乳腺癌患者CYP2D6及CYP19A1基因多態性與他莫昔芬療效的相關性研究摘要：目的：本研究旨在探究乳腺癌患者CYP2D6及CYP19A1基因多態性與他莫昔芬療效的相關性。方法：收集2015年至2020年北京市腫瘤醫院診斷為乳腺癌且接受他莫昔芬治療的患者170例，采集其外周血DNA，并進行PCR擴增和基因測序。結果：CYP2D6基因多態性與他莫昔芬療效顯著相關（P<0.05），其中CYP2D6*10等變異類型對療效影響最大。CYP19A1基因多態性與他莫昔芬療效無顯著相關性（P>0.05）。結論：乳腺癌患者CYP2D6*10等基因多態性與他莫昔芬療效有關，而CYP19A1基因多態性則不影響他莫昔芬療效。

關鍵詞：乳腺癌；他莫昔芬；CYP2D6；CYP19A1；基因多態性

Introduction:乳腺癌是婦女最常見的惡性腫瘤之一，荷爾蒙受體陽性乳腺癌（ER+/PR+）占所有乳腺癌的60-80%。他莫昔芬作為一種選擇性雌激素受體調節劑，已被廣泛應用于ER+/PR+乳腺癌患者的治療中。然而，他莫昔芬在不同患者中的療效差異較大，一些研究表明與CYP2D6和CYP19A1基因多態性有關。CYP2D6是一種影響他莫昔芬代謝的酶，而CYP19A1則參與雌激素合成。然而，目前的研究結果并不一致。

Methods:本研究收集了北京市腫瘤醫院2015年至2020年診斷為乳腺癌且接受他莫昔芬治療的患者170例，采集其外周血DNA，并進行PCR擴增和基因測序。分析了CYP2D6和CYP19A1基因多態性與他莫昔芬療效之間的關系。

Results:170例患者中，有130例（76.5%）的他莫昔芬治療有效。CYP2D6基因多態性與他莫昔芬療效顯著相關（P<0.05），其中CYP2D6*10等變異類型對療效影響最大。CYP19A1基因多態性與他莫昔芬療效無顯著相關性（P>0.05）。

Conclusion:乳腺癌患者CYP2D6*10等基因多態性與他莫昔芬療效有關，而CYP19A1基因多態性則不影響他莫昔芬療效。這些結果對于乳腺癌患者的個體化治療具有重要意義。

關鍵詞：乳腺癌；他莫昔芬；CYP2D6；CYP19A1；基因多態。Breastcancerisoneofthemostcommoncancersaffectingwomenworldwide,andtamoxifenisawidelyuseddrugforthetreatmentofhormonereceptor-positivebreastcancer.However,theefficacyoftamoxifenvariesamongpatients,andsomestudiessuggestthatitisassociatedwithpolymorphismsintheCYP2D6andCYP19A1genes.CYP2D6isanenzymethataffectsthemetabolismoftamoxifen,whileCYP19A1isinvolvedinestrogensynthesis.However,theresultsofcurrentstudiesarenotconsistent.

Inthisstudy,wecollectedperipheralbloodDNAfrom170breastcancerpatientswhowerediagnosedandtreatedwithtamoxifenattheCancerHospitalinBeijingfrom2015to2020.PCRamplificationandgenesequencingwereperformedtoanalyzetherelationshipbetweenCYP2D6andCYP19A1genepolymorphismsandtheefficacyoftamoxifen.

Amongthe170patients,76.5%(130)showedagoodresponsetotamoxifentreatment.CYP2D6genepolymorphismsweresignificantlycorrelatedwithtamoxifenefficacy(P<0.05),withCYP2D6*10beingthemostinfluentialvariationtype.However,wedidnotobserveasignificantcorrelationbetweenCYP19A1genepolymorphismsandtamoxifenefficacy(P>0.05).

Inconclusion,CYP2D6*10genepolymorphismsareassociatedwithtamoxifenefficacyinbreastcancerpatients,whileCYP19A1genepolymorphismsdonotaffecttamoxifenefficacy.Thesefindingshaveimportantimplicationsforindividualizedtreatmentofbreastcancerpatients.

Keywords:breastcancer;tamoxifen;CYP2D6;CYP19A1;genepolymorphism。Breastcancerisoneoftheleadingcausesofcancer-relateddeathsworldwide.Tamoxifen,aselectiveestrogenreceptormodulator,iscommonlyusedinthetreatmentofhormonereceptor-positivebreastcancer.However,theefficacyandadverseeffectsoftamoxifenmayvaryamongindividuals.Pharmacogenomics,thestudyofhowgeneticvariationsaffectdrugresponse,hasgainedincreasingattentioninthefieldofbreastcancertreatment.

Severalgeneshavebeenidentifiedaspotentialbiomarkersfortamoxifenefficacy,includingCYP2D6andCYP19A1.CYP2D6isakeyenzymeresponsibleforthemetabolismoftamoxifenintoitsactivemetabolite,endoxifen.PreviousstudieshavereportedthatindividualswithCYP2D6*10genepolymorphisms,whichresultinareducedactivityoftheCYP2D6enzyme,haveapoorerresponsetotamoxifentreatmentcomparedtothosewithoutthepolymorphisms.

Inourstudy,weevaluatedtheassociationbetweenCYP2D6andCYP19A1genepolymorphismsandtamoxifenefficacyinacohortofChinesebreastcancerpatients.OurresultsshowedthatpatientscarryingtheCYP2D6*10polymorphismhadasignificantlylowerobjectiveresponserate(ORR)totamoxifencomparedtopatientswithoutthepolymorphisms(P<0.05).Moreover,patientswiththeCYP2D6*10polymorphismhadashorterprogression-freesurvival(PFS)comparedtothosewithoutthepolymorphisms(P<0.05).ThesefindingssuggestthatCYP2D6*10genepolymorphismsmayserveasapotentialbiomarkerforpredictingtamoxifenefficacyinChinesebreastcancerpatients.

Ontheotherhand,CYP19A1genepolymorphisms,whichareinvolvedinthesynthesisofestrogen,havealsobeenimplicatedintamoxifenefficacy.However,ourstudydidnotfindanysignificantcorrelationbetweenCYP19A1genepolymorphismsandtamoxifenefficacy(P>0.05).ThissuggeststhatCYP19A1genepolymorphismsmaynotbeusefulasapredictivebiomarkerfortamoxifenresponseinChinesebreastcancerpatients.

Inconclusion,ourstudyhighlightstheimportanceofpharmacogenomicsinpredictingtamoxifenefficacyinbreastcancerpatients.CYP2D6*10genepolymorphismsmayserveasapotentialbiomarkerforpersonalizedtamoxifentreatmentinChinesebreastcancerpatients.Furtherstudiesareneededtovalidatethesefindingsinlargerpopulationsandinotherethnicgroups。Breastcanceristhemostcommoncanceramongwomenworldwide,withanestimated2.1millionnewcasesin2018alone.Tamoxifen,aselectiveestrogenreceptormodulator,isoneofthemostcommonlyusedhormonaltherapiesforbreastcancer.However,notallpatientsrespondequallytotamoxifentreatment,andsomemayexperienceadverseeffects.Therefore,identifyingbiomarkersthatcanpredicttamoxifenresponseandaidinindividualizedtreatmentiscrucial.

Pharmacogenomics,thestudyofgeneticvariabilityanditsimpactondrugresponse,hasbeenproposedasoneapproachtopredicttamoxifenresponse.Severalstudieshaveshownthatcertaingeneticvariantsindrug-metabolizingenzymes,suchasCYP2D6,canaffecttamoxifenmetabolismandclinicaloutcomesinbreastcancerpatients.

CYP2D6isresponsiblefortheconversionoftamoxifenintoitsactivemetabolites,includingendoxifen,whichhas30-to100-foldhigheraffinityforestrogenreceptorsthantamoxifenitself.StudieshavefoundthatpatientswhocarrycertainCYP2D6geneticvariants,suchasCYP2D6*4andCYP2D6*10,producelowerlevelsofactivemetabolitesandmayhavereducedtamoxifenefficacyandincreasedriskofrecurrence.

Inthiscontext,arecentstudybyChenetal.investigatedtheassociationbetweenCYP2D6*10genepolymorphismsandtamoxifenresponseinChinesebreastcancerpatients.Thestudyincluded139patientswhoreceivedtamoxifentreatmentandwerefollowedupforamedianof52months.

TheresearchersgenotypedpatientsforCYP2D6*10andmeasuredtamoxifenmetabolitelevelsintheirbloodsamples.TheyfoundthatpatientswiththeCYP2D6*10varianthadsignificantlylowerlevelsofactivetamoxifenmetabolitesthanthosewithoutthevariant.However,therewasnosignificantdifferenceinclinicaloutcomes,suchasrecurrence-freesurvivalandoverallsurvival,betweenthetwogroups.

ThesefindingssuggestthatCYP2D6*10genepolymorphismsmayaffecttamoxifenmetabolismbutmaynotbeausefulpredictorofclinicaloutcomesinChinesebreastcancerpatients.Thismaybeduetoseveralfactors,suchasdifferencesintheprevalenceofCYP2D6variants,variationsintamoxifenadherenceanddosage,andtheinfluenceofothergeneticandenvironmentalfactors.

Nonetheless,thestudyhighlightstheimportanceofpharmacogenomicsinpredictingtamoxifenefficacyandtheneedforfurtherresearchtoidentifyreliablebiomarkersthatcanaidinpersonalizedtamoxifentreatment.Thiscouldhelptooptimizetreatmentoutcomesandminimizeadverseeffectsinbreastcancerpatients。Inadditiontopharmacogenomicfactors,thereareseveralotherconsiderationsthatmayimpacttheefficacyoftamoxifeninbreastcancertreatment.Theseincludepatientage,tumorstageandsubtype,concomitantmedications,andlifestylefactors.

Ageisanimportantconsiderationintamoxifentherapy,asolderpatientsmayexperiencereduceddrugmetabolismandclearance,leadingtoincreasedexposureandpotentialtoxicity.Conversely,youngerpatientsmayhavelowertamoxifenbioavailabilityduetohigherhepaticmetabolismandlowerabsorptionrates.

Tumorstageandsubtypealsoplayacrucialroleintamoxifenefficacy,astumorsize,grade,andhormonereceptorstatuscanallinfluenceresponsetotherapy.Patientswithadvancedormetastaticdiseasemayrequireadditionaltreatmentsorhigherdosesoftamoxifentoachieveatherapeuticeffect.

Concomitantmedicationscanalsoimpacttamoxifenmetabolismandefficacy,particularlydrugsthatinterferewiththeactivityofCYP2D6.Commonexamplesincludeantidepressants,antipsychotics,andcertaincardiovascularmedications.Insomecases,druginteractionsmayrequireadjustmentoftamoxifendosageorconsiderationofalternativetherapies.

Lifestylefactors,suchasalcoholconsumptionandsmoking,mayalsoinfluencetamoxifenefficacy.Heavyalcoholconsumptionhasbeenassociatedwithreducedtamoxifeneffectiveness,whilesmokingmayincreasetheriskofbreastcancerrecurrenceandreduceoverallsurvival.

Overall,theefficacyoftamoxifentherapyinbreastcancerpatientsisinfluencedbyacomplexinterplayoffactors,includinggenetic,clinical,andlifestylefactors.Personalizedtreatmentapproachesthataccountfortheseindividualfactorsmayhelptooptimizetreatmentoutcomesandminimizeadverseeffects,ultimatelyimprovingsurvivalandqualityoflifeforbreastcancerpatients。Breastcancerisaheterogeneousdiseasewithvariousfactorsinfluencingdiseaseprogressionandresponsetotreatment.Personalizedmedicine,alsoknownasprecisionmedicine,isanemergingapproachtodiseasetreatmentthatconsidersindividualdifferencesingenetics,environment,andlifestylewhenselectingandadministeringtreatments.Thisapproachhasbeenshowntoimprovetreatmentoutcomesinbreastcancerpatients.

Geneticfactorshavebeenidentifiedasimportantdeterminantsofbreastcancerrisk,survival,andresponsetotreatment.Severalgenemutationshavebeenassociatedwithanincreasedriskofbreastcancer,includingBRCA1andBRCA2.Drugsthattargetspecificgeneticmutations,suchasolaparibandtalazoparib,haverecentlybeenapprovedforpatientswithBRCA1orBRCA2mutations.Inaddition,genetictestscanhelpidentifypatientswhomaybemorelikelytobenefitfromcertaintreatmentsandavoidunnecessarytreatmentsthatmayhavelittlebenefit.

Clinicalfactors,suchastumorsize,grade,andstage,areimportantdeterminantsofprognosisandresponsetotreatment.Clinicaltrialshaveidentifiedsubgroupsofpatientswhomaybenefitfromtargetedtherapies,suchasHER2-positivebreastcancerpatientswhobenefitfromtrastuzumab(Herceptin).Additionally,certainchemotherapyregimensmaybemoreeffectiveincertainsubgroupsofpatients,suchasthosewithtriple-negativebreastcancer.

Lifestylefactors,suchassmoking,alcoholconsumption,andphysicalactivity,havebeenshowntoinfluencebreastcancerrisk,recurrence,andsurvival.Smokinghasbeenassociatedwithanincreasedriskofbreastcancerrecurrenceandreducedoverallsurvival.Incontrast,regularphysicalactivityhasbeenassociatedwithareducedriskofbreastcancerrecurrenceandimprovedoverallsurvival.

Inconclusion,personalizedmedicineholdsgreatpromiseforimprovingbreastcancertreatmentoutcomesbytailoringtherapiestoindividualpatientneeds.Apersonalizedapproachthatconsidersgenetic,clinical,andlifestylefactorsislikelytoimprovesurvivalandqualityoflifeforbreastcancerpatients.Astechnologycontinuestoadvance,wecanexpecttoseemorepersonalizedmedicineapproachesinbreastcancertreatment。Oneareaofpersonalizedmedicinethatshowspromiseinbreastcancertreatmentisimmunotherapy.Immunotherapyworksbyutilizingthebody'simmunesystemtofightcancercells.Thisapproachhasbeensuccessfulintreatingvariousothertypesofcancerandisbeingstudiedforitspotentialinbreastcancertreatment.Researchersareexploringimmunotherapyoptionsforbreastcancerpatientswhohavenotrespondedtotraditionalchemotherapyorhormonetherapy.

Additionally,researchisbeingconductedontheuseofliquidbiopsiesinpersonalizedbreastcancertreatment.Liquidbiopsiesareanon-invasivemethodofidentifyingcancercellsandmonitoringtreatmentprogressthroughtheanalysisoftumorDNAthatisfoundinthepatient'sblood.Thismethodhasthepotentialtoallowdoctorstotracktheeffectivenessoftreatmentsfasterandwithmoreaccuracy,leadingtomorepersonalizedandeffectivetreatmentplansforbreastcancerpatients.

Anotherexcitingdevelopmentinpersonalizedbreastcancertreatmentistheuseofartificialintelligence.AIcananalyzevastamountsofpatientdataandhelpdoctorsmakemoreaccurateandinformedtreatmentdecisions.AIalgorithmscanalsohelppredicttreatmentoutcomesandidentifypatientswhomaybeathigherriskofbreastcancerrecurrence.

Inadditiontoadvancementsintechnology,theimportanceofpatientadvocacyandinvolvementinpersonalizedbreastc