1. Biomarkers on tumor tissue: from research to diagnostic tools used in the Clinic Bernard Têtu MD Professor of Pathology Laval University

2. Conflict of interest Currently no conflict of interest to declare. I have been consultant for Diagnocure until 2009

3. Biomarker Gutman et al. Nature reviews/cancer 2006; 6:565-571 Definition: « Any measurable diagnostic indicator that is used to assess the risk or presence of disease. » FDA (diagnostic): determining future risk of disease screening for disease confirming presence of disease determining prognosis or staging monitoring and/or optimizing treatment outcomes drug response toxic reaction to drugs

4. Personalized medicine Biomarkers are expected to play an increasingly important role Cares must be efficient, safe, cost effective integration of pharmaceutical and diagnostic activities are expected to increase We expect more tests to be performed by IHC in pathology laboratories because of ease and low cost

5. Medical product development Canada: Health Canada Québec: Conseil du médicament Tests in pathology Ontario: QMP-LS / CCO Québec: ?

6. Introduction of new tests on tumor tissue in pathology Many new tests are expected in the near future Pathology laboratories are increasingly involved Which laboratory should do the test?: Any laboratory interested at developing new tests? Manufacturers which developed the test? Ministry of health?

7. History of immunohistochemistry Early 1980 ’s: first antibodies for clinical use 1980-2000: antibodies mostly diagnostic or prognostic ER/PR predictive 2000-: FDA 32 Genomic Biomarkers in the Context of Approved Drug Labels Markers on tumor tissue in pathology: HER2/neu EGFR KIT KRAS

8. Immunohistochemistry Type I: any test performed to determine cell differentiation and used for diagnostic purposes (most antibodies) Type II: tests not related to morphology and used for prognostic and predictive purposes (HER2/neu, ER/PR)

9. « For research use only »

10. Répertoire québécois et système de mesure des procédures de biologie médicale

13. Marker testing in Québec in 2009 58 pathology laboratories 37 ER / PR by IHC 21 HER2/neu by IHC 5 HER2 by FISH

14. ENSURING ACCESS TO HIGH QUALITY MOLECULAR ONCOLOGY LABORATORY TESTING AND CLINICALCANCER GENETIC SERVICES IN ONTARIO / Report of the Molecular Oncology Task Force | December 2008 Recommendations: 2) Implement a mandatory approval process for each genetic test performed by laboratories in Ontario and administered by the appropriate regulatory agencies to ensure that only appropriately accredited and licensed laboratories with credentialed personnel are reporting and interpreting laboratory results that impact patient care. The following steps outline the Task Force’s proposed process for bringing new tests into clinical service. VI. The Ministry sets a reimbursement rate for the test and related clinical services. 6) Promote translational research and establish an “advance notice” process to ensure the system is prepared to implement new tests and technologies when evidence warrants. Cancer Care Ontario

15. HER2/neu testing in Ontario overseen by QMP-LS/CCO ($$ per test) 18 HER2/neu by IHC 2 HER2 by FISH 9 testing sites Mount Sinai Hospital QA Ref. centre/ Advanced testing centre Sunnybrook & Women’s QA Ref. centre/ Advanced testing centre New site MOH & CCO

16. ASCO-CAP recommendations 2007 Canadian consensus on HER2/neu testing, 2007 ASCO-CAP Canadian consensus

17. ASCO-CAP recommendations 2007

18. Reproducibility HER2 testing Paik et al, J Nat Cancer Inst 94:852-854,2002 NSABP Local laboratory% Concordance positive cases Total79% small volume (<100/month)76% Large volume97%

19. CEPO (Comité de l’Évolution des Pratiques en Oncologie) recommendations, 2005 use of trastuzumab for the adjuvant treatment of invasive breast cancers. implementation of a quality assurance program to insure reliable HER2/neu testing in pathology laboratories.

20. AETMIS (Agence d’Évaluation des Technologies et des Modes d’Intervention en Santé) « Diagnostic Performance of Techniques Used for HER-2 Testing in Breast Cancer » recommends the implementation of an HER-2 quality assurance program in Quebec At least one reference lab Internal and external quality controls Affiliation of every lab to a reference lab Minimum 250 cases annually Ongoing training for pathologists and lab personnel Central database for evaluation

21. Challenges for Quality assurance in anatomic pathology in Quebec Little hierarchy in service organisation in pathology Participation to proficiency testing not uniform until recently Many authorities involved Ministry of Health INSPQ / LSPQ (public health) Expert committees Comité consultatif en anatomopathologie (advisory committee) Comité d’assurance qualité en pathologie (LSPQ) Professional associations (pathology, microbiology, biochemistry etc)

22. Comité consultatif en anatomopathologie (advisory committee in anatomic pathology) Created by the “Direction de la Lutte Contre le Cancer” in summer 2008 following the publication of AETMIS report Mandate Identify current pathology challenges and recommend specific actions Develop a quality assurance program for pathology and recommend actions for quality improvement Standardize pathology reports for cancer Propose solutions to overcome staff shortage in pathology

23. Comité consultatif en anatomopathologie (advisory committee in anatomic pathology) At minister Bolduc’s request, work on quality assurance was prioritized The Global plan for quality assurance in anatomic pathology was completed in October 2009 16 experts were consulted It was endorsed by the Quebec college of physicians and the Quebec association of pathologists Ministry of Health committed itself to implement the quality assurance program in Québec

24. Global plan for quality assurance Three major Objectives 1. Commitment of the Ministry of Health 2. The program must be mandatory 3. The program must be educational

25. Global plan for quality assurance 20 recommendations Items covered : Internal quality control Proficiency testing (external quality assurance) Laboratory designation Support Evaluation

26. Global plan for quality assurance Internal quality control Development of guidelines of good practice in every laboratory Tissue preparation and fixation Technique validation and standardization Use of positive and negative controls Interpretation Quality indicators

27. Global plan for quality assurance Proficiency testing Mandatory participation to an external quality assurance program Program development under the responsibility of the “Comité d’assurance qualité externe en pathologie” (LSPQ) Preanalytic, analytic and postanalytic phases evaluated Confidential Support given to laboratories experiencing difficulties Progressive implementation Started in Fall 2010

28. Global plan for quality assurance Laboratory designation According to the level of complexity of analyses According to on site expertise Specific to tumour site Related to the presence of a cancer interdisciplinary team Development of accreditation standards specific to pathology Designation under responsibility of another direction at MSSS

29. Global plan for quality assurance Support Continuing training (APQ, OPTMQ) Expert teams in charge of accompanying labs experiencing difficulties Development of guidelines and protocols (Breast cancer, colon cancer) Development of quality indicators Prioritization of the replacement of lab equipment

30. Global plan for quality assurance Program evaluation Implementation Improvement of quality assurance following implementation

31. Introduction of new tests on tumor tissue in pathology Many new tests are expected in the near future Pathology laboratories are increasingly involved Which laboratory should do the test?: Any laboratory interested at developing new tests? Manufacturers which developed the test? Ministry of health?

32. Conclusions and future direction There is a need to anticipate new diagnostic tests on tumor tissue Scientific watch to identify potential new tests (“advance notice”) Experts should be asked to recommend reference labs Coordination with DLCC and MSSS