"Gynaecological cancer: The Genomic Gap and how to close it"
Around 5% of cancers are a result of inherited cancer predisposition syndromes. Arguably all of these cancers could have been prevented. Much attention has been afforded to BRCA1/2 mutation carriers and their associated gynaecological cancer risk. Yet just as common is Lynch syndrome, which confers a lifetime risk of cancer of up 70%. Approximately 3% of endometrial cancers and around 1% of ovarian cancers are associated with the condition and yet low levels of awareness and understanding persist amongst clinicians and patients. Research has also been lacking. This has led to women, up until recently, being unduly disadvantaged by a lack of national guidance and testing strategies.

If awarded this prestigious lecture, I would detail how my research led to a change in current National Institute for Health and Clinical Excellence (NICE) guidance. First, I conducted primary research looking to better understand Lynch syndrome in the context of gynaecological cancer. I found that the biology of ovarian cancer associated with Lynch syndrome is unique. Furthermore, I was able to demonstrate that the type of mutation had an independent impact on the cancer phenotype allowing for more personalised surveillance and risk reducing treatments. Through a large meta-analysis, I was able to define the prevalence of Lynch syndrome in women with endometrial cancer. These data informed a meeting of international experts, hosted by myself and my PhD supervisors, who were able to agree on the first specific gynaecologically focused clinical guidelines for the management of Lynch syndrome. These guidelines called for the universal screening of endometrial cancer for Lynch syndrome, and so I conducted the first study of such a programme in the UK. In total 500 women were tested for Lynch syndrome with 16 (3%) being found to have it. I collected data on the patients’ experience of being consented for Lynch syndrome testing by a gynaecologist and found women were satisfied with the service. In addition, I did both micro-costing analysis and health economical modelling showing that my approach was cheaper than previously thought and cost effective. My robust methodology enabled us to compare the main testing strategies and found that a commonly used test for Lynch syndrome demonstrated poor sensitivity in endometrial cancer.

Mismatch repair deficient endometrial cancer, whether it be from Lynch syndrome or have arisen by somatic mutation, has always been treated as a homogenous group. However, no one had fully investigated this assumption. I have built a unique biobank of endometrial cancers from women with proven Lynch syndrome. With this resource I was able to delineate the unique immune environment and describe a somatic mutational profile of these cancers. These findings have real world treatment implications.

Finally, I would like to develop my ideas for future work and present my current work. I have conducted a nationwide survey of current clinical practice around the management of women with Lynch syndrome and have found it wanting in many respects. Recently I have started to explore the effectiveness of cancer screening in healthy women with Lynch syndrome- something that remains controversial. I am actively looking at new technologies to enable more cost-effective diagnosis. If these costs can be sufficiently reduced it may enable population-based screening and the identification of women with Lynch syndrome before they get cancer. I am also keen to explore novel methods, such as Mendelian randomisation to better understand how risk factors for endometrial cancer apply to women with Lynch syndrome
Date: 15 June 2021, 13:00 (Tuesday, 8th week, Trinity 2021)
Venue: MS Teams Event- please contact seminars@wrh.ox.ac.uk if you wish to join
Speaker: Dr Neil Ryan (UNIVERSITY HOSPITALS BRISTOL NHS FOUNDATION TRUST)
Organising department: Nuffield Department of Women's and Reproductive Health
Organiser: Dr Jen Southcombe (University of Oxford)
Organiser contact email address: seminars@wrh.ox.ac.uk
Booking required?: Not required
Booking email: seminars@wrh.ox.ac.uk
Audience: Members of the University only
Editor: Danielle Hoare