USING PROGNOSTIC & PREDICTIVE FACTORS IN BREAST CANCER

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2006 European Breast Cancer Meeting Stockholm, Sweden 2021 May 2006. USING PROGNOSTIC & PREDICTIVE FACTORS IN BREAST CANCER. Fatima Cardoso, MD Jules Bordet Institute & TRANSBIG. PROGNOSTIC FACTOR. %. Treat. A. Treat. B. +. -. PREDICTIVE FACTOR. Case 1. Case 2. Treat. B. %. %. - PowerPoint PPT Presentation

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  • USING PROGNOSTIC & PREDICTIVE FACTORS IN BREAST CANCERFatima Cardoso, MDJules Bordet Institute & TRANSBIG2006 European Breast Cancer Meeting Stockholm, Sweden 2021 May 2006

  • PROGNOSTIC FACTOR%Treat. ATreat. B+-

  • PREDICTIVE FACTORCase 1Case 2%%++--Treat. BTreat. ATreat. BTreat. A

  • PROGNOSTIC FACTORS

    Who needs a treatment?PREDICTIVE FACTORS

    Which treatment is best?

    THERAPEUTIC CHOICES

    AVOID UNDER AND OVER TREATMENTINDIVIDUALIZE TREATMENTWHY DO WE NEED PROGNOSTIC AND PREDICTIVE FACTORS

  • ER-ER+RFSBasal-like1HER-2-likeLuminal1Luminal2Luminal3Basal-like2Adapted from Sotiriou et al, PNAS, 2003BC GENE EXPRESSION PATTERNS and OUTCOMEMolecular (re-)classification of BC

  • PROGRESS IN ADJUVANT CHEMOTHERAPY FOR BREAST CANCERL-PAM, MFCMF x 6AC x 4FAC FEC x 6A(E) CMFAC x 4 Paclitaxel x 4TAC x 6FEC docetaxelAC paclitaxel dose-dense++++++++++++Average treatment effectFinancial toxicity1970s1980s1990s2000sSuccessive generations of adjuvant CT regimensAdapted with permission from G. Hortobagyid) 20.000 $c) 13.800 $b) 7.400 $a) 800 $ +++ ADJUVANT TRASTUZUMAB +++

  • New prognostic factors accepted: HER-2, vascular invasionNode+ 1-3: in average risk group, if HER-2 and no vascular invasionSt Gallen 2005 Consensus: Whats new?Beyond St Gallen 2005 uPA, PAI-1Cyclin EGenomic signaturesOncotype DX*(predictive & Px)Topo-II-*Genomic Health

  • uPA-PAI-1

  • CLINICAL RELEVANCE OF uPA & PAI-1 IN PRIMARY BREAST CANCERuPA and PAI-1: first novel tumor biological factors in breast cancer with clinical relevance validated at highest level of evidence (LOE I)

    Standardized quality assured ELISA tests: Sweep et al, Br J Cancer 78: 1434-41, 1998 Prospective multi-center therapy trial (Chemo N0): Jnicke et al, JNCI 93: 913-20, 2001 EORTC RBG meta analysis (n=8,377): Look et al, JNCI 94:116-28, 2002 Recommended for clinical risk assessment:AGO Therapy Guidelines breast cancer (since 2002):www.ago-online.deN. Harbeck used with permission

  • uPA AND PAI-1 FIRST NOVEL TUMOR BIOLOGICAL FACTORS IN BC WITH LEVEL 1 OF EVIDENCEWHY ARE THEY NOT WIDELY USED?ELISA not commonly used in pathological practice Biochemistry lab required Further personnel training required$$ requiredFrozen tumor specimen requiredLarge quantity (100 g) requiredTarget population = small tumors feasible ?Population used in validation studies: Interaction with ER status not well defined (?)

  • HOW CAN THEY BECOME WIDELY USED?Refining ELISA testless tissueAlternative techniquesother protein assaysgene expressionFurther validation according to ER statusALL ONGOINGuPA AND PAI-1 FIRST NOVEL TUMOR BIOLOGICAL FACTORS IN BC WITH LEVEL 1 OF EVIDENCE

  • GENOMIC SIGNATURES

    BIG-TRANSBIG Secretariat Used with permission

    IMPROVED RISK ASSESSMENT OF EARLY BREAST CANCER THROUGH GENE EXPRESSION PROFILINGmicroarrayGene-expression profileGood signaturePoor signatureN Engl J Med, Vol 347 (25), Dec. 2002~4% die of breast cancer~96% survive breast cancer~50% die of breast cancer~50% survive breast cancer

  • TRANSLATING MOLECULAR KNOWLEDGEINTO EARLY BREAST CANCER MANAGEMENT

    BIG-TRANSBIG Secretariat Used with permission

    Audited clinical data

    INDEPENDENT VALIDATION : DESIGNRNAAchieved n = 307Target n = 400Amsterdam

    Gene expression profiling

    Agilent platform 70-gene prognostic custom designed chipHigh or low gene signature riskClinical dataLocal pathological dataBrusselsComparison of clinical vs gene signatureassessment of prognostic riskEndpoints1. TDM2. OS 3. DMFS, DFSTissue samples UK (Guys, Oxford) : 1984 => 1996 France (IGR, CRH) : 1978 => 1998 Sweden (Karolinska) : 1980 => 1990 Node negative, untreated < 60 years old > 5 years follow-up T1, T2 Tumor cell % > 50%Centrally reviewed path data (Milan)

    BIG-TRANSBIG Secretariat Used with permission

    OVERALL SURVIVAL by GENE SIGNATURE RISKAmsterdam/Agendia Signature10-year OS89% (81%-94%) 10-year OS70% (62%-76%) Average Survival HR 2.66M. Buyse et al. JNCI 2006. In press

    BIG-TRANSBIG Secretariat Used with permission

    TRANSBIG INDEPENDENT VALIDATION The best signature?Amsterdams Signature70 genesRotterdams Signature76 genesTEST ALL IN VALIDATION SERIES & DECIDEOnly few genes in common But similar biological pathwaysBrussels GGI signature

    BIG-TRANSBIG Secretariat Used with permission

    OVERALL SURVIVAL by GENE SIGNATURE RISKRotterdam/Veridex Signature5-year survival:low risk group: 0.98 (0.88-1.00)high risk group: 0.84 (0.77-0.89)10 year survival:low risk group: 0.87 (0.73-0.94)high risk group: 0.72 (0.63-0.78)C. Desmedt et al. Presentated at: EBCC 2006

  • CONCLUSIONS VALIDATION PHASEThe Amsterdam 70-gene signature has been independently validated The Rotterdam 76-gene & Genomic Grade signatures have been independently validated using the same TRANSBIG validation seriesThe performances of the signatures are similarThere is a strong time dependency of all signatures (better predictors of EARLY RELAPSE), which was not seen for the clinical riskThe Amsterdam 70-gene test is robust (laboratory reproducibility) and available for patient diagnostic testingGREEN LIGHT FOR MINDACT TRIAL!

  • Evaluate Clinical-Pathological risk and 70-gene signature riskClinical-pathological and 70-gene both HIGH riskDiscordant casesClin-Path HIGH70-gene LOWClin-Path LOW70-gene HIGHClinical-pathological and 70-gene both LOW riskUse Clin-Path risk to decide Chemo or notUse 70-gene risk to decide Chemo or not55%32%13%R1ChemotherapyN=3300N=780Endocrine therapyEORTC-BIG MINDACT TRIAL DESIGN6,000 Node negative womenN=1920Potential CT sparing in 10-15% pts

  • GENOMIC GRADE

  • Sotiriou et al., ASCO 2005 Poor inter observer reproducibility G2: difficult treatment decision making, under- or over treatment likely Findings consistent across multiple data sets and microarray platforms More objective assessment Easier treatment decision-making High proportion of genes involved in cell proliferation !C. Sotiriou used with permission

    Histologic GradeG1G2G3

    Genomic GradeGG1

    GG2

    GG3

  • GENOMIC GRADE IN EACH OF THE HISTOLOGIC GRADE SUBGROUPSC. Sotiriou used with permissionC. Sotiriou et al. JNCI 2006

  • Oncotype DX

    NSABP & Genomic Health

  • MULTI GENE RT-PCR ASSAY FOR PREDICTING RECURRENCE IN NODE NEGATIVE BC PATIENTS250 candidategenesTested usingRT-PCR

    Three studies

  • PROLIFERATIONKi-67STK15SurvivinCyclin B1MYBL2ESTROGENERPGRBcl2SCUBE2INVASIONStromolysin 3Cathepsin L2HER2GRB7HER2GSTM1REFERENCEBeta-actinGAPDHRPLPOGUSTFRCBest RT-PCR performance and most robust predictorsCD68 BAG1Paik et al, N Engl J Med 2004THREE BREAST CANCER STUDIES USED TO SELECT CANDIDATE GENES FOR A RECURRENCE SCORE UNDER TAMOXIFEN TREATMENTRecurrence score for TAM-treated pts established and subsequently validated

  • 338 pts

    149 pts

    181 ptsB14-RESULTSDRFSLow, Intermediate, High RS GroupsPaik et al, N Engl J Med 2004

  • PREDICTIVE MARKERS

  • HER-2 neu95% Negative predictive value
  • PREDICTIVE MARKERS FOR CHEMOTHERAPY

  • FISHIHCADJUVANT SETTINGCMF vs. ANTHRA-BASED TOPO II RESULTSDi Leo A et al, Clin Cancer Res, 2002All pts with HER-2 amplificationDi Leo A et al, Ann Oncol 2001

  • Topo IIa pos.

    p-value interaction test: 0.13

    Topo IIa neg.

  • 4 x AC 60/600 mg/m24 x Docetaxel100 mg/m26 x Docetaxel and Carboplatin75 mg/m2 AUC 61 Year Trastuzumab N=3,2221 Year Trastuzumab ACTACTHTCHHer2+(Central FISH)

    N+or high risk N-4 x AC 60/600 mg/m24 x Docetaxel100 mg/m2Slamon D., SABCS 2005BCIRG 006Stratified by Nodes and Hormonal Receptor Status

  • Disease Free Survival% Disease Free0.50.60.70.80.91.0012345Year from randomization77%86%80%73%84%80%86%93%91%Patients Events1073147AC->T107477AC->TH107598TCHHR (AC->TH vs AC->T) = 0.49 [0.37;0.65] PT) = 0.61 [0.47;0.79] P=0.0002Slamon D., SABCS 2005AC->THAC->TTCH

  • DFS CO-AMPLIFIED TOPO II BY ARM% Disease FreeMonths0.50.60.81.0061218243036424854Patients EventsTreatment22723AC->T26513AC->TH25221TCHLogrank P= 0.24TCHAC->THAC->TSlamon D., SABCS 2005

  • DFS NON CO-AMPLIFIED TOPO II BY ARM% Disease FreeMonths0.00.60.81.0061218243036424854Patients EventsTreatment45892AC->T47245AC->TH44654TCHLogrank P= THAC->TSlamon D., SABCS 2005

  • HER-2 AND TOPOISOMERASE-II PROMISING POTENTIAL PREDICTIVE MARKERS OF ANTHRACYCLINE EFFICACYHOW TO OBTAIN LEVEL 1 EVIDENCELARGE PROSPECTIVE TRIALSMETA-ANALYSIS

  • HER-2 AND TOPOISOMERASE-II AS POTENTIAL PREDICTIVE MARKERS OF ANTHRACYCLINE EFFICACY: A META-ANALYSISDANISH TRIALFEC vs CMFUK TRIALECMF vs CMFNCIC-CTG TRIALCEF vs CMFBELGIAN TRIALEC vs CMFTampere University LaboratoryCentral evaluation of HER-2/TOPO II gene amplification by FISHCorrelation with outcome of CMF or anthracycline-based therapy with 4,500 tumor samples

  • TOP TRIAL OR TRIAL OF PRINCIPLEOperable tumors, > 2 cmER-negativeEPIRUBICIN 100 mg/m x 4SURGERYDocetaxel x 4Radiotherapy HTHypothesis : pCr in HER-2 / Topo2 co-amplified tumors pCr in HER-2 - / basal-like 1 tumorsIncisional biopsySnap frozen sampleHER2/Topo2 FISH analysis(Vysis probe)Genomic signatureof response to anthracyclinesInflammatory or LABC ER-negativeEPIRUBICIN 100 mg/m x 6dose dense / 2w + G-CSFGene expression analysis

  • EORTC-BIG-p53 TRANSLATIONAL RESEARCH TRIAL: STUDY DESIGNTarget accrual= 1300 (872 p53-, 436 p53+)Hypothesis: DFS at 3 y by 5% in p53- and by 20% in p53+

  • FRAGRANCE trial4 - 6 monthsLetrozole15 daysMicroarrayAnalysisMicroarrayAnalysisGenomic signature of de novo AI resistanceMicroarrayAnalysis

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