Lynch syndrome-associated endometrial cancer: prevention, screening and prognosis

Lynch syndrome is caused by specific gene faults that make cancer more likely to occur. Lynch syndrome runs in families. Bowel cancer and womb cancer are more common in people with Lynch syndrome. When we know someone has Lynch syndrome, we offer colonoscopy, a camera test to look inside the bowel, to remove any bowel polyps before they become cancerous. This has been shown to save lives. To prevent womb cancer, some women have a hysterectomy once their family is complete. Others have womb cancer screening or take hormone treatments, even though we do not know if these things work.

As many as 1 in 10 women with womb cancer may have Lynch syndrome, although most do not know it. If they knew about the Lynch syndrome, they may choose to have regular screening by colonoscopy to remove bowel polyps. They may also help other family members find out whether they have Lynch syndrome. Womb cancer that develops in women with Lynch syndrome may behave differently and have a different outlook compared with womb cancer that occurs in women without Lynch syndrome. No one has looked at this before.

In this project, I will be conducting three studies:
In Study 1, I will see how many patients with womb cancer have Lynch syndrome that they didn't know about. We can find this out by carrying out specific laboratory tests on the tumours. I will look at 200 women who gave blood and tumour samples for future research projects when they came in for their hysterectomy. I will also test 200 women with new diagnoses of womb cancer as they come through the department for their surgery. If the tumour studies suggest that Lynch syndrome may be present, we will carry out blood tests to see if the gene fault is there. This will be done on the stored blood sample or, for current patients, genetic testing will be carried out through the genetic counselling service in our hospital. We will find out how many women with womb cancer have Lynch syndrome. I will also find out how straightforward it is to test women with womb cancer for Lynch syndrome. I will see whether patients are happy for their tumours to be tested for Lynch syndrome and whether they are prepared to go for genetic counselling. I will see whether they want to undergo colonoscopy to identify and treat bowel polyps. I will also see how much screening for Lynch syndrome in women with womb cancer is likely to cost. This will help us develop guidelines for which patients with womb cancer should be tested for Lynch syndrome in the future.

In Study 2, I will compare womb cancers from women who have Lynch syndrome with those who do not. Using specialised laboratory techniques, I will look to see how the tumours are different and how they are the same. I will look at whether the women with Lynch syndrome were more or less likely to die from their womb cancer than women without. This will help us understand womb cancer more and inform patients better in the future.

Study 3 will look at how effective womb cancer screening and hormone treatments are at preventing womb cancer in women with Lynch syndrome. I will see whether being overweight and inactive make womb cancer more likely in women with Lynch syndrome. This will help us advise women properly when they know they have Lynch syndrome.

Lynch syndrome (LS) is a tumour predisposition condition caused by mutations in the mismatch repair (MMR) genes. Mutation carriers are at increased risk of several cancers including colorectal (CRC) and endometrial cancer (EC). Establishing a diagnosis of LS has the potential to save lives. Intensive cancer surveillance by colonoscopy and removal of colorectal polyps prevents CRC-related death. Prophylactic hysterectomy prevents EC. Benefits extend to other family members who undergo genetic testing/cancer surveillance.

The prevalence of LS in EC patients is unknown. We do not know whether screening for LS is feasible, acceptable to women or cost effective. We do not know if the prognosis of LS-associated EC differs from sporadic EC. There is also no evidence to support progestin chemoprevention or EC screening in LS, even though both strategies are routinely recommended.

Objectives:
1. To determine the prevalence of LS in EC and the feasibility, acceptability and cost effectiveness of screening for LS in EC
2. To compare prognosis and tumour biology of LS-associated and sporadic EC
3. To assess EC rates in LS patients undergoing screening for EC, progestin chemoprophylaxis and prophylactic hysterectomy

Methodology:
1. I will assess 400 EC for microsatellite instability (MSI) and MMR protein loss. Patients with tumour studies suggesting LS will have reflex genetic testing. I will establish the prevalence, feasibility and cost effectiveness of LS screening in EC patients. 2. I will compare MSI, MMR protein loss and other EC biomarkers in 165 archived LS-associated EC and stage-matched contemporaneous sporadic EC controls. I will compare EC-specific survival in the two groups. 3. I will conduct a questionnaire survey to assess the prevalence of EC risk-reducing strategies in women with LS (n=364). I will compare EC rates in women who had a prophylactic hysterectomy with those who did not, age-matched and stratified by risk-reducing strategy.

Scientific advancement
Study 1: I will investigate the prevalence of LS-associated EC, as well as the feasibility, acceptability and cost effectiveness of screening for LS in EC patients. This will be the first study of its kind in the UK. It is hoped that these data will provide a platform for further large-scale screening studies that ultimately impact on patient care.
Study 2 will exploit Professor Evans' unique archival collection of LS-associated EC specimens and compare these with sporadic EC to further our understanding of the biology of the disease. It is anticipated that LS-associated and sporadic EC will differ in their genetic profile, their expression of EC protein biomarkers and in their biological behaviour. The intelligence learned here may pave the way for the development of EC prognostic biomarkers that allow patients to be triaged to receive/not receive adjuvant therapy as well as facilitating the design of novel targeted therapies.
Study 3 will determine what, if any, EC risk-reducing strategy currently routinely recommended for LS patients prior to hysterectomy is effective. Prospective studies in this area are challenging, but it is hoped that the data generated here will direct future research effort into EC prevention strategies in high risk groups.

Impact on the nation's health, wealth and culture
My work could provide the impetus for the development of a national LS screening programme in EC patients. It could influence health policy and directly impact patient care. Individual women identified as having LS could be offered regular colonoscopy, which prevents deaths from colorectal cancer. EC has a better prognosis and typically develops 8-10 years before colorectal cancer in LS, so identifying women with LS at the time of EC diagnosis is particularly apposite. First degree relatives could also be screened for LS. The identification of effective strategies to reduce EC risk in LS patients is also directly relevant to patient care and could have an immediate impact. If EC screening and progestin chemoprophylaxis fails to protect against EC in LS, their use could be abandoned and the resources thus saved directed elsewhere. Women may then be given a strong steer towards undergoing a hysterectomy following completion of their childbearing. On the other hand, if our hypothesis is true and progestin chemoprophylaxis does protect against EC in LS, current recommendations will become evidence based. Women may be more likely to choose progestin chemoprophylaxis and thus EC may be less frequently diagnosed. Furthermore, if weight control and physical exercise reduce the risk of LS-associated EC, patients may then be appropriately counselled and supported to make lifestyle changes.

Public dissemination and engagement
Our patient representative panel will ensure that the patient remains at the heart of everything we do. We will discuss the study design, patient information sheets and dissemination of results with our patient representatives. Patient participation in the prospective arm of Study 1, as well as the questionnaire survey of Study 3, is central to the success of my project and so it is important that we pitch the study appropriately. Every effort will be made to communicate the results of the studies to the public through websites, newsletters, press releases and research roadshows.

Development of skills, capacity and capability
This fellowship offers me the opportunity to undertake a substantive period of focussed research to develop my clinical, laboratory and transferable research skills. Upon completion of the fellowship, I plan to take up a Clinical Lectureship in Gynaecological Oncology so that I can complete my clinical training alongside postdoctoral research. Ultimately I aspire to hold a chair in Gynaecological Oncology when I will lead my own research group and foster the academic development of the next generation of laboratory scientists and clinical academics.