95%CI

2.39–4.61;P\0.0001).Inconclusion,pCRratesincreasesigni?cantlywiththeadditionofcisplatinorcarboplatininTNBCcomparedwithNACcontainingnoplatinumdrugs.TNstatusisapredictorofbene?tfromplatinum-basedNAC.

KeywordsCisplatinÁCarboplatinÁNeoadjuvant

chemotherapyÁTriplenegativeÁBreastcancerÁPathologiccompleteresponse

Introduction

Triple-negativebreastcancer(TNBC),whichlacksexpressionofestrogenandprogesteronereceptors(ERandPgR)andhumanepidermalreceptor2(HER2),isassoci-atedwithadismalprognosisdespiterespondingremark-ablywelltoanthracyclineandtaxane-basedneoadjuvantchemotherapy(NAC).Inparticular,standardpolychemo-therapyresultsinpathologiccompleteresponse(pCR)inmorethan20%ofpatients[1,2],andthisresponseisconsideredasurrogateofincreasedsurvivalcomparedwithpatientswithoutapCR[3].Inameta-analysisof12NACstudies,TNBCwasassociatedwithapooledpCR(theabsenceofinvasiveandinsitucancerinthebreastandaxilla)of34%[4],andpCRwasassociatedwithsigni?-cantlyimprovedevent-freesurvivalcomparedwithnopCRinTNBCpatients(HR=0.24,P\0.001).Inthismeta-analysis,theimprovementinthepCRoddsratio,however,didnotcorrelatewithanimprovementinevent-freeandoverallsurvival(OS).

ThereisaninterestinDNA-damagingagentssuchasplatinumdrugs(cisplatin[CDDP]andcarboplatin[CBDCA])inTNBC.ThisinterestderivesfromthefactthatalmostallTNBCsbelongtothemolecularsubgroupof

F.Petrelli(&)ÁA.CoinuÁK.BorgonovoÁM.CabidduÁM.GhilardiÁV.LonatiÁS.Barni

DivisionofMedicalOncology,DepartmentofMedical

Oncology,AziendaOspedalieraTreviglio,PiazzaleOspedale1,24047Treviglio,BG,Italye-mail:faupe@libero.it

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224basal-likeBCsaccordingtothePerouclassi?cation[5].Thesetumorsexhibithigh-proliferationratesandaresel-domassociatedwithBRCA1mutations.AhighproportionofTNpatientsexhibitBRCA1functionalalterations(BRCAness-likestatus),implyingthatthesetumorsarehighlysensitivetointerstrandcross-linkingagentslikeplatinumsalts.Inaregistryof6,903patients,10outof12patientswithBRCA1mutationsobtainedapCRwhentreatedwithsingle-agentCDDP[6].Similarly,among28TNBCpatientstreatedwithfourcyclesofneoadjuvantCDDP,22%achievedapCR,includingtwoBRCA-mutatedpatients[7].

Todate,however,norandomizedphaseIIIstudyhasevaluatedwhethertheadditionofplatinumsaltstostandardNACincludinganthracyclineandtaxanesiscapableofimprovingtreatmentef?cacyinthesepatients.In2013,atleasttwophaseIIrandomizedtrialsinsteadcon?rmedthebene?tofaddingCBDCAtoNACinTNBC.InaCALGBtrial,theadditionofCBDCAattheAUCof6increasedthepCRratesfrom28to42%instageII-IIIBCs[8].Simi-larly,inaGermanstudy,theintroductionofweeklyCBDCA(AUC1.5–2)tonon-pegylatedliposomaldoxo-rubicin,weeklypaclitaxel,andbevacizumabboostedthepCRratefrom37.9to58.7%[9].

Here,wepresentameta-analysisevaluatingtheasso-ciationofTNhistologywithpCRafterplatinum-basedNACforoperableorlocallyadvancedBCaswellasthebene?toftheadditionofplatinumagentstoconventionalNAC.Furthermore,theactivityofplatinumsaltsinTNBCcomparedwithnon-TNBCwascalculated.

Methods

Searchstrategyandselectionofstudies

PubMed,theWebofScience,EMBASE,SCOPUS,andtheCochraneRegisterofControlledTrials(CENTRAL)weresearchedforstudies(includingconferenceabstracts)evalu-atingthepCRafterplatinum-basedNACinTNBCfrom1990toDecember20th,2013.Weusedthemedicalsubjectheadingterms(‘‘BreastNeoplasms’’[Mesh]AND((‘‘cis-platin’’[MeSHTerms]OR‘‘cisplatin’’[AllFields])OR(‘‘carboplatin’’[MeSHTerms]OR‘‘carboplatin’’[AllFields])OR(‘‘platinum’’[MeSHTerms]OR‘‘platinum’’[AllFields]))AND((‘‘neoadjuvanttherapy’’[MeSHTerms]OR(‘‘neoad-juvant’’[AllFields]AND‘‘therapy’’[AllFields])OR(‘‘neo-adjuvanttherapy’’[AllFields]OR‘‘neoadjuvant’’[AllFields])ORpreoperative[AllFields]ORprimary[AllFields]))andlimitedtheresultstoEnglishlanguagestudies.EligibilitycriteriaincludedrandomizedornonrandomizedstudiesreportingtheproportionofpCRs(bothinbreastandaxilla;ypT0N0)inTNBCs(de?nedasBCwithERandPgR

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BreastCancerResTreat(2014)144:223–232

expressionin\1%ofcellsandHER2-negativestatus)treatedwithCDDPorCBDCA-containingNAC,possiblyincludingataxaneand/orananthracycline.Studiesincludinglessthan10patientsaswellasstudiesevaluatinghigh-dosechemother-apy,phaseIstudies,targetedtherapiesalone,unconventionalcombinations(e.g.,combinationsnotapprovedforadvancedorlocalizeddisease),ortherapiesinvolvingplatinumassingleagentalonewereexcludedfromthisanalysis.Inaddition,thereferencelistsoftheretrievedarticleswerecheckedtoidentifyadditionalrelevantpublications.The‘‘RelatedArticles’’functionwasalsousedtoimprovethesearch.Thestudyselection,dataextraction,anddataentrywereperformedby2authorsindependently(FPandAC),anddiscrepanciesbetweenthetworeviewerswereresolvedbydiscussionandconsensus.The?nalresultswerereviewedbytheseniorinvestigator(SB).Dataextraction

Thefollowinginformationwasextractedfromeacharticle:(1)basicinformation,includingtheyearofpublicationandthe?rstauthor’sname;(2)studyinformation,includingsamplesize,studydesign,numberofTNBC,andnon-TNBCpatients;(3)treatmentinformation,includingneo-adjuvantschedulesandnumberofcycles;(4)outcomesofinterest,suchasthepercentageornumberofpCRsintheTNBCpopulationandthepercentage(ornumber)ofpCRsinthecontrolarmsforrandomizedstudies(NACwithoutplatinumagents);(5)percentage(ornumber)ofpCRsandtheORRinnon-TNBCtreatedwithplatinumagents;and(6)overallclinicalRR(ORR),rateornumberofbreast-conservingsurgery(BCS)intheTNBCpopulation,long-termDFSandOSinTNBCsubgroup,andDFSandOSinTNBCpatientswhoobtainedapCRwithplatinum-basedNAC.

Statisticalanalysis

BoththepooledpCRratesinTNBCstreatedwithplatinum-basedNACandthecomparisonofthepCRratesofplatinum-versusnonplatinum-basedNACinTNBCpatients(forran-domizedstudies)weretheprimaryendpoints.SecondaryendpointswerethecomparisonofpCRsinTNBCsandnon-TNBCstreatedwithplatinumagents,ORR,rateofBCS,DFS,andOS(forbothalltreatedpatientsandpCR-onlypopulation)inTNBCstreatedwithplatinum-basedNAC.ThepCRandothercomparisonsintheTNBCandnon-TNBCsubgroupswerecalculatedusingthemethodfordichotomousdata(assessmentofriskratio[RR];95%CI).Boththe?xed-effectmodel/Mantel–HaenszelmethodwithminimalheterogeneityinthevariablesamongstudiesandtheDerSimonian–Lairdmethod(randomeffectsmodel)whentherewassigni?cantheterogeneitywereused[10].TheCochran’sQtest,witha

关于三阴性乳腺癌

–

50/49.5

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90/95.6

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–

–

–

–

41

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17

–

–

CS)DFS/OS(%)DFS/OSpCRvs.nopCRpts(%)MedianFU(months)

BreastCancerResTreat(2014)144:223–232

71.1vs.52.8/70.1vs.72.5

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b

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226

Table1continued

ScheduleNcycles

pCRTNBCswithplatinum(%)

17–––

40

33.3

60

50–2782–91d––27.5–––

–

––85–––

–

–

–

–

–

–9100–94d–

pCRTNBCswithoutplatinum(%)pCRnotTNBCswithplatinum(%)ORRsTNBCswithvs.withoutplatinum(%)BCS(%)DFS/OS(%)DFS/OSpCRvs.nopCRpts(%)MedianFU(months)

123

EPId1q21?CDDPd1q21?5-FUcid1–2196

NR

ACorFEC100d1q2194?CDDP?3wDOCd1q2194

CBDCAAUC6?wPAC

GEMd1,8q21?ADMd1or2q2194?GEMd1,8q21?CDDPd1q2194

DOCd1q14?CBDCAAUC6d2q1494

GEMd1,8q21?CBDCAAUC5d1q2193

CBDCAAUC6d1q28?w-NAB-PACd1,8,15q2894?ACd1q1494?bevacizumab10mg/kgd1q1496

wADM?oralCTX912weeks?wPAC?wCBDCAAUC2912weeks

CBDCAAUC2d1,8q21?GEMd1,8q21?iniparibd1,4,8,11q2194

w-Nab-PACd1,815q2896?CBDCAAUC2d1,8,15q2896?bevacizumab10mg/kgd1q1595650(3/6)–434–

2440––

853–––314.2–0–444–11.9–

3NR8NR6

34

–

–

–

–

–

–

–

–

.38

–

–

82––––

–

0–

––

––

––

––

–

Author/yearTypeofstudy

N°TN/notTNBCs

Sirohi/2008

Retrospectiveseries

6/54

Fei/2012

Retrospectiveseries

124

Rahal/2010

Prospectiveseries

18

Shinde/2012

Retrospectiveseries

10/29

Julka/2008Phase214/22

Roy/2013Phase29/48

Ithimakin/2013

Phase27/33

Snider/2013

Prospectiveseries

42

Tiley/2012Phase217/0

Telli/2011Phase249/0

Mrozek/2010Phase211/19

Nnumber,wweekly,d=day,–notavailable,TNBCtriple-negativebreastcancer,pCRpathologiccompleteresponseinbreastandaxilla,NRnotreported,BCSbreast-conservingsurgery,ORRoverallresponserate,DFSdiseasefreesurvival,OSoverallsurvival,FUfollowup,CBDCAcarboplatin,CDDPcisplatin,PACpaclitaxel,DOCdocetexel,EPIepirubicin,5-FU5-?uorouracil,NPLDnon-pegylatedlyposomialdoxorubicin,ADMadriamycin,AUCareaunderthecurve,ACadriamycin?cyclophosphamide,ECepirubicin?cyclophospamide,FEC5-?uorouracil?epirubicin100mg/m2?cyclophosphamide,NAB-PACnab-paclitaxel,GEMgemcitabine,CTXcyclophosphamide

a

HER2positivepatientsreceivedconcomitanttrastuzumab?lapatinib

b

Carboplatinversusnocarboplatinarms

c

Withandwithoutanthracyclines

BreastCancerResTreat(2014)144:223–232

d

Nottriple-negativepatients

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BreastCancerResTreat(2014)144:223–232227

Fig.1Selectionofpublicationsincludedinthemeta-analysis

prede?nedsigni?cancePthresholdof0.1,wasusedtoassessthestatisticalheterogeneityamongthestudies.Theassump-tionofhomogeneitywasconsideredinvalidforPvalueslessthan0.1;inthiscase,summaryestimateswerereportedfromtherandomeffectmodels.Subgroupanalysiswasperformedaccordingtotheplatinumagent(CDDPvs.CBDCA)andchemotherapyschedule(platinum?taxanevs.plati-num?taxane?anthracycline)(Table1).

Finally,potentialpublicationbiasesfortheprimaryendpointswereevaluatedusingfunnelplots,whichasses-sedtherelativesymmetryoftheindividualstudyestimatesaroundtheoverallestimate,followedbytheBegg’sandEgger’stests.Atwo-tailedPvalue\0.05withoutadjustmentformultiplicitywasconsideredstatisticallysigni?cant.Theleave-one-outprocedurewasalsoper-formedfortheprimaryendpointanalysis.The‘‘fail-safeN’’wascalculated,whichisde?nedasthenumberofadditional‘‘negative’’studies(studiesinwhichtheinter-ventioneffectwaszero)requiredtoincreasethePvalueforthemeta-analysistoabove0.05.

Atwo-tailedPvalue\0.05wasconsideredstatisticallysigni?cant,andtheresultsofthemeta-analysiswerereportedasclassicforestplots(fortheprimaryendpoints).AllstatisticalanalyseswereperformedusingNCSS2007software(version07.1.21releasedJune1,2011)andComprehensiveMeta-Analysissoftware(version2.2.064;July27,

2011).

Event Lower Upper ratelimitlimitZ-Valuep-Value

chen 2010

frasci 2009kim 2013torrisi 2008

yerushalmi 2009von minckwitz 2013zhang 2013sikov 2013

sikov beva arm 2013

mayer everolimus arm 2013mayer 2013kern 2013

diaz-correa 2011alba 2012hurley 2013chang 2010sinclair 2012

sinclair anthra-arm 2012sikov 2009sirohi 2008fei 2012rahal 2010shinde 2012julka 2008rugo 2013roy 2013

ithimakin 2013snider 2013tiley 2012telli 2011mrozek 2010

0,3300,6200,4200,4000,3500,5870,3860,4240,5000,3500,4200,5500,8400,3000,3100,5460,2700,8100,6700,1700,4030,3330,6000,5000,5200,4400,1420,5300,4000,3400,5000,4500,1740,5050,2860,2430,1770,5090,2590,3270,4000,2550,2750,3640,6200,1870,2400,2680,0890,5500,3790,0240,3210,1580,2970,2600,3660,1740,0190,3550,2020,2220,1680,4010,5360,7230,5670,5810,5740,6610,5310,5270,6000,4590,5800,7230,9440,4440,3900,7980,5830,9370,8710,6330,4920,5710,8420,7400,6700,7460,5800,6980,6380,4820,8320,499-1,6312,044-1,069-1,088-1,3202,176-1,549-1,4520,000-2,674-0,9820,5192,786-2,662-4,4410,305-1,4652,2751,154-1,459-2,142-1,3890,6280,0000,250-0,359-1,6610,328-0,819-2,1990,000-1,9830,1030,0410,2850,2770,1870,0300,1210,1461,0000,0080,3260,6040,0050,0080,0000,7610,1430,0230,2490,1450,0320,1650,5301,0000,8030,7190,0970,7430,4130,0281,0000,047

-1,00

-0,50

0,00

0,50

1,00

Fig.2ThepooledORRforplatinum-basedneoadjuvantchemotherapyintriplenegativebreastcancer

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