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StepsintheProgressionofBreastCancerPrecancerCancerinsituInvasionofnormalbreastSpreadtoregionallymphnodesHematogenousdistributiontodistantorgansDeathNaturalHistoryofBreastCancer

CharacterizedbyLongDurationMarkedHeterogeneityLongDuration

withaprolongedpreclinicalperiod12345678910111213YearsofGrowthGrowthRates&ClinicalEventsDiametercm0.512816110410610810101012Death1mm1cm1kgPremammographicPreclinicalAssumeDoublingTimeof100days10203040NumberofCellDoublingsNumberofCellsGullinoCancer1977GrowthRates&ClinicalEventsDiametercm0.512816110410610810101012PremammographicPreclinicalDeath1mm1cm1kgNumberofCellsPresentationPointforUntreatedPatientsUntreatedBreastCancerSurvivalfromOnsetofSymptoms0.8%2%3.6%9%18%28%44%56%86%83%68%54%41%Years12345101520%Alive10305070100MedianSurvival2.7YearsMiddlesexHospital1805–1933N=250AgedmatchedNoCancerUntreatedHJGBloomet.al.BMJ1962121234567891011131415GrowthRates&ClinicalEvents102030110410610810101012PremammographicPreclinical1mm1cmAssumeGompertzianGrowthYearsofGrowthNumberofCellDoublingsNumberofCellsClinicalGrowthRates&ClinicalEventsWhendodistantmetastasesoccur?Wheredotheyoccur?Howfastdotheygrow?110410610810101012PremammographicPreclinical1mm1cmNumberofCellsThetheorythatleadtoscreeningasymptomaticwomentodetectsmallerbreastcancerlesionsisbasedontheassumptionthatmanydistantmetastasesoccurduringtheintervalwhenthecancercanbedetectedbymammographyandwhenitcanbefeltonphysicalexamination.The(limited)successofscreeningmammographyhasproventhatthisistrueforatleastsomebreastcancers.

GrowthRates&ClinicalEvents110410610810101012PremammographicPreclinical1mm1cmNumberofCellsDistantmetastasesoccurevenbeforetheprimarycanbedetectedinmanyinstancesandislikelyonereasonforthelimitedsuccessofmammography.Thetheorybehindtheuseofadjuvantsystemictherapyisthatmetastasesareestablishedpriortodiagnosis,evenwhendetectedatasmallsize(andthereforeatanearliertimecourse).Thesemetastaseswillnotbeaffectedbylocaltreatments

Thesuccessofadjuvantsystemictherapystrategiesprovesthatthisistrue.Therelativelysmalloverallbenefitfromthesetreatmentsislikelyduetomultiplefactorsincludingthelimitedefficacyofthetreatmentsandthefactthatmanypatientsdiagnosedwithbreastcancerdonothavedistantmetastasesatdiagnosis.

Thetheorybehindtheuseofadjuvantsystemictherapyisthatmetastasesareestablishedpriortodiagnosis,evenwhendetectedatasmallsize(andthereforeatanearliertimecourse).Thesemetastaseswillnotbeaffectedbylocaltreatments.Asecondtheorytoexplainwhyadjuvantchemotherapywillbemoreeffectiveinthepreclinicalperiodisbasedontheassumptionthatthesemicrometastasesaregrowinglogarithmicallyandaremoresensitivetochemotherapy.

GrowthRates&ClinicalEvents110410610810101012PremammographicPreclinical1mm1cmTheclinicalperiodmaybebettercharacterizedbyGompertziangrowth

NumberofCellsClinicalManylongstandingassumptionsaboutthepreclinicalgrowthpatternsofbreastcancerhavebeenchallengedbynewunderstandingofangiogenesisanditsimportanceindetermininggrowthpatternsofboththeprimaryandmicro-metastases.GrowthRates&ClinicalEvents110410610810101012PremammographicPreclinical1mm1cmEventhepreclinicalperiodmaybecharacterizedbyperiodsgrowthalternatingwithplateausNumberofCellsPatientswithbreastcancerhaveamuchmoreprolongedclinicalcoursethanpatientswithmanyothertypesofcancer.Duringthistimetheymayreceiveandhaveatleastsomebenefitfrommanydifferenttypesoftreatment.Andthereisgoodreasontobelievethepreclinicalperiodisalsoprolonged,albeittheeventsinthepreclinicalperiodareclearlymorevariedandcomplexthanthoughtonlyafewyearsago.Fewcancersmetastasizeaswidelyasbreastcancer.SiteofMetastasesPooledFrequencyRangeBone58%44–71Liver54%35–63Lung66%54–77Skin22%7-39Brain16%9–29Ovary13%4–23Adrenal34%8-51PooledResultsof8AutopsySeries,1922-1960Haagensen1971Doesabreastcancerpatienteverreturnto‘normal’lifeexpectancy?051015202510810080604030.518.5AgeMatchedPopulationStagesI&IIAllStages%SurvivalYearsofFollow-upAddenbrookeHospitalN=7041947-1950Brinkley&Haybittle,1977MarkedHeterogeneityMortalityfromBreastCancer5101520510ConnecticutSEERRegistry1950-1973YearAfterDiagnosis%DyingofBreastCancerEachYearFox,JAMA,1979ChangingDefinitionsofBreastCancerPriortomid-19thcentury:ClinicalSignsThisprobablyremainedtrueintothefirst3rdofthe20thcentury.Untreatedvs.HalstedPatients24681012141618202220406080100%AliveYearssince1stSymptomsHalstedradicalmastectomy1889-1931MiddlesexUntreated1805-1933Henderson&Canellos,NEJM1908ChangingDefinitionsofBreastCancerPriortomid-19thcentury:ClinicalSignsMid-19thtomid-20thcenturyHistologicalEvidenceofInvasionInsitubreastcancer1stdescribedinthe1930’sChangingDefinitionsofBreastCancerPriortomid-19thcentury:ClinicalSignsMid-19thtomid-20thcenturyHistologicalEvidenceofInvasionMid-20thtoearly21stcenturyMicroinvasion21stcentury?MolecularmarkersChangingDefinitionsofBreastCancerTheonlydefinitionofbreastcancerthathasbeencorrelatedwithdeathinuntreatedpatientsis‘clinicalsignsandsymptoms.’Bymostpeople’sdefinition,“cancer”isatumorousgrowththatwillkillifleftuntreated.Inpractice,“cancer”isanhistologicalentity.Ethicalconstraintsmakeitverydifficulttocircumventthisproblem.Isthebreastcancertreatedinbreastcancerbetween1950and1973thesamebreastcancerthatwastreatedintheMiddlesexhospitalbetween1805and1933?BreastCancerIncidence&Mortality

Connecticut1935-1975MortalityfromBreastCancer5101520510ConnecticutSEERRegistry1950-1973YearAfterDiagnosis%DyingofBreastCancerEachYearFox,JAMA,1979SubpopulationsofBreastCancerPatients102030405060708090100105152025RelativeSurvival%YearafterDiagnosisConnecticutSEERRegistry1950-197340%dieatrateof25%peryear60%dieatrateof2.5%peryearFox,JAMA,1979102030405060708090100105152025RelativeSurvival%YearafterDiagnosisConnecticut

1950-1973Middlesex

1805-1933105102030405060708090100Survival%Yearafter1stSymptomNaturalHistoryofBreastCancer

ImplicationsBecausethedefinitionsofbreastcancerarechanging,comparisonsofresultsobtainedtodaywiththoseinanhistoricalseriesareoften(usually)misleading.TimeTumorSizeNaturalHistoryofBreastCancer

ImplicationsComparisonsbetweensubgroupsdefinedintwodifferenttimeperiodsareevenmoremisleading.Thisisthereasonthat5–7millionwomenweretreatedwiththeHalstedradicalmastectomybeforewedemonstratedinrandomizedtrialsthatitwasnotsuperiortolessmutilatingsurgery.NaturalHistoryofBreastCancer

ImplicationsRandomizedtrialsareusuallyrequiredtoevaluateinterventions.Becausethedefinitionsofbreastcancerarechanging,comparisonsofresultsobtainedtodaywiththoseinanhistoricalseriesareoften(usually)misleading.BreastCancerIncidenceandDeathRate(US)1973-1998020406080100120140197319761979198219851988199119941997Rateper100,000WhiteBlackWhiteBlackIncidenceDeathsHoweet.al.20011976198219881994197319791985199119970306090120150180Rateper100,000BreastCancerDeathRatesByAge(US)1973-1998Howeet.al.200165-7475+50-64<50AGEClinicalCourseofDiseasePresentationAlumpAbnormalityonscreeningSymptomsofdistantmetastasesHighriskcharacteristicsClinicalCourseofDiseasePresentationWhatdoyoudofirst?PhysicalexaminationMammogram(+ultrasound+MRI)AspirationBiopsyFineneedleIncision/excisionalGuidedbiopsyClinicalCourseofDiseasePresentationWhatdoyoudofirst?DeterminingextentofdiseaseStaging–TNMEvaluationfordistantmetastasesBloodtests,chestX-ray,CTscans,bonescanSurgicalstaging(usuallypartofinitialtherapy)LymphnodesPathology:tumorgrade,receptorstatusBonemarrowbiopsyClinicalCourseofDiseaseLocaltreatmentsLumpectomyMastec

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