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NGS tests and algorithms in (hemato)-oncology ComPerMed

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1 NGS tests and algorithms in (hemato)-oncology ComPerMed
Els Van Valckenborgh – Aline Hébrant Goodmorning and welcome to this symposium. Today I will present the work realized by the Commission Personalized Medicine regarding NGS testing and algorithms in (hemato)-oncology. My colleague Aline Hébrant has been working on solid tumors and I have been working on hematological cancers. The goal of this presentation is to give an update on the different projects, with a focus on the hematological tumors. Rue Juliette Wytsmanstraat 14 | 1050 Brussels | Belgium T | F | |

2 Introduction Targeted NGS is gradually introduced in molecular diagnostics in daily practice as it enables more precise decision-making: diagnosis prognosis therapeutic choices for targeted drugs or conventional treatments A permanent monitoring and assessment of the state-of-the-art in this domain is essential → Commission of Personalized Medicine (ComPerMed) First, a small introduction. Targeted NGS is gradually introduced in molecular diagnostics in daily practice. It enables more precise decision-making for cancer patients by providing detailed information for diagnosis, prognosis and therapeutic choices for targeted drugs or conventional treatments. A permanent monitoring and assessment of the state of the art in this domain is essential and is addressed by the ‘Commission of Personalized Medicine’ (ComPerMed).

3 Commission Personalized Medicine (ComPerMed)
Aim: provide evidence-based advices to the platform CTG-TGR of the RIZIV-INAMI technical aspects of NGS testing clinical use of NGS for detecting somatic mutations in cancer patients assessment of novel ‘omics‘ technologies Belgian professionals and experts in the field of (hemato)-oncology The purpose of the ComPerMed is to give evidence-based advices to the platform CTG-TGR of the RIZIV-INAMI concerning the technical aspects of NGS testing, the clinical use of detecting somatic mutations in cancer patients, as well as the assessment of novel ‘omics‘ technologies. The work by the ComPerMed is supported by a large group of Belgian professionals and experts in the field and the work presented here is realized based on their indispensable advice.

4 Technical aspects of NGS
NGS guidelines: to facilitate the implementation of NGS in the laboratories to help labs to generate accurate NGS data e.g. Identical sample analysis should lead to an identical list of variants even if processed by a different operator on a different day. to facilitate the evaluation by the auditors from the accreditation bodies (Belac) A first project that was tackled by the ComPerMed was the technical aspects of NGS by my colleague Aline Hébrant and a gropu of experts. NGS guidelines were developed to facilitate …, to help… for instance that an identical sample analysis would lead to …. They were also developed to facilitate …, here in Belgium Belac. These guidelines were published in the Belgian Journal of Medical Oncology last April. Belg J Med Oncol 2017 Apr 1;11(2):56-67

5 Clinical use of NGS biomarker/test levels
Selection of genes with regard to their test utility for a specific tumor  diagnosis  therapeutic response (to predict sensitivity or resistance)  prognosis (patient outcome) biomarker/test levels A second project was to define the clinical use of NGS. For the clinical use of NGS we wanted to make a selection of genes with regard to their test utility in diagnosis and/or therapeutic response and/or prognosis (patient outcome) in a specific tumor type. We developed biomarker/test levels to be able to categorize the genes regarding to their importance.

6 Level 1 Level 2 Level 3 Standard of care biomarker for diagnosis and/or prognosis * Biomarker predictive of a response or a resistance to a reimbursed drug in Belgium for this indication A Recommended standard of care biomarker for diagnosis and/or prognosis + Biomarker predictive of response or resistance to an EMA-approved drug for this indication Biomarker predictive of response or resistance to a reimbursed drug in Belgium for another indication (clinical trial available in Belgium or EU) B Compelling clinical evidence supporting the biomarker for diagnosis and/or prognosis Biomarker predictive of a response or a resistance to - a non EMA-approved drug in this indication - a reimbursed drug in Belgium for another indication (clinical trial not available in Belgium or EU) - an EMA-approved drug for another indication Compassionate use of drug We defined 3 levels with level 1 the highest level of importance. We considered level1 and 2A as standard of care and level 2B and 3 are more related to clinical trials, compassionate use and research. * Standard of care: Included in guidelines (WHO) AND consensus from experts ComPerMed + Recommended standard of care: Clinical evidence AND consensus from experts ComPerMed

7 A B Standard of care Clinical trial compassionate use research Level 3
Standard of care biomarker for diagnosis and/or prognosis * Biomarker predictive of a response or a resistance to a reimbursed drug in Belgium for this indication Standard of care A Recommended standard of care biomarker for diagnosis and/or prognosis + Biomarker predictive of response or resistance to an EMA-approved drug for this indication Biomarker predictive of response or resistance to a reimbursed drug in Belgium for another indication (clinical trial available in Belgium or EU) B Clinical trial compassionate use research Compelling clinical evidence supporting the biomarker for diagnosis and/or prognosis Biomarker predictive of a response or a resistance to - a non EMA-approved drug in this indication - a reimbursed drug in Belgium for another indication (clinical trial not available in Belgium or EU) - an EMA-approved drug for another indication Compassionate use of drug * Standard of care: Included in guidelines (WHO) AND consensus from experts ComPerMed + Recommended standard of care: Clinical evidence AND consensus from experts ComPerMed

8 Clinical use of NGS Test utility and level Solid tumors
Hematological tumors Test utility and level was evaluated for solid tumors and for hematological tumors. For hematological tumors we had several meetings with the experts of the ComPerMed. At this moment, the clinical use of NGS is most relevant in myeloid cancers.

9 Clinical use of NGS Test utility and level Solid tumors
Hematological tumors MYELOID CANCERS NGS use in myeloid cancers

10 Clinical use of NGS List of myeloid cancers for which an NGS test is useful: Acute myeloid leukemia (AML) Myeloproliferative neoplasm (MPN) Chronic neutrophilic leukemia (CNL) Primary Myelofibrosis (PMF) Myelodysplastic syndrome (MDS) MDS/MPN Chronic myeolomonocytic leukemia (CMML) Atypical CML (aCML) MDS/MPN-RS-T This is a list of myeloid cancers for which an NGS test is considered useful.

11 Acute myeloid leukemia
Clinical use of NGS List of genes which should be analyzed at minimum by NGS: level 1 & 2A Acute myeloid leukemia Genes Diagnosis Prognosis Therapy ASXL1 x (2A) x (1) CEBPA* DNMT3A* FLT3 x (2B) IDH1 x (3) IDH2 KIT NPM1 RUNX1* TET2* TP53* WT1 For each tumor type we selected a list of genes which should be analyzed at minimum by NGS. The genes in this list have a level 1 or 2A for the specific cancer.

12 Clinical use of NGS List of genes which should be analyzed at minimum by NGS: level 1 & 2A Genes AML MDS MPN PMF CNL MDS/MPN aCML CMML RS-T ASXL1 x CALR CEBPA CSF3R DNMT3A EZH2 FLT3 IDH1 IDH2 JAK2 KIT MPL NPM1 RUNX1 SETBP1 SF3B1 SRSF2 TET2 TP53 U2AF1 WT1 For each tumor type we selected a list of genes which should be analyzed at minimum by NGS. The genes in this list have a level 1 or 2A for the specific cancer.

13 Clinical use of NGS Algorithms
Display the NGS test in the context with all the other molecular tests (FISH, IHC, PCR,…) Define the indications for NGS testing Besides the selection of the different genes for NGS testing, algorithms were developed that displays the workflow of the NGS tests in regards with the other molecular tests. This is helpful to define the indications for NGS testing.

14 Clinical use of NGS Example: algorithm of acute myeloid leukemia
Hematological diagnosis of AML (WHO criteria) (Molecular) Cytogenetics Gene mutations: NPM1, CEBPA, RUNX1, KIT, FLT3, WT1, TET2, ASXL1, DNMT3A, IDH1/2, TP53 Translocations Diagnosis & risk stratification Here is an example of an algorithm that we developed for acute myeloid leukemia. It starts with a first diagnosis based on non-molecular tests and WHO criteria. Then NGS testing for gene mutations together with cytogenetics and translocation analysis will provide more information for further diagnosis and risk stratification and will help in taking treatment decisions. Treatment decision Follow-up

15 Clinical use of NGS Integrate NGS testing and algorithm in a website
The aim is to finally integrate NGS testing and algorithms in a website, which is currently under construction.

16 Clinical use of NGS Integrate NGS testing and algorithm in a website
Aline Hébrant is already working on this for solid tumors. You can see an example here for colorectal cancer. For each tumor type, the incidence (provided by the Cancer Registry), list of experts and the algorithm will be indicated. In the algorithm the molecular test is represented as a red rectangle. When you click on the red rectangle information on test level appears. When you click here, a description of the test will appear. So this figure represent a printscreen of an algorithm, For each tumor type, we have added the incidence, these numbers comes from the cancer registry The algorithm The molecular test which is represented as a red rectangle There you can see the level of evidence of the test for this tumor type And also a brief description of the molecular test

17 Clinical use of NGS Integrate NGS testing and algorithm in a website

18 Clinical use of NGS Integrate NGS testing and algorithm in a website

19 Clinical use of NGS Integrate NGS testing and algorithm in a website

20 Future work Website: January 2018
Regularly update clinical use of NGS: genes and algorithms Clinical use of NGS in other hematological cancers (lymphoid) Clinical use of NGS in pediatric cancers Harmonize variant annotation and clinical interpretation So, the purpose is to open the website in January 2018. Other future work includes to have regularly an update of the selection of genes and algorithms. If needed we will also analyse the clinical use of NGS in other hematological cancers for instance lymphoid tumors. In future we will also consider the clinical use of NGS in pediatric cancers. The purpose is also to further harmonize variant annotation and clinical interpretation.

21 THANK YOU Thank you for your attention and I also would like to thank the Belgian experts for their advice in this project.


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