Title: The early diagnosis of endometrial cancer: overcoming barriers to presentation and developing non-invasive detection tools
Funder: Department of Health and Social Care

Abstract: Background Endometrial cancer (EC) is the most common gynaecological cancer affecting British women, and its incidence and associated mortality are rising steadily. Most EC is diagnosed early following the onset of postmenopausal bleeding (PMB) and has an excellent 5-year survival rate. By contrast, 20% of women present at an advanced stage and a 5-year survival rate of just 15%. New strategies to facilitate early diagnosis are needed to prevent further deaths from the disease.Currently, diagnosis requires specialist referral followed by sequential invasive tests that are poorly tolerated by some, painful in others and unnecessary in most; only 5% of women with PMB have EC. The intrusive nature of the tests may explain why some women with PMB delay seeing their GP. On average, women wait more than a month before they consult their GP and the reasons for this have not been studied before.Reducing barriers to early diagnosis could include the development of new detection tools. A simple, non-invasive primary care-based detection tool that accurately identifies EC and safely reassures healthy women could transform patient care. One approach is to exploit the notion that EC sheds malignant cells through the cervix into the lower genital tract. In a pioneering pilot study of matched urine and vaginal samples, I identified malignant cells in 28/32 (88%) women with known EC and 0/10 (0%) women with unexplained PMB in whom EC was ruled out. Previous studies investigating cytology for EC detection used invasive sampling technology and reported lower detection rates.Aims My aims are to: Assess the diagnostic test accuracy (DTA) of cytology for EC detection in published studies (Study 1) Test our novel urogenital sampling technology for EC detection by cytology in women with known EC and women with unexplained PMB (Study 2) Explore factors that affect women's recognition of 'red flag' symptoms in EC and decision to access medical care (Study 3) Methods In Study 1, I will assess the clinical performance of cytology for EC detection through a Cochrane DTA systematic review. This will inform the clinical utility of cytology as a diagnostic tool in EC and allow fair comparison of our new test (developed in Study 2) with existing sampling technology. In Study 2, I will determine the clinical performance of urogenital cytology in 100 women with known EC and 100 women with PMB. In Study 3, I will assess the factors affecting symptom appraisal and help-seeking behaviour in 30 women with PMB and/or EC through a semi-structured in-depth qualitative interview; results will be analysed using the Model of Pathways to Treatment according to the Framework approach.Anticipated impact This fellowship will: Deliver the first synthesis of the existing literature regarding the DTA of urogenital cytology for EC detection (Study 1); Determine whether our innovative non-invasive urogenital sampling shows sufficient promise for EC detection by cytology that it warrants testing in a large multicentre DTA study (Study 2); and Seek to understand symptom appraisal and barriers to help seeking behaviour in women with PMB (Study 3).

Lay abstract: Background Womb cancer is the most common gynaecological cancer in the UK and its incidence is rising. Most women with womb cancer are cured by hysterectomy. However, 1 in 5 women are diagnosed with advanced womb cancer when cure is unlikely. If we could diagnose all womb cancers early, we would save lives.For most women, the first symptom of womb cancer is postmenopausal bleeding. For 9 in 10 women the bleeding is nothing serious, however, all women undergo a series of tests to exclude womb cancer. These include an internal ultrasound scan, a camera test and a biopsy. These tests are unpleasant due to their intrusive nature. Some women find the camera test so painful they need a general anaesthetic for it to be completed.The unpleasant nature of the tests may be one reason why women with postmenopausal bleeding do not see their GP straight away. The average woman with postmenopausal bleeding waits more than a month before she sees her GP. This may partly explain why some women are diagnosed late. A new test for womb cancer that is quick, accurate and patient-friendly could help.New research shows that womb cancers shed tumour cells that spill out of the womb. In the first study of its kind, we looked for shed tumour cells in urine and vaginal samples of women with womb cancer, using a specialist microscope test called cytology. I found that most of the women with womb cancer (28 of 32) and none of the women without (0 out of 10) had tumour cells in their samples. No one has studied this combination of tests before and we need to test many more women to ensure their use is accurate. Feedback about the tests has been extremely positive.AimsTo carry out a systematic review of published studies to see whether cytology can accurately detect womb cancer (Study 1). To determine how accurate our new test is at picking up and ruling out womb cancer (Study 2). To find out why many women with postmenopausal bleeding don't attend their GP straight away and see whether this affects their outcomes (Study 3). Methods In Study 1, I will carry out a review of all published studies to see whether cytology can detect womb cancer. I will compare and contrast the ways that different studies collected their samples, and calculate the overall success rate of cytology for womb cancer detection. This will show us how well our new test performs in comparison.In Study 2, I will perform urine and vaginal cytology in 100 women with known womb cancer, and 100 women with postmenopausal bleeding. I will compare the accuracy of this test with standard diagnostics. I will ask women to rate the acceptability of our test.In Study 3, I will interview around 30 women from Study 2 about their postmenopausal bleeding, and the factors that influenced when they first saw their GP.Patient and public involvement This research seeks to answer one of the most important unanswered research questions in womb cancer according to patients, carers and healthcare professionals in our recently completed James Lind Alliance Priority Setting Partnership. Patients will help me review existing research studies (Study 1), design my interview questions (Study 3), oversee my project and help me disseminate the results.Dissemination I will present my results at scientific conferences and publish in open access journals. If accurate, our new test could transform the womb cancer diagnostic pathway. Finding out why women with postmenopausal bleeding don't attend their GP straight away will help develop strategies to increase public health awareness.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS