Introduction and Survey Results Dr Katie Snape, Consultant Cancer Geneticist UKCGG and St George’s University Hospitals NHS Foundation Trust K.snape@nhs.net

Background Increasing use of somatic testing in cancer tissue Use of both somatic panels and WGS (with paired germline) in test directory Increasing number of referrals into clinical genetics on basis of somatic data wondering if variants could be present in the germline Increasing number of private and DTC referrals into clinical genetics

Current Situation No clear guidance on Who is/should be eligible for referral to clinical genetics on the basis of a somatic test What the likelihood of finding a germline variant is for an identified somatic variant In associated tumour types In non associated tumour types How consent should operate for somatic testing where germline information may be identified How these novel pathways will impact on resourcing in clinical genetics

Aims of today’s workshop Review novel data which gives insight into the likelihood of a somatically identified variant also being present in the germline Understand current and future policy on somatic/germline cancer gene testing from NHSE Obtain consensus (as much as possible!) on what/who should and should not be referred from oncology to clinical genetics for further assessment/testing Define/debate the novel clinical referral pathways which need to be implemented including where and how consent for germline testing should be undertaken Present our outcomes as an expert working group of clinical scientists, oncologists, pathologists, clinical geneticists and genetic counsellors

Survey Responses 23 respondents Multiple emails saying people did not feel they have enough expertise to complete the survey so were non responders At least two respondents stated they didn’t feel they knew enough to answer specific questions Conclusion: difficult and complex area, with limited expertise amongst oncologists and geneticists

Take home messages Divided on whether the following should be included Age cut offs for tumour types No established germline association with cancer type Variant allele frequency of 40%

Take home messages Divided on whether the following should be included Age cut offs for tumour types No established germline association with cancer type Variant allele frequency of 40%

Take home messages Full or almost full agreement to include Variant is in gene(s) for which diagnostic germline testing is available Established germline association with cancer type Variant is class 4/5 by clinical consensus (e.g. C-VIG), ≥ 2* on Clinvar or LoF variant where that is known pathogenic mechanism of gene

Comments on additional inclusion criteria Assimilate alongside other molecular/pathological data (e.g. IHC/mutational signatures) Clinical actionability e.g. Lower threshold for testing if affects clinical trial eligibility and higher threshold if no clear change in clinical management for patient/relatives Likelihood of germline mutation being present if identified somatically

Genes in breast cancer Other: PTEN/STK11/CHEK2/ATM/CDH1 (lobular)

Genes in serous ovarian cancer Other: RAD51C, RAD51D, BRIP1

Genes in non-serous ovarian cancer Other: RAD51C, RAD51D, BRIP1

Genes in colorectal cancer Other: polyp panel genes

Genes in lung cancer

Themes of gene eligibility Preference for known CPGs in associated tumour types Multiple suggestions to include all CPGs for associated tumours But significant proportion suggesting CPGs in non associated tumour types Opting out of some tumour types which people felt less comfortable with

?Age cut off

Comments on age cut off Tumour dependent E.g. Different age cut offs for breast and prostate cancer with BRCA Becomes complicated... Age not only factor – also family history, histology etc.

Referrals

Referrals

Referrals

Referrals Vast majority currently managing on case by case basis as small numbers Would be helpful to have agreed national standardised criteria for accepting/rejecting referrals for testing or further assessment

Other comments Haem-onc samples – saliva? Paired germline-somatic testing upfront would help resolve many of these issues Need funding/staff/resources as well as clinical pathways What is currently deliverable? What extra resources do we need to implement these workflows?

Aims of today’s workshop Review novel data which gives insight into the likelihood of a somatically identified variant also being present in the germline Understand current and future policy on somatic/germline cancer gene testing from NHSE Obtain consensus (as much as possible!) on what/who should and should not be referred from oncology to clinical genetics for further assessment/testing Define/debate the novel clinical referral pathways which need to be implemented including where and how consent for germline testing should be undertaken Present our outcomes as an expert working group of clinical scientists, oncologists, pathologists, clinical geneticists and genetic counsellors