Presentation on theme: "What’s Positive about Triple Negative Breast Cancer?"— Presentation transcript:
1 What’s Positive about Triple Negative Breast Cancer? Julie R. Gralow, M.D.Jill Professor Endowed Professor of Breast CancerDirector, Breast Medical OncologySeattle Cancer Care AllianceUniversity of Washington School of MedicineFred Hutchinson Cancer Research Center
2 Breast Cancer: Classic Prognostic and Predictive Factors HER-2 +20-25% of Breast CancerEstrogen Receptor (ER) + 75% of Breast Cancer
3 Triple Negative Breast Cancer No expression of ER, PR, ER215% of breast cancersAggressive, higher recurrence ratesChemotherapy is currently main treatment optionMore common in:Young womenAfrican AmericansHispanicsBRCA1+ (80%)
4 Racial Distribution of Triple Negative Breast Cancer Stead LA, et al, Breast Cancer Research 11:R18, 2009
5 Timing of Recurrence in Triple Negative Breast Cancer vs Timing of Recurrence in Triple Negative Breast Cancer vs. Other Subtypes Dent et al. Clin Can Res 2007; 13: 4429
6 Gene Expression Profiling in Breast Cancer Over the last decade, gene expression profiling has given us insights into the biological complexity of breast tumorsClinically applicable gene expression-based assays have been and are being developed for prediction of prognosis and/or treatment benefit
7 Sørlie et al. Proc Natl Acad Sci U S A. 2003;100:8418. Molecular Classification of Breast Cancer: Breast Cancer is NOT One Disease! The Cancer Genome Atlas Network. Nature 490, 2012“Heat Map”Normal Breast–likeLuminal ALuminal BHER-2+BasalRed dots: Genes are “turned up” in cancer cells compared to normal cellsIndividual genesA total of 115 breast cancer tumor tissues and 7 nonmalignant tissues were analyzed for characteristic patterns of gene expression measured by DNA microarrays applicable to classifying tumors into clinically relevant subgroups. Analysis was by hierarchical clustering based on patterns of expression of 534 “intrinsic” genes, delineated relative to 5 tissue subtypes:One basal-like, 1 ErbB2 (HER2)-overexpressing (ERBB2+), 2 luminal-like (subtypes A and B), and 1 normal breast tissue–likeSlide shows the 5 recognized subgroups of coexpressed genes, with group C representing the ErbB2 (HER2)-overexpressing subgroup of genes.Expression of the HER2 gene cluster is most pronounced in the ERBB2+ tissue subtype of tumors, hence its designation.Results strongly support the contention that many breast cancer subtypes represent biologically distinct disease entities.Individual patientsSørlie et al. Proc Natl Acad Sci U S A. 2003;100:8418.
8 Basal Subtype Low expression of luminal and HER2 gene clusters Typically ER-, PR-, and HER-2-negative, but up to 30 percent discordanceHigh expression of proliferation cluster genes, virtually always high grade, widespread genomic instabilityHigh expression of EGFR and unique basal cluster genes (basal epithelial cytokeratins 5, 14, and 17)p53 mutations commonOther receptors and pathways can be altered (c-kit, c-met, RAS-MAPK, mTOR/PI3K)Strong association with cancers in BRCA1 mutation carriers (over 80 percent basal-like)Associated with DNA repair defectsPARP1 commonly increased
9 Clinically Available Genomic Assays in Breast Cancer OncotypeDX and Mammaprint provide prognostic information in early breast cancerOncotypeDX provides predictive information of benefit from adjuvant chemotherapy in ER-positive diseaseGenomic Health Oncotype Dx 21-Gene Recurrence Score AssayAgendia Mammaprint 70-Gene Prognostic Signature Assay
10 PAM50 Breast Cancer Intrinsic Classifier Assay PAM50 classifier identifies the four major biologic subtypes of breast cancer referred to as Luminal A, Luminal B, HER2-enriched, and Basal-likeMeasures 50 classifier genes and 5 control genes through RT-qPCRInvestigational in USClinical validation studies ongoing
11 Not all Triple Negative Breast Cancers are Basal Subtype, and Not all Basal Breast Cancers are Triple Negative Prat A et al, Oncologist 2013 epub ahead of printClinical status (by standard pathology testing): Triple NegativeSubtype status (by genomic profiling): Basal
12 Triple Negative Breast Cancer: Subtypes and Therapeutic Targets Lehmann B, JCI 2011; Pietenpol J. SABCS 2012Genomic Profiling of TNBC: 6 Subtypes Identified!Analysis of 21 public data setsIdentified 587 TNBCs386 in training set201 in validation setDifferential sensitivity of TNBC cell lines to targeted agents due to distinct expression patterns, expression of key mutations in oncogenes and tumor suppressors
13 Treatment Approaches for Triple Negative Breast Cancer Specific chemotherapy agents (e.g. platinums)Anti-angiogenics (blood vessel blockers)Poly ADP ribose polymerase (PARP) inhibitors
14 Preoperative Chemotherapy with Platinum Compounds: Phase II Trials GarberCDDP → SurgN = 28RyanCDDP/BEV → SurgN = 51TorrisiECF → P → SurgN = 30GronwaldCDDP → SurgN = 258060402022154072TripleNegativeBRCA-1Mutation% pCRPt Characteristics1. Garber JE, et al. Breast Cancer Res Treat. 2006;100(Suppl 1): Abstract Ryan PD, et al. J Clin Oncol. 2009;27(15S): Abstract Torrisi R, et al. Cancer Chemother Pharmacol. 2008;62(4): Gronwald J, et al. J Clin Oncol. 2009;27(15S): Abstract 502.14
15 TBCRC 009: Phase II Study of Cisplatin or Carboplatin in Metastatic TNBC Isakoff SJ et al, ASCO 2011 abstract # 1025Patients: 86 metastatic TNBCTreatment: Randomized to cisplatin or carboplatinResults:Response Rate 30% overallCisplatin 37%Carboplatin 23%1st line RR 32%, 2nd line 20%Conclusion: Both active and well-toleratedEvaluating p63/73 for prediction of response
16 Phase III Trial of Eribulin vs Capecitabine for Metastatic Breast Cancer Kaufman P et al, SABCS 2012 Abstract # S6-6Eribulin has demonstrated survival benefit in heavily pre-treated metastatic breast cancerCapecitabine approved for treatment of metastatic breast cancer following exposure to anthracycline/taxaneCo-primary endpointOS and PFSLine of therapy20% 1st line50% 2nd line30% > 3rd line
17 Overall survival by receptor status Phase III Trial of Eribulin vs Capecitabine for Metastatic Breast Cancer Kaufman P et al, SABCS 2012 Abstract # S6-6Overall survival by receptor statusNo significant difference between eribulin and capecitabineExploratory analysis suggests possible increased benefit for eribulin in certain subsets (ER-, TNBC)TNBC: Overall survival 14.4 months eribulin, 9.4 months capecitabine
18 Angiogenesis Inhibition: Agents Targeting the VEGF Pathway Bevacizumab (Avastin) Anti-VEGF Antibody: binds to VEGF and blocks tumor blood vessel growthBLOOD VESSEL CELLVEGFReceptorVEGFOther VEGF/VEGFR inhibitors:sunitinibsorafenibaxitinibpazopanibCANCER CELL
19 1st-Line BevacizumabE2100: Paclitaxel +/- Bevacizumab in Stage IV Breast Cancer Miller KD et al, NEJM 2007Eligibility:- No prior chemo for metsAdjuvant taxane if >12 mos.HER-2+ only if prior trastuzumabRANDOMIZEPaclitaxel + bevacizumabPaclitaxel28-day cycle:Paclitaxel 90 mg/m2 d1, 8, and 15Bevacizumab 10 mg/kg d1 and 15Accrual: 685
20 Paclitaxel +/- Bevacizumab in Metastatic Breast Cancer Miller KD et al, NEJM 357:2666-76, 2007 Paclitaxel alonePaclitaxel + Bevacizumab28months2538%%1116%Slide 20 from Budman’s “Role of Taxanes” file.6
21 Accelerated FDA approval in 2008 E2100: Paclitaxel +/- Bevacizumab in Stage IV Breast Cancer Miller KD et al, NEJM 2007Toxicities (grade 3,4)Paclitaxel Paclitaxel + BevHTN 2% 15% p<0.001Thrombosis 4% 2%Bleeding 0% 2% p=0.02Proteinuria 0% 2% p=0.002Slide 20 from Budman’s “Role of Taxanes” file.Accelerated FDA approval in 2008
22 FDA Revoked Approval of Bevacizumab in Breast Cancer FDA removed metastatic breast cancer from bevacizumab labelNo survival benefitToxicBiologic reality?Rebound effect?Lack of targeting to appropriate population?Which patients?Which tumors?
23 2nd-Line Bevacizumab Phase III RIBBON 2 Trial of Chemo/Bevacizumab in 2nd-line HER2-Negative Metastatic Breast Cancer Brufsky A et al, J Clin Oncol 2011Chemotherapy (taxane*, gemcitabine, vinorelbine, or capecitabine)Bevacizumab 10 mg/kg q 2 weeks or 15 mg/kg q 3 weeksRANDOMIZEInclusion criteria:1 prior chemotherapyHER2 negativePD2:1Chemotherapy (taxane*, gemcitabine, vinorelbine, or capecitabine)Placebo q 2 weeks or q 3 weeksPD(n = 684)* Taxane allowed: q 3weekly docetaxel, paclitaxel, or albumin-bound paclitaxel
24 Chemotherapy/ Placebo Chemotherapy/ Bevacizumab RIBBON 2: EfficacyChemotherapy/ PlaceboChemotherapy/ BevacizumabOverall Response Rate30%39.5%P =Median Progression-Free Survival5.1 months7.2 monthsHR 0.78 (95% CI, ); P =Median Overall Survival (Interim)16.4 months18 monthsHR 0.90 (95% CI, ); P =Response rate, PFS higher with bevacizumab; OS not statistically different
25 RIBBON 2: Progression Free Survival in Triple Negative Subgroup Brufsky A et al, Breast Cancer Res Treatment 20121.00.80.60.40.20.0PFSBEV + CT (N = 112)PLA + CT (N = 47)Events, n (%)94 (84)42 (89)Median, months6.02.7HR0.494Log-rank testp =Estimated probability2.76.0Time (months)2525
26 RIBBON 2: Interim Overall Survival in Triple Negative Subgroup Brufsky A et al, Breast Cancer Res Treatment 2012OSBEV + CT (N = 112)PLA + CT (N = 47)Events, n (%)52 (46)29 (62)Median, months17.912.6HR0.624Log-rank testp =1.00.80.60.40.20.0Estimated probability12.617.9Time (months)2626
27 BEATRICE: Phase III Trial of Adjuvant Bevacizumab in Triple Negative Breast Cancer Cameron D et al, SABCS 2012, Abstract # S6-5EligibilityResected invasive breast cancerNegative for ER, PR, HER2 (centrally confirmed)N=2,59163% lymph node negativeInvestigator’s choice of standard chemo (4-8 cycles)ObservationInvestigator’s choice of standard chemo (4-8 cycles)BEV (5mg/kg/wk equivalent)BEV monotherapy (total duration 1 yr)Chemotherapy optionsTaxane based > 4 cyclesAnthracyclline based >4 cyclesAnthracycline + Taxane (3-4 cycles each)Primary endpoint: invasive disease-free survival
28 BEATRICE: Phase III Trial of Adjuvant Bevacizumab in Triple Negative Breast Cancer Primary Endpoint: IDFSInterim OS (59% of events)No improvement in DFS or OS for addition of bevacizumab
29 BEATRICE: Phase III Trial of Adjuvant Bevacizumab in Triple Negative Breast Cancer Disappointing1st randomized Phase III adjuvant trial specifically for triple negative population3 year survival better than anticipatedNo significant improvement in DFS/OS with addition of bevacizumabAdverse event profile consistent with that previously seen
30 Recently Reported Preoperative Trials of Bevacizumab in Breast Cancer NSABP B-40 (Bear H et al) NEJM 2012Preop anthracycline/taxane chemotherapy +/- bevacizumabImproved pathologic Complete Response (pCR) with bevacizumab: 28.4% vs 34.5%, p = 0.027Geparquinto (Von Mickwitz G et al) NEJM 2012Overall (HER2-): pCR 15% vs 17.5% p = nsTriple negative subset: pCR 27.8% (no bev) vs 36.4% (with bev) p = 0.21Will this translate into improved DFS and OS in the adjuvant trials? Possible reason for optimism?
31 The Human Epidermal Growth Factor Family of Receptors LapatinibHER3HER1EGFRHER2HER4Tumor CellThe human epidermal growth factor family of receptors consists of 4 transmembrane proteins with different properties (HER1-4), all involved in regulation of cell proliferation and survival.1-5The prototype HER member HER1/EGFR (Erb-B1) binds a variety of growth factors, with ligand binding activating tyrosine kinase activity within the cytoplasmic domain and through various signal transduction intermediates.1HER2 has no known ligand-binding activity, but its tyrosine-kinase activity is transactivated through HER2 interaction with other HER members (heterodimerization), usually following ligand binding to those receptors.3The HER2 extracellular domains are fixed in an open conformation (exposed domain II loop) that resembles a ligand-activated state, and thus HER2 can constitutively interact functionally with other HER members.6HER3 lacks inherent tyrosine kinase activity, but ligand binding promotes HER heterodimerization, resulting in complexes (eg, HER2/HER3) with highly proliferative signaling activity.2,4The HER signaling network, mediated by these receptor interactions, stimulates and regulates not only cell proliferation, but also mobility, adhesion and survival.4,5 The activity of HER2/HER4 dimers is unclear, but may be implicated in providing survival signals to cardiomyocytes.4,5ErlotinibGefitinibCetuximabTrastuzumabPertuzumab1. Ritter and Arteaga. Semin Oncol. 2003;30(suppl 1):3.2. Hung and Lau. Semin Oncol. 1999;26(suppl 12):51.3. Tzahar and Yarden. Biochim Biophys Acta. 1998;1377:M25.4. Pinkas-Kramarski et al. EMBO J. 1996;15:2452.5. Zhao et al. J Biol Chem. 1998;273:10261.6. Cho et al. Nature. 2003;421:756.
32 EGFR Targeted Therapy in Unselected Metastatic Breast Cancer n RR CB TTPGefitinibRobertson (2003) 33 7% 30% ?Baselga (2003) % 6% 8 wksAlbain (2002) % 5% 8 wksErlotinibWiner (2002) 69 3% 6% 6 wksConclusions:Minimal clinical activity in heavily pretreated, unselected breast cancer patientsPharmacodynamic results were seen: EGFR signaling pathway is affected in tumor and skinPossible role in “triple negative” population?
33 Carboplatin + Cetuximab Cetuximab + Carboplatin TBCRC 001: Randomized Phase II Study of Cetuximab in Combination with Carboplatin in Stage IV TNBC Carey LA et al, J Clin Oncol 30, 2012Eligibility:Metastatic TNBC102 patientsRANDOMIZECarboplatin + CetuximabCetuximab + CarboplatinCetuximabPD
34 TBCRC 001: Randomized Phase II Study of Cetuximab in Combination with Carboplatin in Stage IV TNBC Carey LA et al, J Clin Oncol 30, 2012CetuxumabCetux Cetux + CarboCetux + CarboComplete Response1.4%Partial Response6%17%15%Stable Disease16%25%23%Progressive Disease77%50%52%Overall ResponseClinical Benefit Rate10%31%
35 TBCRC 001: Randomized Phase II Study of Cetuximab in Combination with Carboplatin in Stage IV TNBC Carey LA et al, J Clin Oncol 30, 2012Despite strong preclinical data, combination cetuximab plus carboplatin in metastatic TNBC produced responses in fewer than 20% of patientsEGFR pathway analysis showed that most TNBCs involved activationHowever, cetuximab blocked expression of the EGFR pathway in only a minority, suggesting that most had alternate mechanisms for pathway activation
36 Ongoing Study at UW: Combined Targeted Therapies for TNBC: Phase II Trial of Weekly Nab-Paclitaxel and Bevacizumab Followed by Maintenance Bevacizumab and Erlotinib PI: J SpechtLocally recurrent or metastatic ER/PR/HER2 negative breast cancer; >6 mos from weekly paclitaxel (n=63)Nab-paclitaxel 100 mg/m2 IV Qwk x 24 + Bevacizumab 10 mg/kg IV Q2wk x 8CR, PR, SDBevacizumab 10 mg/kg IV Q2wk + Erlotinib 150 mg PO dailyPrimary objective: PFSSecondary objectives: RR, OS, Safety, EGFR, SPARC expression in primary tumor, CTC, CEC
37 PARP as a Target for Therapy Enzyme with role in DNA repairIncreased levels in triple negative breast cancerAllows cancer cells to be more resistant to chemotherapy and radiation therapy effectsNeeded for survival of BRCA-deficient cells
38 PARP is an Important Enzyme in DNA Repair of Normal Cells as Well as Cancer Cells Environmental factors(UV, radiation, chemicals)DNA DAMAGENormal physiology(DNA replication)Cell DeathChemotherapy, RadiotherapyReplication LesionsBase excision repairPARP1DNA REPAIR PATHWAYSSingle Strand BreaksBase excision repairPARP1Double Strand BreaksHomologous recombinationBRCA1/BRCA2DNA Adducts/Base DamageBase excision repairPARP1
39 PARP Inhibitors as Therapy in Breast Cancer Potentiate effects of chemotherapy-induced DNA damageSingle agent activity in BRCA1/2 deficient tumorsCurrently being evaluated in clinical trialsPARP inhibitors with reported clinical data to date:Iniparib (BSI-201)Veliparib (ABT-888)Olaparib (AZD 2281)
40 Oral PARP Inhibitor Olaparib in BRCA-deficient Advanced Breast Cancer Tutt A et al, ASCO 2009, abstract # 501Patients: BRCA1/ BRCA2 + advanced, chemotherapy refractory breast cancerTreatment:Cohort 1: olaparib 400 mg po BID (27 patients)Cohort 2: olaparib 100 mg po BID (27 patients)Results:– Objective response rate 41%– Median PFS: 5.7 monthsRare grade 3 nausea, fatigue, vomiting40
41 Randomized Phase II vs Phase III Trial Results Gemcitabine/Carboplatin +/- Iniparib in Triple Negative Metastatic Breast Cancer O’Shaughnessy et al, NEJM 2011 and ASCO 2011, abstract 1007Chemo aloneChemo + PARP inhibitorP=0.28P=0.02711.811.1P=0.005monthsmonths126.96.36.199.15.13.3Slide 20 from Budman’s “Role of Taxanes” file.Randomized Phase II studyRandomized Phase III studyFar less impressiveIniparib originally thought to be PARP inhibitor, now uncertain
42 Rodler E et al, SABCS 2011, abstract P1-17-04 UW/SCCA Phase I Trial of Cisplatin/Vinorelbine with PARP Inhibitor ABT-888 (Veliparib) in Metastatic Breast CancerRodler E et al, SABCS 2011, abstract PCisplatin 75 mg/m2 IV Day 1Vinorelbine 25 mg/m2 Days 1,8Veliparib Days 1-14Dose escalationevery 21 daysPatients with metastatic TNBC and/or BRCA mutation associated breast cancer
43 Maximum Tumor Response (%) from Baseline UW/SCCA Phase I Trial of Cisplatin/Vinorelbine with ABT-888 (Veliparib)Maximum Tumor Response (%) from Baseline36 patients enrolled to dateCurrently at dose level 7 of veliparib
44 Triple Negative Breast Cancer is a Highly Diverse Group of Cancers 6 subtypes of TNBC identified by gene expression array!Lehmann BD, et al. J Clin Invest 121: , 2011
45 6 Types of Triple Negative Breast Cancer Basal-like 1 and 2 (BL1, BL2)High expression of cell cycle and DNA response genesMore responsive to platinum chemotherapyImmunomodulatory (IM)Mesenchymal (M) and Mesenchymal-stem Like (MSL)Enriched for genes associated with epilthelial-mesenchymal transitionResponsive to mTOR, PI3K, abl-src pathway drugsLuminal Androgen Receptor (LAR)Sensitive to androgen receptor drugs
46 TNBC LAR Subtype Not Yet Reported TBCRC 011: Targeting Androgen Receptor for the Treatment of AR+/ER-/PR- Metastatic Breast Cancer Gulcap A et al, ASCO 2011, abstract # 12210-20% of TNBC are Androgen Receptor PositiveDrugs targeting AR are typically used in treating prostate cancerBicalutamide (Casodex)Enzalutamide (Xtandi)TBCRC 011: Treatment with bicalutamideStudy: 230 TNBC patients tested, 27 AR+No results to date
47 Claudin-low Subtype Claudin-low Basal 5-10% of tumors HER2BasalClaudin-low Subtype5-10% of tumorsTypically ER-, PR-, HER2-Low expression of cell-cell junction proteinsLymphocyte infiltratesStem cell + EMT featuresLuminalProliferation
48 TNBC M/MSL and Claudin-low Subtypes Metaplastic Breast Cancer Subtype of triple negative breast cancerRare, but increasing incidenceDistinct subtype by molecular profilingClaudin-lowEnriched for epithelial-to-mesenchymal transition (EMT) markers~50% of tumors have PI3K mutations or loss in PTENIncreased VEGF productionChemorefractory<10% pCR rate with neoadjuvant chemotherapyLittle data regarding response in metastatic setting
49 DAT in Advanced Cancers Cancer Moroney J et al, Clin Cancer Res 18, 2012 136 patients with advanced cancer29 breast cancer (12 metaplastic)RegimenLiposomal doxorubicin (Doxil) 30mg/m2 IV every 3 weeksBevacizumab (Avastin) 15mg/kg IV every 3 weeksTemsirolimus (Torisel) 25mg IV weeklyResultsResponse in metaplastic breast cancer: 5/12 (42%)
50 TNBC M/MSL and Claudin-low Subtypes Proposed SWOG Clinical Trial: DAT for Metaplastic Triple Negative Breast Cancer PI: S MoulderTriple negative, metastatic breast cancerHigh grade metaplastic, spindle cell, or myoepithelial histologyVimentin positive‘Claudin-low’ or Mesenchymal-like tumors by profilingRegimen: DAT vs liposomal doxorubicinLiposomal doxorubicin (Doxil) 30mg/m2 IV every 3 weeksBevacizumab (Avastin) 15mg/kg IV every 3 weeksTemsirolimus (Torisel) 25mg IV weekly
51 Molecular Characterization of Residual Triple Negative Breast Cancer after Preoperative Chemotherapy Balko JM et al, SABCS 2012 Abstract # S3-6114 clinically-defined TNBC patients with residual disease after preop chemoImmunohistochemistryKi67, ER, PR, HER2, AR 112/114Nanostring digital expression analysis450 genes89/114Next generation sequencing182 oncogenes and tumor suppressors
52 Molecular Characterization of Residual Triple Negative Breast Cancer after Preoperative Chemotherapy Balko JM et al, SABCS 2012 Abstract # S3-6 Clinically Targetable Pathways in TNBCNo. of samples with aberrationsPI3K/mTOR inhibitorsDNA repair-targeting agentsRAF/MEK inhibitorsCell cycle/ mitotic spindle inhibitorsTargeted RTK inhibitorsThese data show that TNBC after preoperative chemotherapy is heterogeneous and has multiple alterations that are targetable with existing drugs in development
53 veliparib + vorinostat cisplatin + vorinostat Treatment with Histone Deacetylase Inhibitors Creates ‘BRCAness’ and Sensitizes Triple Negative Breast Cancer Cells to PARP Inhibitors and Cisplatin Bhalla KN et al, SABCS 2012 Abstract # S3-7Synergism dataMethods:Used human triple negative cell linesBRCA-mutant (SUM159PT)BRCA non-mutant (MDA-MB-231, HCC1937)Treated with HDACi (vorinostat), PARPi (veliparib), & cisplatinResults:Vorinostat synergistically enhanced PARPi and cisplatin-induced induced DNA strand breaks and apoptosisSynergistic inhibition in TNBC cells (CIs <1.0)0.20.40.60.81.00.51.5Fractional EffectCISUM159PTveliparib + vorinostatHCC193188.8.131.52.81.0Fractional EffectCIHCC1937cisplatin + vorinostatMDA-MB-231Supports evaluation of HDAC inhibitors with PARP inhibitors and cisplatin in TNBC
54 Triple-Negative Tumor Conclusions Triple-negative breast cancers are a heterogeneous group primarily composed of Basal-like breast tumorsClaudin-low tumors are also a major constituent of Triple-negative cancersChemotherapy benefit is typically high, although subsets have little chemo benefitMany biologically targeted agents are being tested on this group including PARP inhibitors, angiogenesis inhibitors, HER1/EGFR and mTOR/PI3K pathway inhibitors
55 Treatment of Triple Negative Breast Cancer: The Future is Looking Up!
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