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ASCO Viewing Presentation

ASCO Viewing Presentation. Title: Estrogen receptor alpha ( ESR1 ) gene amplification status and clinical outcome in tamoxifen -treated postmenopausal patients with endocrine-responsive early breast cancer: An analysis of the prospective ABCSG-6 trial. (19 slides ) Oral Abstract Session

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ASCO Viewing Presentation

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  1. ASCO Viewing Presentation Title: Estrogen receptor alpha (ESR1) gene amplification status and clinical outcome in tamoxifen-treated postmenopausal patients with endocrine-responsive early breast cancer: An analysis of the prospective ABCSG-6 trial. (19 slides) Oral Abstract Session Tumor Biology Track 2012 ASCO Annual Meeting Chair(s):  Robert Arthur Kratzke, MD; Priyanka Sharma, MD; Presentation Author:
Christian Singer, MD Subcategory:  Genomic and Epigenomic Biomarkers Category:  Tumor Biology Meeting:  2012 ASCO Annual Meeting Session Type and Session Title:  Oral Abstract Session, Tumor Biology Abstract Number:  10501 Citation:  J ClinOncol 30, 2012 (suppl; abstr 10501) Competing Financial Interests: The University Medical Centre Hamburg-Eppendorf has filed a patent application for certain technology described in this presentation.

  2. Estrogenreceptoralpha (ESR1) geneamplificationstatusandclinicaloutcome in tamoxifen-treated postmenopausal patientswithendocrine-responsiveearlybreastcancer: An analysisoftheprospective ABCSG-6 trial Christian F Singer & FrederikHolst, Stefan Steurer, EikeBurandt, HellmutSamonigg, SigurdLax, RaimundJakesz, MargarethaRudas, Herbert Stöger, Richard Greil, Otto Dietze, Guido Sauter, Martin Filipits, Ronald Simon & Michael Gnant, on behalf of ABCSG

  3. EstrogenReceptor - Background • expressed in 70% of invasive breastcancercases • establishedprognosticparameter • predictsresponsetoendocrinetherapy • actsas DNA-bindingtranscriptionfactor • 2 receptorsubtypes (ERaandERb) • ERaisencodedbyESR1 gene Thomas & Gustafsson, Nature Med 2011

  4. Biological Rationale • 5 yearsofadjuvant TAM reduce 15-year risksofrecurrenceanddeath in ER+ breastcancer • In neoadjuvantsetting: responsetoTAM dependson theamountofER proteinexpression • ER IHC standardmethod but inaccurate • Technical reasons (tissuepreparation,stainingprotocols,...) • Analytical reasons (cut-off forpositivity, interpretation,...) • ESR1copynumberstatussuperiorprognosticparameter in ER+ breastcancer? EBCTCG, Lancet 2011 Ellis et al., JCO 2001 Hammond et al., JCO 2010

  5. Study Objective • Toinvestigate the value of ESR1copy number status in predicting the long-term clinical outcome in TAM-treated postmenopausal women with endocrine-responsive breast cancer

  6. ABCSG 6 - Synopsis • Designedtodeterminewhethertheadditionofaminoglutethimide (ORI) to TAM improvesoutcome in postmenopausal womenwithhormonereceptor-positive earlystagebreastcancer • Prospectivelydesignedrandomizedmulticentertrial; 2021 patientsrandomizedbetween 1990 and 1995 • 5y of TAM vs 5y of TAM + 2 yofORI • 5 y DFS: 83,7% vs 83,6% (p=0,89), OS: 91,2% vs 92.4% (p=0,74) • Long-term FU and FFPE tumorsamplesavailable Schmid et al., JCO 2003

  7. ABCSG6 - Key elegibilitycriteria • Histologicallyconfirmedprimarybreastcancer • Stage I or II disease • Postmenopausal status • ER and / orPgRpositivity • Knownnodalstatus • Nopriorsystemicanticancertreatment

  8. ABCSG 6 - Study Flow

  9. ESR1CopyNumber Status by FISH CEP6 ESR1 Normal copynumber: ESR1/CEP6 Ratio ≤ 1 Low Level Gain: ESR1/CEP6 Ratio > 1 to <2.0 Amplification: ESR1/CEP6 Ratio ≥ 2.0 Holst et al., Nature Genetics 2007

  10. ESR1CopyNumber Status by FISH No ESR1 amp/gain ESR1 amp/gain Normal copynumber: ESR1/CEP6 Ratio ≤ 1 Low Level Gain: ESR1/CEP6 Ratio > 1 to <2.0 Amplification: ESR1/CEP6 Ratio ≥ 2.0 Holst et al., Nature Genetics 2007

  11. Patient Characteristics

  12. Receptor Status

  13. ESR1CopyNumber Status and ER Expression Chi-Quadrat, Pearson: p<0.0001

  14. Cox proportional hazard modelsDistant RFS and BCSS

  15. DistantRecurrence-Free Survival(Allred Score)

  16. DistantRecurrence-Free Survival(ESR1CopyNumber Status) /gain /gain

  17. BreastCancer-SpecificSurvival(Allred Score)

  18. BreastCancer-SpecificSurvival(ESR1CopyNumber Status) /gain /gain

  19. Conclusions • ESR1 copy number increase in 47% of ER positive breast cancer cases • ESR1 copy number status is significantly correlated with ER protein expression in IHC • ESR1copy number status is a predictor for long-term distant recurrence-free and breast cancer-specific survival in TAM-treated postmenopausal women • Standardized criteria for identification of ESR1 amp/gain urgently needed

  20. Acknowledgements Institute ofPathology, Universitätsklinikum Hamburg Eppendorf • Frederik Holst • Ronald Simon • Stefan Steurer • Eike Burandt • Guido Sauter Austrian BreastandColorectalCancer Study Group (ABCSG) • Michael Gnant • Martin Filipits • Raimund Jakesz • Hellmut Samonigg • Sigurd Lax • Margaretha Rodas • Herbert Stöger • Richard Greil • Otto Dietze ABCSG Study Nurses, Investigators Patientsparticipating in ABCSG 6

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