HER2 resistance - können wir den richtigen Prädiktor finden?

Transkript

1 HER2 resistance - können wir den richtigen Prädiktor finden? Volkmar Müller Klinik für Gynäkologie, Brustzentrum am UKE Universitätsklinikum Hamburg-Eppendorf Heilung durch Innovation, Kompetenz und Partnerschaft

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3 Adjuvante Therapie mit Trastuzumab plus Paclitaxel bei nodal-negativem Mammakarzinom

4 OS (%) Gesamtüberleben metastasiertes Mammakarzinom in der Cleopatra-Studie Pertuzumab + Trastuzumab + Docetaxel: median 56.5 months Pla + T + D: median 40.8 months HR % CI = 0.56, 0.84 p = Time (months)

5 HER2 Resistenz: Immer noch ein klinisch relevantes Problem! Metastasierte Erkrankung nicht heilbar Adjuvante hoch-risiko Patientinnen mit Heilungsraten unter 90% Eine Vielzahl von Substanzen verfügbar oder in der Entwicklung

6 Wir brauchen Prädiktoren Besseres Verständnis warum Therapie nicht funktioniert Bessere Vorhersage welche Therapie funktionieren wird

7 Welche Prädiktoren sind untersucht? HER2 Expression / Amplifikation Hormonrezeptor-Expression PI3 Kinase PTEN Das Immunsystem

8 pcr: ypto/is ypn0 Pathologische Komplettremission HER2-positiv: Zentral negativ versus positiv Denkert et al., 2013

9 HER2 Expression / Amplifikation Eine valide HER2-Testung ist der elementare prädiktive Faktor für eine erfolgreiche HER2- gerichtete Therapie

10 San Antonio Breast Cancer Symposium December 9-13, 2014 Hormonrezeptor-Status This presentation is the intellectual property of the presenter. Contact for permission to reprint / distribute

11 San Antonio Breast Cancer Symposium December 9-13, 2014 Neo-Altto This presentation is the intellectual property of the presenter. Contact for permission to reprint / distribute

12 pcr, % 95% CI San Antonio Breast Cancer Symposium December 9-13, 2014 NEOSPHERE ER or PR positive ER and PR negative TH THP HP TP This presentation is the intellectual property of the presenter. Contact (sibylle.loibl@germanbreastgroup.de) for permission to reprint / distribute

13 Hormonrezeptor-Expression Höhere Rate pcr bei Hormonrezeptornegativen Tumoren Interaktion zwischen Östrogenrezeptor und HER2-Signalweg möglicherweise Ansatzpunkt für Therapie

14 Die Signalwege von HER2 sind kompliziert PI3 Kinase spielt eine wichtige Rolle Input layer LPA, thrombin ET, etc. TGFa (1) 1 3 EGF (1) 1 2 Epiregulin (1,4) 1 1 b-cellulin (1) 2 2 HB-EGF (1,4) Amphiregulin (1) a NRG1 b NRG2 a b (3,4) (4) NRG3 (4) 3 4 NRG4 (4) 3 3 Cytokines Ligands Receptor dimers Src Signalprocessing layer Cbl PLCg PKC PI3K Shp2 GAP Akt Bad S6K Ras-GDP Ras-GTP RAF MEK MAPK Sos Grb2 Shc PAK JNKK JNK Nck Vav Rac Abl Grb7 Crk Jak Adaptors and enzymes Cascades Jun Sp1 Myc Fos Elk Egr1 Stat Transcription factors Output layer Apoptosis Migration Growth Adhesion Differentiation Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol 2001;2:127 37

15 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 10-14, 2013 PIK3CA Mutation analysis (Exon 9 & 20) in FFPE samples of the GeparQuinto and GeparSixto study HER2+ tumours n=360 triple-negative tumours n=285 7,4 20,8 PIK3CA mt PIK3CA wt 79,2 92,6 Loibl S et al. ASCO 2013 This presentation is the intellectual property of the authors. Contact them at sibylle.loibl@germanbreastgroup.de for permission to reprint and/or distribute.

16 PI3 Kinase Mutationen und pcr Loibl S et al. JCO 2014;32: by American Society of Clinical Oncology

17 San Antonio Breast Cancer Symposium December 9-13, 2014 Multivariable Analysis* for Prediction of pcr in HER2+ Breast Cancer Odds ratio 95% CI P-value PIK3CA wt mut Hormone receptor status neg pos * adjusted for therapy, age, tumour and nodal status, histotype and grading, study and anti-her2 therapy Loibl S et al. J Clin Oncol 2014 This presentation is the intellectual property of the presenter. Contact (sibylle.loibl@germanbreastgroup.de) for permission to reprint / distribute

18 San Antonio Breast Cancer Symposium December 9-13, 2014 NeoPHOEBE: Pi3k inhibition in Her2 OverExpressing Breast cancer: Phase II, randomized, two stage, placebo-controlled 6 Weeks 12 Weeks HER2+ >2cm Newly diagnosed Loi S et al. SABCS 2013 PIK3CA mutant PIK3CA Wild-type R A N D O M I Z A T I O N R A N D O M I Z A T I O N Trastuzumab + Placebo Trastuzumab + BKM120 Trastuzumab + Placebo Trastuzumab + BKM120 Trastuzumab + Paclitaxel + Placebo Trastuzumab + Trastuzumab BKM120 + Paclitaxel + + Paclitaxel BKM120 Trastuzumab + Paclitaxel + Placebo Trastuzumab + Trastuzumab BKM120 + Paclitaxel + + Paclitaxel BKM120 S U R G E R Y ENDPOIN T: RATE OF pcr PER COHORT This presentation is the intellectual property of the presenter. Contact (sibylle.loibl@germanbreastgroup.de) for permission to reprint / distribute

19 PI3 Kinase Mutationen: Alles klar? Unlike results seen in the metastatic and neoadjuvant clinical trials, PIK3CA intrinsic subtypes were not predictive biomarkers for adjuvant trastuzumab in NSABP B-31 These data suggest that results from the metastatic and neoadjuvant setting may not be always applicable to the adjuvant setting

20 PTEN (Phosphatase and Tensin homolog) Aktiviertes PTEN unterbricht den PI3K-AKT/PKB- Signalweg

21 San Antonio Breast Cancer Symposium December 9-13, 2014 PTEN und pcr: Hohes PTEN mit besserem Therapieansprechen assoziiert Overall N=108 PIK3CA wt N=65 HR positive N=93 PTEN low PTEN high OR (95% CI) ( ) p- value* OR (95% CI) ( ) p- value* OR (95% CI) ( ) abbreviations: wt, wildtype; HR, hormone receptor, OR, odds ratio; CI, confidence interval adjusted for baseline factors: age, tumor stage, nodal status, HR, HER2, histologic type and grading p-value* This presentation is the intellectual property of the presenter. Contact for permission to reprint and/ or distribute

22 San Antonio Breast Cancer Symposium December 9-13, 2014 Summary Low PTEN was significantly associated with lower pcr PTEN added independent predictive information in the overall HER2+ cohort PTEN added independent predictive information in the PIK3CA wt and HR+ cohort This presentation is the intellectual property of the presenter. Contact for permission to reprint and/ or distribute

23 San Antonio Breast Cancer Symposium December 9-13, 2014 Das Immunsystem LPBC= lymphocyte predominant breast cancer 60% percentage of TILs This presentation is the intellectual property of the presenter. Contact for permission to reprint / distribute

24 San Antonio Breast Cancer Symposium December 9-13, 2014 This presentation is the intellectual property of the presenter. Contact for permission to reprint / distribute

25 San Antonio Breast Cancer Symposium December 9-13, 2014 Immunmodulation auch Ansatz bei HER2- positivem Mammakarzinom? This Nada presentation R et al.; SABCS is the intellectual 2014 # S1-09 property of the presenter. Contact (sibylle.loibl@germanbreastgroup.de) for permission to reprint / distribute

26 Fazit: Prädiktoren HER2-positiv HER2 Expression: Zuverlässigkeit der HER2- Testung entscheidend Hormonrezeptor-Expression: Interaktion mit HER2 mögliches Therapieziel PI3 Kinase Mutation/Aktivierung: Rolle in der Resistenz, therapeutisches Ziel für weitere Studien PTEN niedrig: Resistenzmarker, klinischer Nutzen noch nicht absehbar Das Immunsystem: Besseres Verständnis notwendig, potentielles Therapieziel

27 Vielen Dank Für viele der Folien: Prof. Sibylle Loibl Für die Zusammenarbeit: GBG Subboard Translationale Forschung Für Ihre Aufmerksamkeit

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30 San Antonio Breast Cancer Symposium December 9-13, 2014 PTEN and PIK3CA but not p4ebp1 are associated with low rates of pathological complete response (pcr) to trastuzumab based chemotherapy in primary HER2-overexpressing breast cancer Sibylle Loibl 1, Silvia Darb-Esfahani 2, Alexander Klimowicz 3, Gunter von Minckwitz 1, Bianca Lederer 1, Jens Huober 4, Arndt Hartmann 5, Holger Eidtmann 6, Berit Pfitzner 2, Peter A. Fasching 7, Katharina Tiemann 8, Christian Jackisch 9, Keyur Mehta 1, Michael Untch 10, Carsten Denkert 2 This presentation is the intellectual property of the presenter. Contact (sibylle.loibl@germanbreastgroup.de) for permission to reprint / distribute

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32 San Antonio Breast Cancer Symposium December 9-13, 2014 This presentation is the intellectual property of the presenter. Contact for permission to reprint and/ or distribute

33 San Antonio Breast Cancer Symposium December 9-13, 2014 This presentation is the intellectual property of the presenter. Contact for permission to reprint and/ or distribute

34 San Antonio Breast Cancer Symposium December 9-13, 2014 Neoadjuvant therapy in HER2- positive breast cancer, latest developments and biomarkers and how it serves as a discovery platform Sibylle Loibl MD, PhD German Breast Group Sana Klinikum Offenbach This presentation is the intellectual property of the presenter. Contact (sibylle.loibl@germanbreastgroup.de) for permission to reprint / distribute

35 corebiopsy central HER2-testing Surgery San Antonio Breast Cancer Symposium December 9-13, 2014 Afatinib as part of the dual blockade multicenter, prospective, open-label phase II study 2 wks. 4 wks. Afatinib 11 weeks 4 weeks ** 2 wks.** 12 weeks 12 weeks 24 weeks N = 65 P a c l i t a x e l E C E E E C C C Trastuzumab Tras tuzu mab 30 weeks Hanusch C et al. ESMO corebiopsy pcr by other definitions: ypt0/is, ypn0 49.2% ypt0, ypn0 33.9% ypt0/is, ypn0/+ 55.4% yptany, ypn0 83.1% pcr and ER ypt0/is, ypn0: ER+ (n= 46) 43.5% ER- (n=19) 63.2% pcr and PIK3CA status: wild type 54.2% mutant 38.5% (p=0.363) pcr and LPBC (stil+) status: without LPBC 26.8% With LPBC 77.8% (p=0.0053) Clinical Response 36.8% at week 6 This presentation is the intellectual property of the presenter. Contact (sibylle.loibl@germanbreastgroup.de) for permission to reprint / distribute

36 Double-blockade San Antonio Breast Cancer Symposium December 9-13, 2014 Summary Significantly higher pcr rates ER+: double-blockade +ER treatment as sole therapy? PIK3CA genotype is associated with significant lower pcr rates Predictors ER-status PIK3CA status TILs Study Designs Window-of opportunity studies Post-neoadjuvant studies for new treatment options This presentation is the intellectual property of the presenter. Contact for permission to reprint / distribute

37 San Antonio Breast Cancer Symposium December 9-13, 2014 Acknowledgements We would like to thank all patients, clinicians, and pathologists participating in the clinical studies and the biomaterial collection GBG Ccharité Gunter von Minckwitz Valentina Nekljudova Keyur Mehta Stephan Gade Christiane Rothhaar Translational Subboard of GBG Neoadjuvant Subboard of GBG No Carsten Denkert Britta Beyer Jan Budczies Silvia Darb-Esfahani Frederick Klauschen Ines Koch Berit Müller Judith Prinzler Bruno Sinn Wolfgang Schmitt Petra Wachs Stephan Wienert Manfred Dietel This presentation is the intellectual property of the presenter. Contact for permission to reprint / distribute

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39 Beispiel für Forschungsprojekte: Quantitative Bestimmung von HER2 im Serum Die Extrazelluläre Domäne von HER2 kann im Serum nachgewiesen werden Untersuchungsmaterial ist einfach zu erhalten Ermöglicht die Bestimmung HER2 im zeitlichen Verlauf der Erkrankung

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