Gynecologic Cancer InterGroup Imaging & Pathology Brainstorming Day October 2018 - Munich Integration of molecular markers in epithelial ovarian carcinoma Dr Kurosh Rahimi MD, MSc,FRCPC, CRCHUM-Montreal (Canada)
COEUR program High grade serous EOC Low grade Mucinous Clear Cell 5 distinct histotypes serous 4% Endometrioid 13% Low grade High grade 5% serous serous Endometrioid 15% 63% Clear Cell Mucinous Overall Survival in EOC LGSC EC HGSC CCC MC N=16057 J Natl Cancer Inst. April 28, 2018. doi:10.1093/jnci/djy072- Peres et al. (American cohort)
COEUR program a pan-Canadian biomarker validation platform • To improve the clinical management of ovarian cancer patients, the COEUR program proposed to: ➢ Develop an unique platform of Canadian banked biospecimens annotated with clinical data. ➢ Validate biomarkers that can be used in the stratification of ovarian cancer patients. ➢ Integrate molecular studies to build a unique nomogram of molecular signatures.
COEUR program a pan-Canadian biomarker validation platform 5 provinces- 2 languages Pathology Gynecologic oncology 12 biobanks- Medical oncology 16 hospitals Fundamental scientist • RRC- CHUM (Montreal, QC) • RRC-CHU Quebec (Quebec, QC) • RRC-CHU Sherbrooke (Sherbrooke, QC) • RRC-McGill University – LDI (Montreal, QC) • Ontario Health Reasearch Institute (Ottawa, ON) • Ontario Tumor Bank (Toronto, ON) • UHN Biobank (Toronto, ON) • Sunnybrooke biobank (Toronto, ON) • Biobank of Cancer Breast Cancer Fundation (Calgary/Edmonton, AB) • Manitoba Ovarian Biobank Program (Winnipeg, MB) • OvCare (Vancouver, BC) • Tumor Tissue Repository (Victoria, BC)
Biobanking process blood ascites Tumor tissue Clinical data PATIENTS Informed consent Lab/pathology Pathology report processing REB Biospecimen repository Frozen tissue FFPE Plasma/serum cut slides/IHC Database Research data DNA/RNA extraction microarray INVESTIGATORS genomics Inventory IHC/IF Lab report Quality proteomics control Storage
biobanking Translational Derivates Biospecimens Processing/QA Analysis use Genotyping Primary culture Biomarkers Cell culture sequencing Tumor ( diagnostic epigenomics DNA-RNA Tissue Pronostic Molecular classification Frozen IHC/IF/FISH Therapeutic target ) microarray Tissue proteomics FFPE cut slides Therapeutic Targets Genotyping DNA-RNA Drugs evaluation sequencing Cell separation epigenomics Blood serum (normal tissue) plasma Proteomics New methods (expression, DNA-RNA of diagnostic Cell separation structure) Ascites Ascites fluid Primary culture
Histotyping: 2-step pathology review P53 Whole slide Pathologist 2 WT1 FFPE H&E (CosPv3 P16 panel) ER/PR ARID1A TFF3 Pathologist 1 Vim Napsin Final histotyping
Histotyping: 2-step pathology review Original Revised registry file histotypying BDL HGSC EC LGSC CCC MC HGSC 1 1135 13 28 9 2 Original registry file EC 1 43 268 0 0 2 LGSC 8 19 0 66 0 0 CCC 1 4 4 0 248 0 MC 10 6 9 0 0 84 The most common errors are found in Endometrioid and Low Grade Serous Carcinoma
Re-Histotyping: Effect on outcome Advanced stages diseases Low grade serous carcinoma and mucinous have a worse prognostic than usually reported and need a closer follow-up of patients and personalized medecine
Re-Histotyping: Effect on biomarker evaluation P16 in Low grade serous EOC Before histotyping After histotyping P=0.032 P=0.068 CDK4/6 should be considered as p16 a therapeutic target In Low Grade Serous carcinoma CDK4/6
BRCA INCIDENCE in HGSC Double BRCA1/2 BRCA2 VUS WT BRCA BRCA- 7% 1% 3% VUS BRCA1 14% Non carrier HGSC 750 110 (15%) 17 75% LGSC 62 3 (5%) 0 EC 92 1 (1%) 1 CCC 54 1 (1%) 0 Non carrier BRCA1 BRCA2 Double BRCA1/2 BRCA germline mutation is largely restricted to High Grade Serous cases BRCA carriers, and particularly BRCA2, carriers have a better survival than WT
ACKNOWLEDGMENTS Molecular pathology platform Fundamental research Biobanking Liliane Meunier Euridice Carmona Lise Portelance Principal investigators Veronique Barres Hubert Fleury Manon deLadurantaye Anne-Marie Mes-Masson Christine Caron Laudine communal Jennifer Dupont Diane Provencher Kossay Zaoui Kim Leclerc-Deslaulniers Kurosh Rahimi COEUR team • Anne-Marie Mes-Masson, Diane Provencher, David Huntsman (directors) • Kurosh Rahimi, Martin Kobel, John Bartlett, (Pathologits) • Patricia Tonin, Barbara Vanderhyden, Brad Nelson, Anna Tinker, Stéphnie Scott, Stéphanie Lheureux (S. C.) • Walter Gotlieb, Dimcho Bachravov, Mark Nachtigal, Alain Piché, Marcus Bernardini, Peter Watson (biobanks) • Cécile Le Page (Coodinator)
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