Ductal Carcinoma in situ: Overview and Updates

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Ductal carcinoma in situ (DCIS) refers to breast epithelial cells that have become “cancerous” but still reside in their normal place in the ducts and lobules. In this setting, cancerous means that there is an abnormal increase in the growth of the epithelial cells, which accumulate within and greatly expand the ducts and lobules (Figure 1). DCIS is a non-lethal type of cancer because it stays in its normal place. However, DCIS is very important because it is the immediate precursor of invasive breast cancers (IBCs), which are potentially lethal. This presentation will provide a general overview of DCIS, including historical perspective, and methods of classification, as well as an update regarding recent important advances in understanding the development and progression of DCIS at the molecular level.

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Ductal Carcinoma in situ: Overview and Updates

  1. 1. Ductal Carcinoma In Situ (DCIS)of the Human BreastOverview and UpdatesD. Craig Allred, MD
  2. 2. NormalTDLUEarlyExpansion ofTDLU by DCISCompleteExpansion ofTDLU by DCISLook Like Ducts“Ductal” Carcinoma In SituDefinition of DCISBreast epithelial cells that have become "cancerous" but still residein their normal place inside the ducts and lobules.
  3. 3. IBCTDLUADHCCHDCISALH LCISTime (decades in most cases)Immediate precursor of invasive breast cancerImportance of DCISTDLUADHCCHDCISALH LCISTime (decades in most cases)Late stage in breast cancer evolution
  4. 4. DCIS is the Immediate Precursorof Invasive Breast Cancer (IBC)
  5. 5. Historical Perspectiveof Invasive Breast CancerAncientGreeceDarkAgesMiddleAgesRenaissanceTodayToday1600 BCEdwin SmithPapyrusEgyptHistorical Perspectiveof DCISEarly 1900sFirst Realized DCIS ≠ IBC2-3% all Breast CancerTx = Radical Mastectomy (Cure)Major Milestones Since:DCIS = Precursor of IBCNeeds Detection and TherapyScreening MammographyDCIS = 20-30% all Breast CancerLumpectomy + Adjuvant Rad TamRadical Mastectomy
  6. 6. Natural History of DCISDCIS(Non-Lethal)IBC(Potentially Lethal)DHDCISIBCALH LCISes)TDLUADHCCHDCISIBCALH LCISTime (decades in most cases)OverallProportionUnknown≥ 30-40% over 30 yearsJAMA 239:1863, 1978Cancer 46:919, 1980Cancer 49:751, 1982Sem Diag Pathol 11:223, 1994Absolute ProportionToo HighAll IBCs from undetected DCIS
  7. 7. Classification of DCISComedo Cribriform SolidPapillaryMicropapillarySubtypes of DCIS based on gross appearanceand predominant microscopic growth pattern
  8. 8. Classification of DCISSubtypes of DCIS based on gross appearanceand predominant microscopic growth patternProblem = Intra-Tumor DiversitySolid/ComedoCribriform≥50% DCISwith >1 patternClin Cancer Res 14:339, 2008
  9. 9. Classification of DCISHistological Grade:The Degree that TumorResembles NormalHistological Scoring and Grading of DCISBased on Scarff-Bloom-Richardson method of grading IBCClin Cancer Res 14:339, 2008210 - 75%intermediate1 - 210 - 50%Score1> 75%low< 1< 10%3< 10%high> 2> 50%Microscopic FeatureA. Glands/papillaeB. Nuclear gradeC. Mitotic rateD. Central necrosis= total score (range 4-12)Grade 1 = 4 -7 points (well differentiated)Grade 2 = 8-9 points (intermediate differentiated)Grade 3 = 10-12 points (poorly differentiated)A=1B=1C=1D=1Total=4Grade =1A=2B=2C=2D=2Total=8Grade =2A=3B=3C=3D=3Total=12Grade =3
  10. 10. Classification of DCISHistological Grade:The Degree that TumorResembles NormalProblem = Intra-Tumor DiversityGrade 3Grade 1≥50% DCISwith >1 GradeClin Cancer Res 14:339, 2008
  11. 11. Classification of DCISBiological FeaturesStandard Prognostic BiomarkersHistological Score (Modified SBR; Clin Cancer Res 14:339, 2008)4567891011120Percent102030405060708090100N=200% ER+% PgR+% p53+% HER2+% CasesPure DCISavg %Ki67WellDifferentiatedPoorlyDifferentiated456789101112N=20056789N=200IBC DCIS (+IBC)34DCIS IBC
  12. 12. From: Solin, et al: J Clin Oncol 14:754, 1996.Histological Grade and Standard Biomarkersin DCIS are Related to Rate butnot Fate of Progressing to IBC.
  13. 13. LuminalER/PR+GATA3+ERBB2-CK18+Other...BasalERBB2-ER/PR-CK5+Other…MixedERBB2ERBB2+ER/PR-GRB7+Other...Sorlie et al. PNAS 98:10869, 2001DCIS IBCClassification of DCISBiological FeaturesIntrinsic Molecular SubtypesERBB2BasalMixedLuminalDCISAllred et al. Clin Cancer Res 14:339, 2008IBC
  14. 14. Grade 1 Grade 2 Grade 3Case#020Case#01229.2% 22.5% 2.5%30.0%9.2%6.6%30% 60% 10%10% 85% 5%Diversity of Histological (Nuclear) GradeWithin Cases of DCIS (n=120)Allred et al. Clin Cancer Res 2008
  15. 15. Category1. No Diversity2. Grade3. Grade + Biol% Cases51.8%48.2%13.4%Diversity of Histological Grade andBiological Characteristics Within Cases (n=112)(ER, GATA3, Her2, CK5, CK18 and p53)(Allred et al. Clin Cancer Res, 2008)(1 vs. 2 vs. 3)p=0.0016% p53+13.8%40.5%45.5%Example:Case106H&EH&E ER=7/8ER=5/8Her2=0/8Her2=6/8 p53=6/8p53=0/8Grade 1(60%)Grade 2(40%)p=0.2833% ER+70.7%60.8%57.6%p=0.8296% Her2+39.7%39.2%57.6%
  16. 16. Diversity of Histological Grade and IntrinsicSubtypes Within Cases of DCIS (n=112)(Allred et al. Clin Cancer Res, 2008)Luminal ALuminal BBasalERBB2Different SubtypesSame Subtype73% (11/15) of DCIS with diversityof histological (nuclear) grade and biomarkersalso showed diversity of intrinsic subtypesof nearly all possible combinationsLumA + erbB2 = 4 casesLumA + Basal = 1 caseLumA + LumB = 3 casesLumB + erbB2 = 2 casesBasal + erbB2 = 1 caseCancer Stem Cell Conundrum
  17. 17. DCIS(Non-Lethal)IBC(Potentially Lethal)DHDCISIBCALH LCISes)TDLUADHCCHDCISIBCALH LCISTime (decades in most cases)DCIS ≠ IBC Regarding InvasionTumor EpithelialCells Very SimilarMolec Cancer Res 1:362, 2003PNAS 100:5974, 2003Stromal CellsVery DifferentCancer Cell 6:17, 2004
  18. 18. Genetic Differences DCIS vs. IBCJuly, 20125 Cohorts DCIS vs. IBC54 samples each type50% LCM microdissectedAffymetrix microarrays
  19. 19. Supervised Comparisons≥ 2 Fold; p < 0.05472 Genes ≥ 1 Group This Study74 Genes ≥ 2 Groups This StudyMeta-analysis:69% Overlap with ≥1 ofall Previous Microarry StudiesAverage = 3.8 Studies/GeneRange = 3 to 7 StudiesIBC > DCIS (n=42)Candidate Promotersof Tumor Progression
  20. 20. DCIS > IBC (n=32)Candidate Suppressorsof Tumor ProgressionSupervised Comparisons≥ 2 Fold; p < 0.05472 Genes ≥1 Group This Study74 Genes ≥2 Groups This StudyMeta-analysis:38% Overlap with ≥1 ofall Previous Microarry StudiesAverage = 3.8 Studies/GeneRange = 3 to 5 Studies
  21. 21. Gene Expression Signature (n=74)DCIS vs. IBC96% Correct Classification Study SamplesHierarchical Clustering74-Gene Signature(avg = 34/74 per group)DCISIBC
  22. 22. Gene Expression Signature (n=74)DCIS vs. IBC95% Correct Classification Samplesin 3 Independent StudiesDCISIBC
  23. 23. Ontologies and Pathways Associated withthe Progression of DCIS to IBCAdjusted p-value
  24. 24. Ontologies and Pathwaysin Tumor Epithelium vs.StromaEMT+
  25. 25. Functional StudiesMammary Intraductal DCIS (MIND) Xenografts(Behbod et al. Breast Cancer Res, 2009)DCISIBCDCIS.COM shCSTA-A9DCIS.COM shCSTA-A9
  26. 26. Functional StudiesHuman DCIS Cell LinesCell Line1. DCIS.COM2. DCIS.SUM.2253. DCIS.FSK-H74. hDCIS.015. hDCIS.026. hDCIS.037. hDCIS.048. hTDLU.019. hCCH.0110. hCCH.02Max Pass #>100>10055>10011716131510Keratin IHC+++++++++++++++++++++++++++++MIND Xenografts ≤10 WksNone10%30%30%20%ndndndndndndDCIS60%70%70%60%ndndndndndndIBC30%0%0%20%ndndndndndnd1 2 3 4 56 7 8 9 10
  27. 27. Knock Down (shRNAi) “Suppressors”Predict Increased Tumor Progression1. I-A7 (hairpin)2. I-A9 (hairpin)3. I-D4 (hairpin)4. RFP-1 (control)5. RFP-2 (control)6. DCIS.COM-CBRz (control)1 2 3 4 5 6b-ActinCSTAWestern Blot3 of 3 hairpinssignificantly decrease proteinexpression in DCIS.COM(1A7>IA9>1D4)Real-time PCR3 of 3 hairpinssignificantly decrease RNAexpression in DCIS.COM(1A9>1A7>1D4)completeknockdownDCIS.COM Transduced with CSTA shRNAi (n=3)
  28. 28. Effects ofKnocking Down“Suppressors” InVivo(DCIS.COM)Normally Suppress Invasion:CSTA (Cystatin A)DST (Dystonin)FAT1 (Procadherin)TMEM45A (Transmembrane Protein 45A)
  29. 29. Validation in Additional DCIS Cell LinesNormallySuppress Invasion:CSTADSTFAT1
  30. 30. Validation of CSTA at Protein Levelby IHC in Human Breast TissueDCISA BFC DETDLUDCISDCISIBCIBCCCHTDLUTDLU CCH DCIS IBCCSTA Pos 96% 95% 58% 26%#Cases 27 40 92 228P <0.001Normally Expressedin Myoepithelial CellsFrequently Mislocalizedto Luminal Cells in DCISSignificantly Reducedin IBC vs. DCIS
  31. 31. DCIS.COM.shCSTA.1A7 MIND XenograftsIHC for p63(human and mouse specific)IHC for Vimentin(human specific)Human DCIS Cell Lines are Pluripotential(Myoepithelial and Luminal)MECsMECsLUMLUM
  32. 32. 0.020.040.060.080.0100.0120.0pB-pu CILP-pu FAP-pu> 205 - 200 - 5noneDCIS.COMPromote Invasion:CILP (Cartilage Intermediate Filament Protein)FAP (Fibroblast Activation Protein Alpha)Overexpress (cDNA) “Promoters”Predict Increased Tumor Progression
  33. 33. Improved detection, diagnosis, and surgery(lumpectomy) of DCIS through targetedimaging based on molecular features specificfor DCIS vs. IBC.By understanding more about DCIS we cansignificantly decrease the incidence of IBC (atleast 10%) during the next decade by:Improved prognostication, therapy, andprevention of DCIS based on targetingmolecular features regulating the progressionDCIS to IBC.

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