Neues aus der Translationalen Forschung -

Transkript

1 Neues aus der Translationalen Forschung - TILs and beyond GBG Jahrestreffen 2017, Prof. Dr. Carsten Denkert Institut für Pathologie Charité Berlin

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3 Stromale und intratumorale TILs L

4 Stromale und intratumorale TILs Stromal TILs located in the connective tissue within the tumor majority of TILs in breast cancer best parameter for evaluation intratumoral TILs directly infiltrating the tumor cell nests additional parameter for evaluation L Lymphocyte predominant breast cancer (LPBC) more lymphocytes than tumor cells 10-25% of BC

5 Immun-Gensignaturen und therapeutische Targets mrna of 12 immunological genes, GeparSixto trial, n=481 Therapeutische Ansätze: A C B Denkert et al., J. Clin. Oncol stils (%) PDL1 IDO1 PD1 CTLA4 CXCL9 CD8A CCL5 CXCL13 IGKC CD21 FOXP3 CD80 PDL1: atezolizumab, avelumab, durvalumab IDO1: epacadostat, indoximod, NLG919 PD1: nivolumab, pembrolizumab CTLA4: ipilimumab Drake et al., Nat. Rev. Clin. Oncol. 2013

6 anti-pd1 JCO, July 20 th, 2016 TNBC, n=32 PDL1+ in stroma or in 1% of tumor cells (>58% of TNBC screened) overall response rate 18.5% ongoing phase 2 study (KEYNOTE-086 trial)

7 Phase 1 trials checkpoint inhibitors in TNBC Keynote Pembrolizumab 18,5 Emens et al. - Atezolizumab 24 Adams et al. - Atezolizumab + NAB- Paclitaxel overall response rate (%) Sylvia Adams, SABCS 2015 Denkert et al. Lancet 2016

8 PD1 mrna PD1 mrna Immun-Gensignaturen und diagnostische Tests TNBC and HER2+ BC, GeparSixto trial, n=481 TNBC and HER2+ BC, GeparSixto trial, n=481 PDL-1 mrna Tumorinfiltrierende Lymphozyten (%)

9 PD1 mrna PD1 mrna Immun-Gensignaturen und diagnostische Tests TNBC and HER2+ BC, GeparSixto trial, n=481 TNBC and HER2+ BC, GeparSixto trial, n=481 pcr Rate 75-85% 65-75% 55-65% 45-55% 35-45% 25-35% 15-25% PDL-1 mrna Tumorinfiltrierende Lymphozyten (%) Jan Budczies, 2D STEPP analysis

10 TIL Metaanalyse Transcan Projekt Vorhandene TIL Daten GeparDuo, GeparTrio GeparQuattro, GeparQuinto GeparSixto, GeparSepto Zusammenfassende Analyse pcr und DFS TILs in molekulare Subtypen Unterschiedliche Therapien

11 stromal TILs (%) San Antonio Breast Cancer Symposium, December 6-10, 2016 Stromal TILs as a continuous parameter 100,00 80,00 60,00 40,00 20,00 0, all tumors sorted by increased TILs This presentation is the intellectual property of the author/presenter. Contact them at carsten.denkert@charite.de for permission to reprint and/or distribute.

12 stromal TILs (%) San Antonio Breast Cancer Symposium, December 6-10, 2016 Stromal TILs - predefined subgroups 100,00 80,00 60,00 40,00 20,00 0, % TILs 11-59% TILs 60% TILs all tumors sorted by increased TILs This presentation is the intellectual property of the author/presenter. Contact them at carsten.denkert@charite.de for permission to reprint and/or distribute.

13 San Antonio Breast Cancer Symposium, December 6-10, 2016 Distribution of TILs in different breast cancer subtypes all TNBC low (0-10%) intermed. (11-59%) HER high ( 60%) lum/her % 20% 40% 60% 80% 100% % of tumors This presentation is the intellectual property of the author/presenter. Contact them at carsten.denkert@charite.de for permission to reprint and/or distribute.

14 pcr rate (%) San Antonio Breast Cancer Symposium, December 6-10, 2016 TILs are linked to increased pcr rates in all subtypes 20 p< p< p< p< n= all patients lum/her2- HER2+ TNBC 31 low (0-10%) intermed. (11-59%) high ( 60%) pcr: ypt0ypn0 This presentation is the intellectual property of the author/presenter. Contact them at carsten.denkert@charite.de for permission to reprint and/or distribute.

15 San Antonio Breast Cancer Symposium, December 6-10, 2016 TILs as continous parameter: increased pcr rates in all subtypes univariate analysis multivariate analysis increased pcr rate (OR per 10% increase in TILs) OR p- value all tumors 1.20 < TNBC 1.16 < HER < lum/her < all tumors 1.17 < TNBC 1.17 < HER < lum/her < ,80 1,00 1,20 1,40 odds ratio per 10% increase in stromal TILs This presentation is the intellectual property of the author/presenter. Contact them at carsten.denkert@charite.de for permission to reprint and/or distribute.

16 Survival rate (%) Survival rate (%) San Antonio Breast Cancer Symposium, December 6-10, 2016 TILs and prognosis differences between TNBC and luminal tumors TILs high TILs low TILs high TILs intermed. TILs low TILs intermediate TNBC: DFS p=0.02 OS: p=0.071 lum/her2- : OS p< DFS:p=0.036 Disease-free survival time (months) Overall survival time (months) This presentation is the intellectual property of the author/presenter. Contact them at carsten.denkert@charite.de for permission to reprint and/or distribute.

17 San Antonio Breast Cancer Symposium, December 6-10, 2016 Prognostic impact of TILs in subtypes possible interpretation TNBC and HER2+ tumors high TILs improved survival most clearly seen for DFS = early in the therapeutic course improved survival can be explained by increased pcr rate TILs: positive predictive factor and positive prognostic factor luminal breast cancer low TILs improved survival most clearly seen for OS = late in the therapeutic course Interpretation / limitations: chance finding (?) no mechanistic data, correlative study high TILs in luminal tumors: more aggressive phenotype Hypothesis: TILs may be linked to reduced endocrine response. Validation studies are needed! This presentation is the intellectual property of the author/presenter. Contact them at carsten.denkert@charite.de for permission to reprint and/or distribute.

18 San Antonio Breast Cancer Symposium, December 6-10, 2016 Prognostic impact of TILs in subtypes possible interpretation TNBC and HER2+ tumors high TILs improved survival most clearly seen for DFS = early in the therapeutic course improved survival can be explained by increased pcr rate TILs: positive predictive factor and positive prognostic factor luminal breast cancer low TILs improved survival most clearly seen for OS = late in the therapeutic course Interpretation / limitations: chance finding (?) no mechanistic data, correlative study high TILs in luminal tumors: more aggressive phenotype Hypothesis: TILs may be linked to reduced endocrine response. Validation studies are needed! This presentation is the intellectual property of the author/presenter. Contact them at carsten.denkert@charite.de for permission to reprint and/or distribute.

19 2017: Untersuchung sequentieller Biopsien G4-G6, n=385 Diagnose 1. Biopsie Neoadjuvante Chemotherapie 2. Biopsie Operation Ansprechen? 1. Tumorgehalt, Ki67, TILs 2. Molekulare Alterationen Quattro N = 127 Paare Quinto N = 181 Sixto N = 77 Katharina Sychra, Bruno Sinn, BIH

20 D Ki D Ki67 Erste Ergebnisse Veränderung von Ki67 Ki67 (Proliferation) G4 G5 G6 Katharina Sychra, Bruno Sinn, BIH 2017/01/19

21 ca. 10 mm Molekulare Untersuchung RNA Sequencing HTG Edge System HTG Molecular Oncology Biomarker Panel Targeted RNASeq (~2,500 Transkripte) Makrodissektion von FFPE Gewebe, 1,5 mm 2 eines 5 μm Schnitt (1-5 ng) 1. Untersuchung in sequentiellen Biopsien G4, G5, G6 2. Immunsignaturen in GeparNuevo

22 GBG Biobank 2017 Möglichkeiten für zukünftige Projekte : Proben in der GBG Tumorbank Forschungsanträge an das Translationale Subboard der GBG sind sehr willkommen! Vielen Dank an alle Patientinnen, Studienzentren und Pathologen, die Gewebeproben zur Verfügung stellen. year

23 GBG Sibylle Loibl Gunter von Minckwitz Karsten Weber Bianca Lederer Valentina Nekljudova Keyur Mehta Gustavo Werutsky Bärbel Felder Christiane Rothhaar Stefanie Lettkemann Translational Subboard of GBG Neoadjuvant Subboard of GBG Selected research partners Sherene Loi Christos Sotiriou Fabrice André Roberto Salgado TIL working group EU/BMBF Transcan UGI1 We would like to thank all patients, clinicians, and pathologists participating in the clinical studies and the biomaterial collection. EU FP7 No TransLuminal-B Charité Britta Beyer Jan Budczies Silvia Darb-Esfahani Sylwia Handzik Barbara Ingold Heppner Paulina Janusz Paul Jank Frederick Klauschen Ines Koch Judith Lindner Berit Pfitzner Barbara Meyer-Bartell Bruno Sinn Wolfgang Schmitt Katharina Sychra Eliane Taube Sonia Villegas Ann-Christin von Brünneck Stephan Wienert Peggy Wolkenstein Manfred Dietel