CCFP, MHSc, FRCPC, FCFP, NCMP · 2018. 6. 4. · 6/4/18 124 16th WCM Pre-Congress Workshop Case 2: Breast Cancer in the perimenopause Dr. Marla Shapiro C.M. CCFP, MHSc, FRCPC, FCFP,

6/4/18 12416thWCMPre-CongressWorkshop

Case2:BreastCancerintheperimenopause

Dr.MarlaShapiroC.M.CCFP,MHSc,FRCPC,FCFP,NCMP

Professor,UniversityofToronto


FinancialDisclosures

SpeakerBureau:Merck,Amgen,AMAG,Pfizer,BayerAdvisoryBoard:Merck,Amgen,Pfizer,Mithra,AMAG,GSKOther:CTVMedicalConsultant


“TheThreeSeasonsofSurvival”

FitzhughMullanNEJM1985

Acute

Extended

Permanent


Needs of Breast Cancer Survivors

Late effect RiskRecurrence 0-100%

2nd primary 1-2%

Psychological distress 30%

Lymphedema 10-25%

Premature menopause, infertility and osteoporosis

45%

Estrogen deprivation >50%


Needs of Breast Cancer Survivors

Late effect Risk

Weight gain 50% 2.5-5Kg20% 10-20Kg

CVS disease 0.5-1% CHF

Fatigue 30% 1-5 yrs after diagnosis

Cognitive impairment 30%

Familial risk 5-10%


SymptomManagement

ü Women with breast cancer have many adverse symptoms, of which some are specific to premenopausal patients

ü Hot flushes: non-hormonal drugs, such as antidepressants and anti-seizure compounds

ü Vaginal dryness and dyspareunia-Non-estrogenic vaginal lubricants

ü Cancer-related fatigue- exercise

Loprinzi, C. L., S. L. Wolf, et al. (2008). "Symptom management in premenopausal patients with breast cancer." Lancet Oncol 9(10): 993-1001


MeetJoan

• 52,3yearspostER/PRpositivebreastcancer• TAHBSO,BilateralMastectomy• Chemotherapeuticregime• Onarimidex


Concerns

• Hotflashesandnightsweats• Whatareheroptions?


NonprescriptionProductsHave LimitedDatatoSupportEfficacyinRelievingVasomotorSymptomsAgent Study Design Efficacy Adverse Events

Soy-derived isoflavones1Systematic review of 25 randomized controlled trials of phytoestrogens (≥4 weeks) involving 2,348 symptomatic women

7 of 8 soy food trials, 3 of 5 soy extract trials, and 3 of 5 red clover trials showed no significant difference from placebo

Most common adverse events were gastrointestinal disorders

Black cohosh2N=80 late perimenopausal or postmenopausal women; 160 mg/day

No significant difference from placebo

Both groups reported gastrointestinal symptoms; nausea and vomiting; fatigue, asthenia, or malaise; and headaches

Evening primrose oil3 N=56 menopausal women; 4000 mg/day for 6 monthsNo significant difference from placebo

Minimal side effects, including slight nausea

Dong quai4 N=71 menopausal women; 4.5 g/day for 6 monthsNo significant difference from placebo

Both treatment groups reported burping, gas, and headaches

Ginkgo biloba5,6N=87 menopausal women;120 mg/day for 6 weeks5

N=31 menopausal women;120 mg/day for 1 week6


None reported

Ginseng7 N=384 menopausal women; 100 mg/day for 4 monthsNo significant difference from placebo

Both treatment groups reported influenza or colds, headaches or migraines, and gastrointestinal disorders

Vitamin E8Alpha E, Amino-Opti-E, Aquasol E, Aquavite-E, Centrum® Singles-Vitamin E, E Pherol, E-400 Clear, Nutr-E-Sol

N=120 women with a history of breast cancer; 800 IU/day for 4 weeks in a crossover design


Both groups reported headaches, fatigue, and nausea

1. Krebs EE, et al. Obstet Gynecol. 2004;104:824-836.

2. Newton KM, et al. Ann Intern Med. 2006;145:869-879.

3. Chenoy R, et al. BMJ. 1994;308:501-503. 4. Hirata JD, et al. Fertil Steril. 1997;68:981-986. 5. Elsabagh S, et al. J Psychopharmacol.

2005;19:173-181. 6. Hartley DE, et al. Pharmacol Biochem Behav.

2003;75:711-720. 7. Wiklund IK, et al. Int J Clin Pharmacol Res.

1999;19:89-99. 8. Barton DL, et al. J Clin Oncol. 1998;16:495-500.

There are limited data comparing the above referenced products to one another or to approved FDA treatments. Therefore, comparative efficacy cannot be determined based on the above.

6/4/18 13316thWCMPre-CongressWorkshopNorthAmericanMenopauseSociety.Menopause.2015;22(11).

Twomind-bodytherapieshavelevelIevidenceshowingpositiveeffectsn Cognitivebehavioraltherapy(CBT)protocols(MENOS1andMENOS2)

n Clinicalhypnosis:Elkinsprotocol

© 2015

Recommend:NonRx


North American Menopause Society. Menopause. 2015;22(11).

n FDA-approved low-dose paroxetine salt

n Other SSRIs and SNRIs yielding significant VMS reductions in large RCTs

n Gabapentin and pregabalin

© 2015

Recommend:PrescriptionTherapies


OtherSSRIs,SNRIs

n LargeRCTsshowsignificantVMSreductions with— Paroxetine— Escitalopram— Citalopram— Venlafaxine— Desvenlafaxine


© 2015



Dependson

n Prioreffectivetherapyn Patienthistoryn Adverseeventsprofileandtoleranceofadverseeffects

n Co-administeredmedications

©2015

PrescriptionTherapies:Choice


Concerns

• Vaginaldryness


Concerns

• Vaginaldrynessoptions………..• MoisturizersandLubricants• Vaginalestrogen• VaginalDHEAS• Lasertherapy


Concerns

• Sexualissues


Concerns

•Experiences a degree of distress and depression


BreastCancerandDepression:TamoxifenandAntidepressantsviaCytochromeP4502D6

ü Women taking tamoxifen for the treatment or prevention of recurrence of breast cancer are likely to take antidepressants either for a psychiatric disorder or for hot flashes

ü Some antidepressants inhibit the metabolism of tamoxifen to its more active metabolites by the cytochrome P450 2D6 (CYP2D6) enzyme, thereby decreasing the anticancer effect

Desmarais, J. E. and K. J. Looper (2009). "Interactions between tamoxifen and antidepressants via cytochrome P450 2D6." J Clin Psychiatry 70(12): 1688-1697


InteractionsbetweentamoxifenandantidepressantsviacytochromeP4502D6

2D6interaction

Fluoxetine +++ Strong:tobeavoided

Paroxetine +++ Strong:tobeavoided

Citalopram + Mild

Escitalopram + Mild:studieslacking

Bupropion +++ Strong:tobeavoided

Sertraline ++ Moderate

Fluvoxamine ++ Moderate2D6and3A4:studieslacking

Venlafaxine -/+ Minimal

Desvenlafaxine - Minimal:studieslacking

Mirtazapine + Minimal:studies lacking

Desmarais, J. E. and K. J. Looper (2010). "Managing menopausal symptoms and depression in tamoxifen users: implications of drug and medicinal interactions." Maturitas 67(4): 296-308

Desmarais, J. E. and K. J. Looper (2009). "Interactions between tamoxifen and antidepressants via cytochrome P450 2D6." J Clin Psychiatry 70(12): 1688-1697


Concerns

• Whataboutboneloss?• Isdepressionanadditionalriskfactorforherbones?


DepressionasaRiskFactorforOsteoporosis

ü Associationbetweendepressionandlowbonemineraldensity

üDepressionmayinducebonelossandosteoporoticfracturesü Viaspecificimmuneandendocrinemechanismsü Potentialeffectofspecificantidepressantsü Possibleroleofpoorlifestyle

Cizza, G., S. Primma, et al. (2009). "Depression as a risk factor for osteoporosis." Trends Endocrinol Metab 20(8): 367-373


ManagementofMSKhealthWomenstartingaromataseinhibitortherapy

Baseline DXA scan of hip and spine (T score)

Normal Low Bone Mass Osteoporotic

Nutritional supplement

Lifestyle choices

BMD measurement: every 1-2 years

Nutritional supplement

Lifestyle choices

Annual BMD measurement

Candidate for bisphosphonate/denosumab treatment

Refer to rheumatologist or endocrinologist


Concerns

• Sheisworriedaboutherhearthealth


Concerns

• Sheisworriedaboutgettingcanceragain


Evidence Based InterventionsLate effect InterventionsRecurrence and 2ndprimary

Mammo/hx/px22

Psychological distress Psychosocial interventions4

Lymphedema MLD, compression, complex decongestive therapy4

Premature menopause 7 Assessment of sexual reproductive technologies 4

Bone health programs Estrogen deprivation Diet/exercise and drugs

promising


Evidence Based Interventions

Late effect Interventions

Weight Gain Diet /exercise

CVS disease Prevention strategies, cardiac work up

Fatigue Exercise promising

Cognitive impairment No evidence

Familial risk Genetic counseling 1


Discussion


Perimenopause—ChallengesandSolutionsCase3:CVDandDiabetesduringPerimenopause

CynthiaA.Stuenkel,MDUniversityofCalifornia,SanDiegoNothingtoDeclare


Ihavenofinancialrelationshipstodisclose.


NCDRiskFactorCollaboration.Lancet2016;387;1513-30


TenCountrieswiththeLargestNumberofAdultswithDiabetesin1980and2014

NCDRiskFactorCollaboration.Lancet2016;387;1513-30.


NationalDiabetesStatisticsReport

>100MillionUSAdultsAffected

§ Asof2015,intheU.S.§30.3million 9.5%diabetes§84.1million >33.3%pre-diabetes

§ AgerelatedDMprevalence

§18-44y 4%§45-64y 17%§> 65y 25%

www.cdc.gov/media/releases/2017/p0718-diabetes-report.html


CriteriaforDiagnosisofDiabetes

§FPG> 126mg/dL 7.0mmol/L

§2-hPG> 200mg/dL 11.1mmol/L

§A1C > 6.5% 48mmol/mol

§RandomPG> 200mg/dL 11.1mmol/Lsymptoms

Diabetes Care 2018;41(Suppl 1)S13-S27


CriteriaforDiagnosisofPrediabetes

§FPG> 100-125mg/dL 5.6- 6.9mmol/L

§2-hPG> 140-199mg/dL 7.8-11.0mmol/L

§A1C > 5.7-6.4%39-47mmol/mol



CriteriaforTestingforDiabetesorPrediabetes inAsymptomaticAdults

ConsiderforalladultsBMI> 25*with> 1addedrisk:§First-degree relative with DM§High-risk race/ethnicity§Hx of cardiovascular disease§HTN > 140/90 or Rx HTN§HDL < 35 (0.90 mmol/L) and/or TG

> 250 (2.82 mmol/L)

§Polycystic ovary syndrome§Physical inactivity§Insulin resistance: severe obesity, acanthosis nigricans§Prediabetes test yearly§Gestational diabetes every 3y

Diabetes Care 2018; 41(Suppl 1):S13-S27. *Asian Americans, BMI > 23)


CriteriaforTestingforDiabetesorPrediabetesinAsymptomaticAdults

§ Testingshouldbeginatage45yearsforallpatients1§ Repeattesting ataminimumof3yearintervals ifresultsarenormal1

§ InaSwedishpublichealthprogram,ageatDMdiagnosiswas4.6ylowerinthosewhowerescreen-detected2§ Clinicaldetectedcaseshadworsehealthoutcomes2

Diabetes Care 2018; 41(Suppl 1):S13-S27. *Asian Americans, BMI > 23); 2. Feldman AL, Diabetologia 2017


ChallengesofPerimenopause andDM

§ Symptomsofestrogenwithdrawalcaninitiallybeconfusedwiththoseofhypoglycemia

§ Bloodglucosecontroloftendeterioratesduringtheluteal phase—perimenopausal hormonefluxescreatehavoc

§Weightgainchallengesglucose,BP,andlipidcontrol§Menstrualirregularitiesareofaddedconcernasriskofendometrialcanceriselevated


MenopauseandDiabetesRisk

§Naturalmenopause,occurringattheaverageage,doesnotappeartoincreaseDMrisk1,2

§ DurationofreproductivelifespanmaycontributetoDM—bothshorter(<30yr)andlonger(> 45y)3,4

§HysterectomyisassociatedwithincreasedDMrisk;oophorectomy didnotconferaddedrisk5

1.StuenkelCA,Climacteric,2017;2.Mauvais-JarvisF,EndocrineReviews,2017;3.LeBlancES,Menopause,2017;4.Muka T,Diabetologia,2017;5.Luo J,AmJEpidemiol, 2017.


MenopauseandDiabetesRisk

§Theexacteffectofmenopauseonglucosehomeostasis,independentfromchronologicalaging,isstillcontroversial1,2

§Relationshipsbetweenearlymenopauseanddiabetes(amongotherCVDriskfactors)maybebidirectional3

1.StuenkelCA,Climacteric,2017;2.Mauvais-JarvisF,EndocrineReviews,2017;3.MansonJEandWoodruffTK,JAMACardiol,2017.


VasomotorSymptomsandDMRisk

§ InAustralianLongitudinalStudy,earlysevereVMSwereassociatedwithDMrisk;OR1.55(1.11-2.17)1

§ In2largecohortstudies,VMSwereassociatedwithincreasedriskofType2DM2

§ IntheWHIstudies,VMSwereassociatedwithDM,particularlynightsweats,possiblyrelatedtosleepdisturbance3

Herber-Gast GC,Menopause,2014;2.vanDijk GM,Maturitas,2015;3.GrayKE,Menopause,2018


WomenwithDiabetes

§DiabetesisconsideredbytheAHAtobeaCHDriskequivalent§RCTevidenceofCVDoutcomeswithMHTinwomenwithDMismostlylacking§RCTofMHTshowneutralorbeneficialeffectsonglucosecontrol§Evidenceinadequatetomakefirmrecommendations

StuenkelCA,etal.JClin Endocrinol Metab 2015;100:3975-4011.


RecommendationsforTreatingVMSwithMHTinDMOrganization Citation BottomLine

NAMS Menopause,2017 Not addressed

IMS Climacteric,2016 Not addressed

UKNICE PostReprod Health,2015 MHTnotadverseforglucose controlConsiderMHTaftertakingcomorbidities intoaccount

EndocrineSociety JCEM, 2015 EvidenceforsafetyinadequateSomewomenmaybecandidates forMHTafterassessingCVDriskPreferTDE2andMP

Canadian MenopauseSociety

JOGC ,2014 MayprescribeMHTforsymptomrelief

ACOG PracticeBulletin, 2014 NotaddressedStuenkelCA,Climacteric,2017;updatedJune,2018.


WomenwithDiabetes

§Anindividualizedapproachtotreatingmenopausalsymptomscouldbeconsidered§Lowthresholdtorecommendnonhormonal therapies,particularlyinwomenwithconcurrentCVD§SomewomenwithDM,afterevaluationofCVDrisk,maybecandidatesforMHT§Prefertransdermal estrogenandmicronizedprogesterone—moremetabolically‘friendly’



ACCEPTABLE

EVALUATECARDIOVASCULAR

RISK

HIGH *

CONSIDEROTHER OPTIONS

* Includes known CHD, CVD, PAD, etc.

ApproachtoPatientwithVMSConsideringMHT



Cardiovascular RiskAssessment

§ BoththeEndocrineSociety1 andNAMS2 arealignedinrecommendingquantifying10yearCVDrisk

§UsetheAHA/ACCriskcalculatororothervalidatedcountryorpopulation-specificinstrument

§ Ifresourcesallow,CACdeterminationcancontributetoriskassessmentif> 40y3

§ Cardiovascular‘age’isaconceptunderdevelopment4

1. Stuenkel CA,JCEM,2015;2.NAMSHTPS,Menopause,2017;3.AmericanDiabetesAssociation,DiabetesCare,2018;4.SantenRJ,Menopause,2017


Evaluate Cardiovascular Risk

StuenkelCA,etal.JClin Endocrinol Metab 2015;100:3975-4011;NAMSHTPS,Menopause,2017.


TreatmentofMenopausalSymptomsinYoungWomenwithDiabetes

Mauvais-JarvisF,etal.EndocrineReviews, 2017

andnormalweight

orifobese

OralMHTOKTDpreferred


SexDifferencesintheCVDConsequencesofDMComparedwithmen:§CVDriskprofileismoreadverseinwomen§WomenwithDMhave2-foldexcessriskCHD§MIoccursearlierandhashighermortality§Revascularizationrateslower;survivalless§Ratesofincidentheartfailurehigher§DMisstrongerriskfactorforstrokeandPVD

Regensteiner JG,etal.Circulation 2015;132:2424-2447.


RecommendationsforCVDRiskFactorManagementinT2DM

Risk Recommendation§Nutrition Individualize;Mediterraneandiet§Obesity SurgeryBMI> 40or> 30glucose§Bloodglucose A1C < 7.0%(53mmol/mol)§Bloodpressure RxtoachieveBP<140/90§Cholesterol > 40yRxmoderateintensitystatin§Low-doseaspirin> 50y+1risk,Rx75-162mg/d

AmericanDiabetesAssociation.DiabetesCare,2018


WhataboutnewdrugsforCVDriskreductioninT2DM?

SecondaryPreventionBenefitinRCTsLDLloweringasadjuncttostatin therapy§ Ezetimibe§ PCSK9inhibitor:evolocumab,alirocumab

Glucoseloweringagents§ SGLT2inhibitors:empagliflozin, canagliflozin*§ GLP-1agonists:liraglutide,semaglutide

Anti-inflammatoryagents§ Interleukin-1betablocker:canakinumab

AmericanDiabetesAssociation.DiabetesCare,2018;*2-foldincreasedamputations;boldFDAapprovedforCVDeventreduction.Dapagliflozin effectiveinobs studyinlowerriskpatients.


HealthConsiderationsforWomenwithDM§Osteoporosisandfracturerisk§ Cancerrisk:breast,colorectal,andendometrial§Obstructivesleepapneacommon§ Cognitivedeclineanddepression§Genitourinarysyndromeofmenopause

StuenkelCA,Climacteric,2017


PreventionorDelayofType2DiabetesForpatientswithprediabetes,referforintensivedietandexercisebehavioralcounseling§ Targetlossof7%initialbodyweight§ Increasemoderate-intensityphysicalactivityto150min/wk§ Technology-assistedtools(internetbasedormobileapps)

§Metformin maybeconsideredBMI> 35,age<60,GDM§MonitorVitaminB12deficiency(anemiaorneuropathy)



MHTforPreventionofDM?

§Notgovernmentapprovedforthisindication§Notappropriateduetocomplexrisksandbenefits§Notaddressedbymostsocietyguidelines§Nottheendofthestory…

StuenkelCA,Climacteric,2017;Mauvis-JarvisF,EndocrineReviews,2017


CVDandDMinthePerimenopauseSummaryandConclusions

§ Diabetesisaburgeoninghealthconcern,amenabletoreversalwithlifestyleinterventionsandweightloss

§ Theinteractionofmenopauseanddiabetesiscomplex§ Cardiovascularmorbidityandmortalityarethemostserioushealthsequelae forwomenwithDM

§Myriadhealthconcernsrequireadditionalclinicalemphasisandstudytodefineoptimalmanagement


Discussion


NutritionBreak


MenopausalHormoneTherapyRegimensinthePerimenopause

Robert L Reid, MD FRCSCProfessor Ob/Gyn,

Division of REIQueen’s University,

Kingston ON


RobertReidDisclosures

Relationshipswithcommercialinterests:

Advisoryboards:Bayer,Merck,Mithra

Speaker’sBureau:Pfizer


Objectives

• Afterthispresentationparticipantswillbeableto:

• Describetheerraticonsetofmenopausalsymptomsthatmaycharacterizetheperimenopausal transition

• Definetheparticularsituationandselecthormonetherapyappropriatetotheunderlyingpathophysiology


Perimenopausal MenstrualIntervalVariation

Treloar AE.Menstrualcyclicity andthepre-menopause.Maturitas 1981;3(3-4):249-64


MenstrualIntervalVariationThroughReproductiveYears

Treloar AE.Menstrualcyclicity andthepre-menopause.Maturitas 1981;3(3-4):249-64


MenstrualCyclicity OveraLifetime

16 40 45 50Regularmonthlycycles-every

28–30d

Shortenedfollicularphase-

22-24daycycles

Irregularunpredictable

cycles

Menstrualperiodscease

8-12Thelarcheindicatesfirstestrogenexposure


OvulatoryCycles

Menses Menses

EstrogenProgesterone

Ovulation CL

DominantFollicle

ProgesteronecausesformationofcytosolicvacuolescontainingPG

ProgesteronewithdrawaltriggersPGreleasewith

“Synchronousshedding”


Perimenopausal Anovulatory Cycles

NoprogesteroneexposureHencenosynchronousendometrialSheddingandriskforhyperplasia

CirculatingEstrogen

Bleeding

Sustainedanovulation

Amenorrheaorgradualendometrialproliferation


Perimenopause:aTimeofUnpredictability

Occasional ovulation mixed with periods of ovarian quiescence

The few remaining follicles are those that are most resistant to FSH stimulation

As FSH levels rise these follicles activate and estrogen levels riseWith cessation of hot flashes

Hot Flashes


ClinicalSituationsforHRTinPerimenopause

1. HormonetherapyforthewomanwithirregularmensesandperiodicVMSa) WithcontraindicationstoCHCb) WithoutcontraindicationstoCHC

2. Womenwithpre-existinginsertionofLNGIUSforbleedingcontrolwhosubsequentlydevelopsVMS

3. Womenlessthan1yearfromLMPwithamenorrheaandcontinuousVMS


DefiningtheClinicalSituation

• Notalwaysprecise• FSHnothelpfulbeyondage45

• inyoungerwomenmayhelpdifferentiatePOIfromothercausesofamenorrhea• Durationofamenorrhea

• After6monthsamenorrheaabout50%havehadFMP;at12months90%• Needforcyclecontrolorcontraception?


1.HormoneTherapyfortheWomanwithIrregularMensesandPeriodicVMS

• InthissituationCHClevelsofhormonesarerequiredtooverrideoccasionalspontaneousovulationthusmaintainingcyclecontrolwhilepreventingVMS

• Alsoaffordscontraceptionandsomenon- contraceptivebenefits(boneprotection,reducedriskofendometrialanduterinecancer)

• IfacontraindicationtoCHC:• LNGIUSforcontraceptionandbleedingcontrol• SystemicestrogenforVMS

• IfnocontraindicationtoCHC:• ConsiderextendedcycleorcontinuousCHC


2.VMSDevelopinginaWomanwithLNGIUSforHMB

• LNGprovidingcyclecontrolandcontraception• OfflabeladditionofsystemicestrogenforcontrolofVMS

LNGIUSInsertedVMS


3.ContinuousVMSandAmenorrheabutNotMeetingCriteriaforMenopause

• Do not need to wait for 1 year of amenorrhea to start treatment for VMS

• Start with standard menopausal HRT and only switch to CHC (or LNG IUS and estrogen if contraindications to CHC exist) for troublesome bleeding (periodic menses)

7 months since LMP

EstrogenVMS

Progesterone


Conclusions

• Doyourbesttodefinetheindividualsituationbasedonhistory(age,durationofamenorrhea,onsetandseverityofVMS)

• SelectatherapythatwillrelieveVMSwhilealsoaddressingissuesofcyclecontrolandcontraception(ifneeded)


Discussion

Documents

CCFP, MHSc, FRCPC, FCFP, NCMP · 2018. 6. 4. · 6/4/18 124 16th WCM Pre-Congress Workshop Case 2: Breast Cancer in the perimenopause Dr. Marla Shapiro C.M. CCFP, MHSc, FRCPC, FCFP,