Wat is de potentiële waarde van ctdna? PLCRC - MEDOCC

Transcription

1 Wat is de potentiële waarde van ctdna? PLCRC - MEDOCC Translational Gastrointestinal Oncology Remond Fijneman r.fijneman@nki.nl Department of Pathology, Amsterdam, NL

2 Wat is de potentiële waarde van ctdna? PLCRC - MEDOCC Remond Fijneman Geraldine Vink Veerle Coupé Jill Phallen Daan van den Broek Karlijn van Rooijen Victor Velculescu Gerrit Meijer Miriam Koopman and many more

3 Disclosures Research support: Merck BV Personal Genome Diagnostics (PGDx) Biomedical Diagnostics (BMD)

4 5-year survival rate (%) Colorectal cancer Clinical needs: 1. Diagnosis 2. Prognosis 3. Prediction 4. Monitoring CRC stage: Stage I+II Stage III Stage IV Clinical behavior

5 5-year survival rate (%) Colorectal cancer Clinical needs: 1. Diagnosis 2. Prognosis 3. Prediction 4. Monitoring CRC stage: Stage I+II Stage III Stage IV normal colon adenoma progressive adenoma localized CRC CRC lymph node metastasis CRC (liver) metastasis Clinical behavior tumor biology

6 5-year survival rate (%) Colorectal cancer Clinical needs: 1. Diagnosis 2. Prognosis 3. Prediction 4. Monitoring CRC stage: normal colon adenoma Diagnostic biomarkers progressive adenoma Prognostic biomarkers Predictive biomarkers Disease monitoring biomarkers Stage I+II localized CRC Stage III CRC lymph node metastasis Stage IV CRC (liver) metastasis Key molecular features Wnt signaling APC*, genomic instability (CIN, MSI) many gene mutations KRAS*, BRAF*, TP53*, Clinical behavior tumor biology molecular alterations

7 Tumor tissue DNA mutation analysis Tissue DNA analyses Example: Determine primary resistance to anti-egfr treatment (panitumumab, cetuximab)

8 Tumor tissue DNA mutation analysis Tissue DNA analyses Example: Determine primary resistance to anti-egfr treatment (panitumumab, cetuximab) CAIRO5

9 Tumor tissue DNA mutation analysis Tissue DNA analyses Example: Determine primary resistance to anti-egfr treatment (panitumumab, cetuximab) Tumor tissue DNA mutation analysis suited for: Diagnosis: Prognosis: Prediction: Monitoring: Presence of tumor cells (CIN, MSI) chance of recurrence after surgery primary resistance to treatment of primary tumor? primary resistance to treatment of metastases? is the treatment (still) successful? acquired resistance to treatment?

10 Liquid biopsy ctdna mutation analysis Liquid biopsies contain minute amounts of free circulating tumor DNA (ctdna) Detection of somatic DNA mutations (biomarkers with high specificity) Tumor information, even when access to tumor tissue is limited Minimal invasive, easy to obtain, longitudinal measurements Bettegowda et al., Sci Transl Med 6, 224ra24 (2014)

11 Liquid biopsy ctdna mutation analysis Plasma ctdna analyses Example: Determine primary resistance to anti-egfr treatment (panitumumab, cetuximab) CAIRO5 Project # 10438

12 Liquid biopsy ctdna mutation analysis Plasma ctdna analyses Example: Determine primary resistance to anti-egfr treatment (panitumumab, cetuximab) Liquid biopsy DNA mutation analysis potentially suited for: Diagnosis: Prognosis: Prediction: Monitoring: Presence of tumor cells (CIN, MSI) chance of recurrence after surgery primary resistance to treatment of primary tumor? primary resistance to treatment of metastases? is the treatment (still) successful? acquired resistance to treatment?

13 Liquid biopsy ctdna mutation analysis Plasma ctdna analyses - High specificity! - Sensitivity?

14 Liquid biopsy ctdna mutation analysis Plasma ctdna analyses - High specificity! - Sensitivity? Biology Bettegowda et al., Sci Transl Med 6, 224ra24 (2014)

15 Liquid biopsy ctdna mutation analysis Plasma ctdna analyses - High specificity! - Sensitivity? Biology & Technology Targeted error correction sequencing Phallen et al., Sci Transl Med 9 (2017)

16 Molecular Early Detection of Colorectal Cancer Gerrit Meijer (NKI-AvL, Amsterdam) Victor Velculescu (JHU, Baltimore) Photo from KWF website:

17 stage II CRC ctdna analysis Is presence of ctdna after surgery in stage II colon cancer patients associated with recurrence of disease? n = 850 Diagnose Pre-op sample Post-op sample 6 maanden 18 maanden Inclusie PLCRC Operatie 12 maanden 24 maanden 36 maanden Presence of ctdna associated with recurrence?

18 stage II CRC ctdna analysis Is presence of ctdna after surgery in stage II colon cancer patients associated with recurrence of disease? n = 850 Diagnose Pre-op sample Post-op sample 6 maanden 18 maanden Inclusie PLCRC Operatie 12 maanden 24 maanden 36 maanden How to collect blood samples from stage II CRC patients before staging, in a multi-center setting?

19 Prospective Dutch CRC cohort - Providing an infrastructure for scientific research - Geraldine Vink, MD PhD Project Manager g.vink@iknl.nl

20 Prospective Netherlands CRC cohort Informed Consent options Clinical data: Consent to retrieve clinical data Biobanking (optional): Consent to collect and store tumor tissue (primary tumor) Consent to collect and store blood Consent to be informed when new information regarding value of relevant DNA variations is available Health Related Quality of Life (optional): Consent to send questionnaires regarding Quality of Life Studies in the future (optional): Consent to be invited for future (interventional) studies (also studies according to cmrct design)

21 Plasma collection in multi-center studies Collect blood in cell-stabilizing tubes, ship to central within ~3 days Parpart-Li et al., Clin Cancer Res; 23(10), 2017 Cell- and DNA-stabilizing tubes offer a simple and pragmatic solution for collection of plasma for ctdna studies in multi-center setting

22 Well-defined CRC cohorts Clinical need CRC stage Cohort Patient # Longitudinal plasma collection (partially) funded by early diagnosis, prognosis II MEDOCC (PLCRC) 850 prognosis III CATCH (PLCRC) 350 Sacha Swarttouw-Hijmans prediction, monitoring IV Not liver limited ORCA (PLCRC) 100 prediction, monitoring prognosis, monitoring IV Liver limited IV Peritoneum CAIRO5 560 CAIRO6 350 Stop Darmkanker

23 Well-defined CRC cohorts Clinical need CRC stage Cohort Patient # Longitudinal plasma collection (partially) funded by early diagnosis, prognosis II MEDOCC (PLCRC) 850 prognosis III CATCH (PLCRC) 350 Sacha Swarttouw-Hijmans prediction, monitoring IV Not liver limited ORCA (PLCRC) 100 prediction, monitoring prognosis, monitoring IV Liver limited IV Peritoneum CAIRO5 560 CAIRO6 350 Stop Darmkanker

24 ctdna analysis ddpcr COBAS 480z Ydilla BEAMing NGS-based methods Detection of ctdna hotspot mutations KRAS, NRAS, BRAF, ctdna mutations in panel of genes Daan van den Broek, PhD Head Clinical Chemistry, NKI-AVL Apply and compare various technology platforms for putative clinical implementation

25 Example of ctdna as prognostic biomarker Similar study as PLCRC-MEDOCC performed by Tie et al., (2016) Diagnose Pre-op sample Post-op sample Operatie Presence of ctdna associated with recurrence?

26 Example of ctdna as prognostic biomarker Similar study as PLCRC-MEDOCC performed by Tie et al., (2016) Diagnose Pre-op sample Post-op sample Operatie Tie et al., Sci Transl Med 8 (2016) Presence of ctdna associated with recurrence? YES!

27 ctdna as prognostic biomarker MEDOCC observational study MEDOCC-CrEATE intervention study Diagnose Pre-op sample Post-op sample 6 maanden 18 maanden Inclusie PLCRC Operatie 12 maanden 24 maanden 36 maanden Presence of ctdna associated with recurrence Intervention: offer ACT to ctdna-positive patients

28 marker identification ctdna is potentially a great biomarker prospective validation assay development marker validation Turn research into care Well-defined CRC cohorts Multi-center plasma collection ctdna analysis Intervention studies Data management Health Technology Assessment Reimbursement cost effectiveness clinical trial test approval & implementation COIN: Circulating tumor DNA On the road to Implementation in the Netherlands

29 Data management: Capture data for translational research Biobanks, cohorts PROMs Clinical records Imaging Omics Digital Microscopy FAIR data stewardship Health-RI Dutch nation-wide Research Infrastructure for Personalized Medicine and Health

30 Office 365 for translational research

31 Summary The 5Ds organise excellent clinical trials o Facilitates observational (ctdna) studies o Facilitates (ctdna biomarker-driven) intervention studies ctdna is a highly specific biomarker with great potential to support better diagnosis, prognosis, therapy prediction, and treatment evaluation o Translation towards clinical implementation is ongoing o More studies are needed to support clinical implementation New studies? Include blood draws for ctdna analysis! Thanks for your support and attention!