TargetedDrugTherapyAndImmunotherapyFor BreastCancer
AccordingtotheWorldHealthOrganization,breastcanceristhemost commoncancerworldwide,surpassingevenlungcancer.Accordingtothe lateststatisticsin2020,therewereapproximately23millionnewbreast cancerpatientsworldwidethatyear,resultingin685,000deaths.Andbreast cancerisnotlimitedtowomen,inrarecases,mencangetbreastcancertoo
Withthedevelopmentoftissuetypeandmolecularpathologicaldetection methodsforbreastcancer,thetreatmentofbreastcancerhasgradually steppedintothestageofindividualizedprecisionmedicineAccordingtothe officialinformationoftheAmericanCancerSociety,wereviewed thetargeteddrugtherapyandimmunotherapycurrentlyavailableforthe clinicaltreatmentofbreastcancer
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WhatTargetedTherapiesAreCommonlyUsedInBreastCancer Treatment?
Targeteddrugsworkonbreastcancercellsbyinhibitingcancer-causing targetsthathelpthemgrow,spreadandsurvive,eitherbydestroyingcancer cellsorslowingtheirgrowthTargeteddrugscommonlyusedinthetreatment ofbreastcancercanbedividedintofourcategoriesaccordingtotheirdifferent targets
1.WhatarethetargeteddrugsforHER2?
About15%to20%ofbreastcancercasesareHER2-positivebreastcancer,a proteinthatpromotescancergrowthandspread,sopatientswith HER2-positivebreastcancertendtoprogressfasterandmetastasizemore easilythanthosewithHER2-negativebreastcancer.Sofar,researchershave successfullydevelopedavarietyofdrugsthattargettheHER2protein
MonoclonalAntibodyDrugs
Monoclonalantibodydrugsthatareclinicallyusedtotreatbreastcancer includetrastuzumab,pertuzumab,andmargetuximab,allofwhichtarget HER2.
Trastuzumabcanbeusedasmonotherapyorincombinationwith chemotherapydrugstotreatearlyandadvancedbreastcancerTheUSFDA hasapprovedthecombinationoftrastuzumabandcapecitabinein2020forthe treatmentofpatientswithunresectablelocallyadvancedormetastatic HER2-positivebreastcancerwhohavereceivedoneormoreprioranti-HER2 regimensThedrughasbeenapprovedformarketingbytheNationalMedical ProductsAdministration(NMPA)forthetreatmentofavarietyofsolidtumors, includingHER2-positivebreastcancer
Pertuzumab(Perjeta)hasbeenwidelyusedintheclinicaltreatmentofbreast cancer.In2012,theUSFDAapprovedpertuzumabforthetreatmentofbreast cancer-relatedindications,suchasHER2-positivemetastaticbreastcancer, HER2-positivelocallyadvanced,inflammatoryorearlybreastcancer neoadjuvanttherapy(beforesurgery),andincombinationwithtrastuzumab andchemotherapyasadjunctivetherapyforHER2-positiveearlybreast cancerathighriskofrecurrence(postoperative).Thedrughasalsobeen approvedbytheNationalMedicalProductsAdministration(NMPA)forthe treatmentofHER2-positivebreastcancer.
Comparedwiththeabovetwodrugs,margetuximab(tradename:Margenza) waslaunchedlater,anditsmarketingapplicationinChinaisstillunderreview
HuatengPharma https://ushuatengscicom TheUSFDAapproveditin2020forthetreatmentofpatientswithmetastatic HER2-positivebreastcancerwhohavereceived2anti-HER2treatment regimens(atleastoneofwhichisatreatmentregimenformetastaticdisease)
AntibodyDrugConjugates
Anantibodydrugconjugate(ADC)isamonoclonalantibodylinkedtoa chemotherapydrugTakinganti-HER2ADCdrugsasanexample,antibodies targetingHER2actas"homingsignals"byattachingtotheHER2proteinof cancercells,deliveringchemotherapydrugsdirectlytotumorcellsADC drugscurrentlyusedforthetreatmentofbreastcancerinclude ado-trastuzumabemtansine(Kadcyla)andfam-trastuzumabderuxtecan (tradename:Enhertu).
ThedrugmoleculedesignofTrastuzumabemtansinelinksanantibody targetingHER2withthechemotherapydrugemtansinetofightHER2-positive cancerstogether.Emtansine,apaclitaxel-likedrug,canbeusedbyitselfin patientswithearly-stagebreastcanceraftersurgery,orinpatientswith advancedbreastcancerwhohavealreadybeentreatedwithtrastuzumaband chemotherapyIn2013,theUSFDAapprovedTrastuzumabemtansineand paclitaxelaloneorincombinationforthetreatmentofpatientswith HER2-positivemetastaticbreastcancer,andfurtherexpandeditsindications in2019:fortheadjuvant(post-operative)treatmentofHER2-positive early-stagebreastcancer.Atpresent,Trastuzumabemtansinehasbeen approvedformarketingbytheNMPAfortheindicationofHER2-positivebreast cancer.
ThemolecularstructureofFam-trastuzumabderuxtecanisalsoacombination ofantibodyandchemotherapydrugsThedruglinkedtoFAM-Trastuzumab deruxtecanisasimilardrugofirinotecan.ItwasapprovedbytheUSFDAin 2019forthetreatmentofpatientswithunresectableormetastatic HER2-positivebreastcancerwhohavereceivedmorethantwoprevious anti-HER2therapies,andfurtherexpandedforindicationsin2022:Forthe treatmentofunresectableormetastaticbreastcancerwithlowHER2 expressionandrecurrence6monthsafterpreviouschemotherapyor completionofadjuvanttherapy.Fam-trastuzumabderuxtecan'sapplicationfor marketinginChinaisstillunderreview
KinaseInhibitors
HER2isaproteinwithkinaseactivity.Kinasesareproteinmoleculesinvolved insignaltransmission(suchascellgrowthsignals)incellsForcancercells, blockingtheactivityofkinasesmayinhibittheirgrowth.HER2kinaseinhibitors commonlyusedinthetreatmentofbreastcancermainlyincludeLapatinib
HuatengPharma https://ushuatengscicom (Tykerb),Neratinib(Nerlynx),andtucatinib(Tukysa)Atpresent,both LapatinibandNeratinibhavebeenapprovedformarketinginChina,andthe marketingapplicationoftucatinibisstillunderreview
2.Whatarethetargeteddrugsforhormonereceptorpositivebreast cancerpatients?
Aboutthree-quartersofbreastcancercasesarehormone(estrogenor progesterone)receptor-positivebreastcancer,forwhichhormonetherapyis usuallyeffective,andsometargetedtherapydrugscanmakehormonetherapy evenmoreeffective.Accordingtothedifferenttargets,thetargeteddrugs commonlyusedinthetreatmentofhormonereceptorpositivebreastcancer canbedividedintothreecategories--CDK4/6inhibitors,mTORinhibitorsand PI3Kinhibitors
CDK4/6Inhibitors
CDK4/6inhibitorscommonlyusedintheclinicaltreatmentofbreastcancer includePalbociclib(Ibrance),Ribociclib(Kisqali)and Abemaciclib(Verzenio),whichblockcyclin-dependentkinases(CDKs)in cancercells,specificallytargetingCDK4andCDK6BlockingtheseCDK proteinsinhormone-receptor-positivebreastcancercellshelpspreventcell division,whichinturnslowstumorgrowth
TheabovethreedrugshaveallbeenapprovedbytheUSFDAPalbocicliband AbemaciclibcanbeusedincombinationwithLetrozole,Fulvestrant,or aromataseinhibitorsforthetreatmentofpatientswithhormone receptor-positive,HER2-negativeadvancedormetastaticbreastcancer. Ribociclibisprimarilyusedwitharomataseinhibitorsasinitialendocrine therapyforpremenopausal,postmenopausal,orpostmenopausalpatientswith advancedormetastaticbreastcancerThemoleculartypingofthesepatients washormonereceptorpositiveandHER2negative.Inaddition,Ribociclibcan beusedincombinationwithFulvestrantasafirst/secondlineendocrine therapyforpostmenopausalbreastcancerpatients.
PalbociclibandAbemaciclibhavebeenapprovedinChinaforthetreatmentof hormone-receptor-positive,HER2-negativebreastcancerpatients,andthe marketingapplicationforRibociclibisstillpending
mTORInhibitorDrugs
mTORinhibitorscanspecificallyblockmTORsignaltransduction,aprotein thathelpscellsgrowanddivide.Blockingtheactivityofthisproteincaninhibit tumorprogressionOnemTORinhibitorcommonlyusedinbreastcanceris
HuatengPharma https://ushuatengscicom Everolimus(Afinitor),whichslowstumorgrowthbyblockingtheproductionof newbloodvessels.Intheclinicaltreatmentofbreastcancer,Everolimuscan helphormonedrugsworkbetterTheFDAapprovedEverolimusand exemestanein2012forthetreatmentofpostmenopausalwomenwith hormone-receptor-positive,HER2-negativeadvancedbreastcancerwhowere treatedwithletrozoleoranastrozoleTheNMPAalsoapprovedthemarketing applicationofEverolimusinFebruary2022forthetreatmentofhormone receptorpositive,HER2-negativebreastcancer
PI3KInhibitorDrugs
ThePI3Kproteindrivesthegrowthofcancercells,andblockingitsactivitycan halttumorprogression.ThePI3Kinhibitordrugcommonlyusedinbreast cancertreatmentisAlpelisib(Piqray),whichisusedwithfulvestranttotreat hormonereceptor-positive,HER2-negativeadvancedbreastcancerin postmenopausalwomenwhodevelopPIK3CAgenemutationsduringorafter treatmentwitharomataseinhibitors.AlpelisibreceivedFDAmarketing approvalin2019incombinationwithFulvestrantforthetreatmentofwomen andmenwithhormonereceptor-positive,HER2-negative,advanced postmenopausalormetastaticbreastcancerwithaPIK3CAgenemutation Alpelisib'sapplicationtolistinChinaisstillunderreview
3.TargetedTherapiesForBRCAGeneMutations
CommontargeteddrugsusedclinicallyforbreastcancerpatientswithBRCA mutationsincludeOlaparib(Lynparza)andTalazoparib(Talzenna),bothof whicharePARPinhibitorsThePARPproteinhelpsrepairdamagedDNAin cells,asdotheBRCAgenes(BRCA1andBRCA2),butmutationsineitherof thesegenescandisableDNArepairPARPinhibitorsworkbyblockingthe PARPprotein,whichoftenleadstotheaccumulationofDNAdamageandcell deathbecausetheDNArepairfunctionoftumorcellswithBRCAmutations hasbeenimpaired.
OlaparibreceivedFDAapprovalin2018forthetreatmentofmetastaticbreast cancerwithBRCAgermlinemutations,andanewindicationwasapprovedin 2022forthetreatmentofHER2-negativeearlybreastcancerpatientswithor suspectedBRCAgermlinemutationswhohadpreviouslyreceived chemotherapybefore/aftersurgeryAtpresent,Olaparibforbreastcancer indicationhasbeensubmittedtotheNMPAformarketingapplication. TalazoparibwasapprovedbytheUSFDAin2018forthetreatmentoflocally advancedormetastaticbreastcancerwithgermlineBRCAgenemutations andHER2-negativediseaseTheindicationsforbreastcancerhavenotyet beenfiledwithChineseregulators.
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4.TargetedTherapiesforTripleNegativeBreastCancer
Intriple-negativebreastcancer(TNBC),thecancercellsdonothaveestrogen orprogesteronereceptorsandhaveverylowornolevelsoftheHER2protein, sothisgroupofpatientsisnotsensitivetoendocrinetherapyortodrugs targetingthehormonereceptor,HER2Currently,SacituzumabGovitecan (Trodelvy)isthemaintargetdrugthatcanbeusedforTNBCtreatmentinclinic. Itisanantibody-drugconjugateconsistingofachemotherapydruganda monoclonalantibodyboundtoit.Whenthedrugentersthebody,its monoclonalantibodycomponentcanattachtoaproteincalledTrop-2on breastcancercellsandbringchemotherapydrugstothecancercellstoexert theireffectsBecausecancercellshavemuchhigherlevelsoftheTrop-2 proteinthannormalcells,thisapproachcanpartlyreducethedamage chemotherapydrugsdotohealthycells
In2020,theUSFDAapprovedSacituzumabGovitecan(Trodelvy)as monotherapyforthetreatmentofpatientswithadvancedormetastatic TNBCwhohavepreviouslyreceivedatleasttwoormoresystemictherapies InJunethisyear,SacituzumabGovitecan(Trodelvy)wasapprovedbythe NMPAforthetreatmentoftriple-negativebreastcancer
WhatAreTheImmunotherapiesForBreastCancer?
Immunotherapyworksbyusingdrugstoboosttheimmunityofthebody'sown immunesystemtomoreeffectivelyidentifyanddestroycancercells
Immunotherapyusuallyworksonspecificproteinsinvolvedinthefunctionof theimmunesystemThemainimmunotherapycurrentlyusedintheclinical treatmentofbreastcanceristhedrugPembrolizumab(Keytruda),an inhibitoroftheimmunecheckpointPD-1,whichhassideeffectsdifferentfrom thoseofchemotherapy.
Pembrolizumab(Keytruda)isadrugthattargetsPD-1,animportant componentofimmunecells--aproteinonTcellsthathelpsTcellsnotattack healthytissueinthebody.ByblockingPD-1,thesedrugsboosttheimmune system'simmuneresponseagainstbreastcancercells,causingtumorsto shrink.
TheUSFDAapprovedPembrolizumabin2020tobeusedincombinationwith chemotherapyforthetreatmentofnon-resectablelocallyrecurrentor metastatictriple-negativebreastcancerIn2021,Pembrolizumabwas approvedforanewindication:theUSFDAapprovedcombination chemotherapyasaneoadjuvanttherapyforhigh-riskearly-stage triple-negativebreastcancerpatients,andcontinuedasamonotherapy
HuatengPharma https://ushuatengscicom adjuvanttherapyaftersurgeryPembrolizumabhasbeensubmittedtoChinese regulatorsforanindicationforbreastcancer.
Conclusion
Withtheincreasingapplicationofinnovativetreatmentmodelsrepresentedby targetedtherapy,immunotherapyandcombinationtherapyinbreastcancer patients,wehavemadesomeprogressincurbingtumorgrowthandimproving thesurvivalrateofbreastcancer.Moreresearchisneededonhowtouse preciseandindividualizedtreatmenttoimprovetheefficacy,andhowtofind betterbiomarkerstomakeindividualizedtreatmentmorefeasibleinclinical practice,whichwillbethedevelopmentdirectionofbreastcancerinthefuture Onlysomebreastcancertreatmentsareintroduced,notallofthemarelisted. Wewillalsopaycloseattentiontotheprogressofcancerresearchand introducethelatesttreatmentmethodstoreaders.
Asaprofessionalmanufacturerofpharmaceuticalintermediates,Huateng Pharma,providesPalbociclibandRibociclibkeyintermediateswithhighpurity Polyethyleneglycol(PEG)isoneofthemostwidelyusedlinkersintargeted therapiesWearededicatedtobeingyourmostreliablepartnertoprovide high-qualityPEGlinkerstopromotetheprogressofyourADCR&D
References:
[1]TargetedDrugTherapyforBreastCancer,RetrievedOct24th,2022, fromhttps://wwwcancerorg/cancer/breast-cancer/treatment/targeted-therapy-for-breastcancerhtml
[2]ImmunotherapyforBreastCancer,RetrievedOct24th,2022, fromhttps://www.cancer.org/cancer/breast-cancer/treatment/immunotherapy.html
[3]Arnold,Melinaetal“Currentandfutureburdenofbreastcancer:Globalstatisticsfor 2020and2040.”Breast(Edinburgh,Scotland),vol.6615-23.2Sep.2022, doi:101016/jbreast202208010
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