Big Data and Smart Data in Oncology

Transcription

1 Big Data and Smart Data in Oncology Prof. Dr. Christof von Kalle, Head of the Department of Translational Oncology National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Speaker (DKFZ) twitter handle

2 THE PARADIGM SHIFT: IMAGING EACH INDIVIDUAL PATIENT S CANCER AT THE MOLECULAR LEVEL 2

3 DKTK MASTER - WORKFLOW IMPLEMENTATION Goal: 28 days 3 Joint DKTK activity since 03/16 Institutional Review Board approval Internet-based clinical data repository Access to sequencing data 8 Partner Sites (11 Comprehensive Cancer Centers) DKTK MASTER Molecular Tumor Board Weekly videoconference DKTK MASTER Scientific Board DKTK MASTER Case by Case Monthly videoconference NCT/DKTK MASTER PI3K-AKT-mTOR RAF-MEK-ERK Tyrosine Kinases Cell Cycle Dev. Pathways DNA Damage Immune Evasion Intervention Baskets

4 4 NCT RESEARCH PROGRAMS MOLECULAR DIAGNOSTICS NCT MASTER WES/WGS and RNA-S in young adults/patients with rare tumors Treatment options for individual patients Basis for molecularly stratified clinical trials Fertile ground for translational research Management recommendation: 83% (843/1017) Genomics-guided management: 34% (282/843) Clinical benefit rate (CR, PR, SD): 42% PFS ratio > 1.3: 44% Unbiased functional testing Focused functional testing Validation rate > 95% N = 1212 N = 1017 Breast Dermatologic Urogenital Gynecologic Hematologic Hepatobiliary Pancreatic Lung Gastric Head and Speaker twitter handle Other CUP Colorectal Sarcoma Neuroendocrine Clinical trials: NCT PMO-1601 (NCT ): Palbociclib in CDKN2A/B-deficient chordoma NCT PMO-1601/TOP-ART (NCT ): Trabectedin and olaparib in cancers with defective homologous recombination DNA repair NCT PMO-1604 (in prep.): Afatinib in NRG1-rearranged cancers SoraTram (in prep.): Sorafenib and trametinib in cancers harboring BRAF mutations with impaired or unknown kinase activity Selected publications: Heining et al. Cancer Discov 2018 Chudasama et al. Nat Commun 2018 Forschner et al. Clin Cancer Res 2017 Horak et al. Int J Cancer 2017 Chudasama et al. Clin HIMSS Cancer Res 2017 Dieter et al. Ann Oncol 2017 Kordes et al. Leukemia 2016

5 GENOMICS OF DRUG SENSITIVITY OF PRIMARY CANCER CELLS PARALLEL MOLECULAR AND FUNCTIONAL CHARACTERIZATION 5 Zenz et al.

6 OS Probabilty Months after Speaker twitter handle OUTCOME MEASURES - DESCRIPTIVE Implemented Therapies (N=282) Median Age 45 years Range years Male 145 Female 137 Median Survival after MTB 12 months Breast Urogenital Gynecologic Dermatologic Lung Gastric Other Sarcoma Hematologic Hepatobiliary 6 Pancreatic Head and Neck CUP Neuroendocrin e Colorectal

7 7 COMPARISON OF PRECISION ONCOLOGY PROGRAMS May 2018 DKTK-MASTER MI-ONCOSEQ 1 MOSCATO 01 2 ProfiLER 3 MSK-IMPACT 4 Institution NCT Heidelberg University of Michigan Institut Gustave Roussy Centre Léon Bérnard MSKCC Enrollments Tumor board decisions Recommendation rate 83% (843) 72% (360) 49% (411) 35% (676) - Method WGS(WES)+TS WES+TS Panel+CGH (+TS+WES)* Panel+CGH Genomics-guided management 33% (282) 5-11% 48% (199) 21% (143) 11% (527) Reevaluation of clinical diagnosis 5% Pathogenic germline variants 11% 12% WGS: Whole-Genome-Sequencing; WES: Whole-Exome-Sequencing; TS: Transkriptome-Sequencing ; CGH: Comparative Genomic Hybridization *TS and WES in 472 and 166 patients, respectively 1 Nature 2017 Aug 17;548(7667): Cancer Discov Jun;7(6): ASCO Nat Med Jun;23(6): Panel

8 BRCANESS AS ACTIONABLE FEATURE OF LEIOMYOSARCOMA Newly diagnosed, locally recurrent, metastatic (n=49) Extra-uterine and uterine Whole-exome and RNA sequencing Mutational heterogeneity Near-universal inactivation of TP53 and RB1 Widespread DNA copy number alterations Chromothripsis (35%) Whole-genome duplication (55%) Alternative telomere lengthening (78%) Defective homologous recombination DNA repair (>90%) Gene mutations Pattern of DNA copy number alterations Alexandrov-COSMIC mutational signature AC3 8 Chudasama et al. Nat Commun 2018

9 GENOMICS-GUIDED BASKET STUDIES WITHIN DKTK NCT/DKTK MASTER PI3K-AKT-mTOR RAF-MEK-ERK Tyrosine Kinases Cell Cycle Dev. Pathways SoraTram (N. von Bubnoff [Freiburg], H. Glimm, S. Fröhling) Sorafenib/trametinib in patients with non-v600 BRAF mutations NCT PMO-1601 (S. Fröhling, C. Heilig, R. Schlenk) Palbociclib in patients with CDKN2A/B-deficient chordoma 9 DNA Damage NCT PMO-1603 (S. Fröhling, S. Gröschel, R. Schlenk) Eligibility Immune Evasion Trabectedin/olaparib in patients with Advanced-stage cancer DNA repair-deficient cancers Prior standard treatment Actionable molecular alteration, as determined by analysis within NCT/DKTK MASTER

10 INFORM = INDIVIDUALIZED THERAPY FOR RELAPSED MALIGNANCIES IN CHILDHOOD Feasibility-Registry Study (Year 1+2) ALL AML HGG (incl. DIPG) Medullo/Ependym. Ewing Sarcoma Neuroblastoma Angelika Eggert Enrollment Olaf Witt Peter Lichter Clinical Trial (Year 3-5) Phase I/II Standard of Care: Backbone Chemotherapy Stefan Pfister Backbone 10 NHL Rhabdomyosarcoma Osteosarcoma Rhabdoid Tumors Targeted Drug 1 Targeted Drug 2

11 NCT RESEARCH PROGRAMS - IMMUNOTHERAPY Interrogating mechanisms of response and resistance in individual patients identifies novel target structures (tumor and stromal antigens) Integrated data analysis Pathway analysis Regulatory networks Statistical analysis Generation of therapeutic monoclonals, bispecifics and CAR constructs Preclinical evaluation using explant models (fully human, fully immunocompetent) Clinical development Selected publications: Halama et al. Cancer Cell 2016 Zoernig et al. Int J Cancer 2015 Weber et al. J Immunol Res Example: Identification of CCL5/CCR5 pathway as novel mediator of an immunosuppressive environment Clinical testing of CCR5 antagonists in metastatic colorectal cancer patients Clinical development of combination strategies, e.g. CCR5 and PD1/CTLA4 blockade

12 NCT DataThereHouse SEQUENCING DATA PHYSICIAN ARRAY DATA CLINICAL PATHWAYS UNSTRUCTURED DATA INDIVIDUALIZED TREATMENT PLAN SCIENTIST TUMOR BOARD CASE MANAGER Display Data from Various Sources for a Comprehensive Overview of Information Relevant for Personalized Treatment DOCTOR S LETTER STUDY NURSE 12 STRUCTURED DATA DOCUMENTALIST

13 NCT DataThereHouse: Current scenario REPORT REPORTER PHYSICIAN SCIENTIST = KIS, PUBMED, UPTODATE, BIOBANK, INTRANET, REGISTER CASE MANAGER KIS, PACS, REGISTER BOARD EINBINDUNG ARZT FORSCHER POP* NEUE STUDIE EINSCHLUSS & AUSSCHLUSS KRITERIEN HYPOT HESE LOI* DOKUMENTAR 13 PATIENT BEGLEITEN DE DIENSTE SPRECH- STUNDE/ AMBULANZ THERAPIE AM NCT ODER EXTERN SOP* ARTEFAKT E STUDIEN PROTOKOLL STUDY NURSE ABLAUF DATENFLU AUFKLÄ RUN/SC REENIN G BEGLEITEN DE DIENSTE PATIENTEN PFAD THERAPIE ARZTBRIEF PATIENTEN KONFEREN SS DATENBAN AKTE Z K

14 NCT DataThereHouse: NCT Clinical Development Strategy MONITORING DOKUMENTAR DOKUMENTAR DOKUMENTAR Organized in SAP HANA IS-H, PUBMED, UPTODATE, BIOBANK, INTRANET, IS-H, PACS FORSCHER PATIENT ARZT ARZT FORSCHER DIAGNOS E THERAPIE AM NCT KLINISCH E STUDIEN PUBLIKATION 14 NCT CANCER REGISTRY IS-H, PUBMED, UPTODATE, BIOBANK, INTRANET, IS-H, PACS DOKUMENTAR

15 Text Speaker twitter handle INNOVATIVE DIAGNOSTICS AND THERAPIES DataThereHouse PACS HD HIS Interfaces to Networks (e.g. DKTK) Optimize patient treatment 15 Medical Reports NCT Cancer Registry NCT Biobank LIMS Radiomics Diagnoses Stratification Therapies Findings Follow-up Data Doctors Letters Genomics Data Integration Suite Big Data Analytics Suite Physician Researcher Generate new insights Patient DKFZ HIPO Working copy of all patient-related records from UKHD computer sources, coupled with steadily expanding scientific data sets, as intuitive tool for clinical decision making and translational research

16 DataBox: The IDEA Management of complex health datasets patient-centered platform Data derived from different sources Integration of innovative big-data analysis concepts Machine Learning Artificial Intelligence approaches 16

17 DataBox: The Challenge The patient is confronted with a clutter of data distributed over several clinical systems actively request copies of his data from health service providers Clinic Health insurance 17 General practitioner Patient

18 DataBox: Added Value for Patient and Society Pseudonymized basic datasets can be queried by certified institutions, in order to e.g. search for study candidates Information to patients about e.g. clinical and scientific trials (after consent) 18 DataBox Clinical studies Information Analysis Services

19 SMART DATA IN ONCOLOGY Personalized medicine needs to RETHINK the old & the new needs SMART Data is a TEAM Effort 19

20 NCT PARTNERSHIPS Academic Collaboration EMBL DKFZ-ZMBH ALLIANCE DKTK Joint Industry-Academia Collaboration 20 Cancer Core Europe Consortium Centers

21 NATIONAL CENTER FOR TUMOR DISEASES NCT Speaker twitter handle THANK YOU 21