Variant Triaging and ESMO Guidelines Chris Wragg

Chris Wragg Cancer Validation and Reporting Meeting, 7th November 2018 Variant Triaging Chris Wragg Cancer Validation and Reporting Meeting, 7th November 2018

Introduction Increase in diagnostic somatic NGS Test directory requires expanded Cancer NGS Panels Analysis of 100k genome results Discrepancies between labs in how variants are classified and reported Majority use 5 Class system (ACMG) Not suitable for somatic variants Li et al (2017)

Standardisation Rare disease classification has been standardised through adopting the ACMG guidelines Workshops established (scientist + clinician) Monthly WebEx Disease specific working groups e.g. C-VIG Data sharing

Somatic

Actionability A variant can be considered a biomarker that affects clinical care (clinically actionable) if it: Predicts sensitivity, resistance, or toxicity to a specific therapy Alters the function of the gene which can be targeted by approved investigational drugs Serves as an inclusion criterion for clinical trials Influences disease prognosis Assists in establishing a diagnosis of a cancer Warrants implementing surveillance measures for early cancer detection Li et al. The Journal of Molecular Diagnostics, Vol. 19, No. 1, January 2017 Section 3.1.1 Cancer Validation and Reporting Guidelines

UK Somatic Variant Interpretation Group Stakeholders from across Cancer Clinical and Diagnostic Community aiming to: Establish current practice Identify and share good practice Standardise assessment of pathogeneticity/actionability Develop/adopt national SVI guidance Mainstreaming/Education

UK-SVI Workshop 21st September 2018, Birmingham EQA scheme experience of SVI (GenQA, UKNEQAS LI) Competency schemes (G-TACT) How to establish pathogenicity How to establish actionability Results of practice variant classification Lightning presentations capturing current practice Focussed discussion

UK-SVI Workshop Working groups established: Pathogenicity Actionability Germline findings Reporting

UK-SVI: Pathogenicity Current practice: Predict functional consequences (literature, in silico predictions) Mechanism of activity (activate oncogene/inactivate TS) Population databases Cancer specific databases Driver annotation: Establish resources/databases Train classifiers Validate

UK-SVI: Actionability Paper Definition Therapy Investigational Prognosis /Diagnosis Hypothetical Target Germline therapy Germline Risk Van Allen (2013) ✔ Meric-Bernstam (2015) Sukhai (2016) Li (2017) Mateo (2018)

UK-SVI: Actionability Guidelines agree on what should be used to determine actionability Actionability determined through assessment of: Known associated therapies / prognostic or diagnostic implications Clinical trial results Eligibility criteria for a clinical trial Preclinical data for response to therapy / association with prognosis or diagnosis Literature Guidelines differ on how the evidence is used – weighting of evidence and classification framework

UK-SVI: Next Steps Working groups established and ToR being defined Aligning with parallel projects e.g. from CRUK (SMP2) Seeking expanded involvement to include more Oncologists/Haematologists Aim to produce harmonised UK Somatic Variant Interpretation recommendations Best practice guidance for somatic bioinformatic pipelines being developed Data sharing opportunities under review Education/Training/Mainstreaming