Molecular Research within EMBRACE Studies BIO-EMBRACE-1

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1 Molecular Research within EMBRACE Studies BIO-EMBRACE-1 Remi Nout, LUMC, Netherlands Supriya Chopra,Tata Memorial Centre, India

2 Biomarker Studies: Cervical Cancer Biological Variable Tumour Hypoxia ++ COX-2 ++ VEGF + HPV18 HPV Integration Site SOX-2/OCT-4 (Stem Cell)/CD44/CD66 + CXCR7 + DNA Ploidy + p53 + BCL-2 + EGFR - P16,21,27 - L1CAM/Vimentin/PDL-1/CD8+/CD14+ + Prognostic Variable All Studies in small cohorts <250 patients Gadducci et al, Critical Reviews in Hematology and Oncology,2013 Shen, Huang, J Histochemistry and Cytochemistry

3 Molecular Landscape of Cervical Cancer: TCGA Keratin Low Keratin High Adenocarcinoma Histology Squamous/?Adeno Squamous Adeno/Adenosqaumous/Sq HPV A9/ (HPV 16)++ A7 (HPV 18)++ A9 (HPV16)+++ A7(HPV18)+ A9/ (HPV 16)++ A7 (HPV 18)++ Methylation Intermediate/Low Intermediate/Low High Copy Number Copy Number High Copy Number High Low pi3akt Hormone EMT

4 PI3AKT EMT Pathway Based on small number of events (n=12) in 115 patients Cancer Genome Atlas Network, Nature 2017

5 Strengths within EMBRACE Study Group

6 IHC: Epithelial Mesenchymal Transition Leiden Group 6 Jordanova, with permission (under submission) Leiden 26-Mar-18

7 Diffuse PD-L1 expression and PD-L1 tumor associated macrophages 7 Heeren et al. Modern Pathology Mar-18

8 Local Relapse Free Survival: Tata CD44+ ESC+/CD44+ CD44- ESC+/CD44-91% vs 68% 96% vs 55%

9 Systemic- Inflammation- Immune Response Systemic Inflammation Immune Index HCC, Colorectal, Esophageal and Small Cell Lung cancer. Platelet Lymphocyte Ratio or Neutrophil Lymphocyte Ratio Balance between Host Inflammatory and Immune Response High Index : High Inflammatory Index (Expected to do worse) Low Index: Preserved Immune Response Platelets Neutrophils: Involved in VEGF/TGFBeta based Distant Metastasis Lymphocytes: Interferon based immune response, kill tumour cells

10 Disease free Survival: Systemic Inflammation Immune Index Low SII Index P=0.02 High SII Index Derived by Neutrophils, Lymphocytes and Platelets On Multivariate Analysis : Stage, ESC+/CD44- and Syst Inflammation/Immune Index

11 Aims Translational Research EMBRACE Confirm most relevant prognostic markers from TGCA/BioRAIDS Unique cohort: large, uniform selection and treatment (Retro)EMBRACE: paraffin embedded EMBRACE-II: paraffin embedded; opportunity to included frozen and blood

12 Strategy: Limited funding Start with pilot study Explore further options among centres within EMBRACE network related to ongoing research Apply for grant based on prelim results pilot work

13 Summary Survey 15 centers responded 14 interested for EMBRACE II prospective collection FFPE 13 interested to collect blood frozen etc. 13 would try for FFPE from EMBRACE I Majority would be able to ship out.

14 Name of Centre Survey: Tissue Based Research Paraffin Block EMBRACE Paraffin Block EMBRACE II Blood Frozen Biobankin g Facilities Ship to central Facility UMCU Y Y Y Y Y Y Leiden Y Y Y Y Y Y Osla Y Y Y Y Y Y Cross Cancer Y Y Another Facility. Need for funding Ljublajana (2) Y Y Y Y Y Y ACTREC,Tata Y Y Y Y Y N (Feasible with concrete proposal) MASTRO Y Y Y Y Y Y IGR Y Y Y Y Y Y Vienna Aarhus Yes, Response to survey awaited No, Need a concrete proposal to get legal approval to ship Addenbrokke Y Y Y Y Y Y Insti Claudius Y Y Y Y Y Y Navarra Y Y Y Y Y Y Erasmus MC Y Y Y Y Y Y McGill N Y N N N Y Y

15 BIOEMBRACE

16 Biomarkers to be performed Immunohistochemistry

17 Current Proposal Central IHC analysis for centers that can send out blank slides (N=5+1 H&E) from paraffin embeded tissue: Leiden Acces to Vectra multistainer 6-8 simultaneous IHC s on 1 blank slide

18 Shipping Requirements Funding for Shipping of slides is being organised by Study Chairs.. Shipping to: Leiden University Medical Centre Protocol: Detailed Shipping Address and Forms to be submitted along

19 Consent: (Retro)EMBRACE

20 IRB Approval EMBRACE II Prospectively Preserve Paraffin Blocks And optional Blood and Frozen Tissue Paraffin material already prospectively included in Informed Consent

21 Material Transfer Agreement

22 Consent for EMBRACEII Paraffin Block consent Difficulty in obtaining consent What % do not provide consent Storing blocks of EMBRACE II Leiden Yes Yes No Yes Tata Yes Yes No <10% Paraffin/Frozen /Blood Aarhus Yes Yes Institution also Vienna Yes Yes Some Variable Yes (?) Leeds Recruitment to be initiated Yes Llubjana Yes Yes :general consent No Not anticipated Not anticipated Yes No 0% No AMC,Netherlands Yes Yes No <10% No Alberta Recruitment to be initiated Oslo Yes As part of genral consent No reply No 6% Paraffin Frozen Cambridge Yes Yes No No No Mount Vernon Recruitment to be initiated Yes Recruitment to be initiated

23 Funding Application