Title: Urine testing for cervical screening: is it effective and can it improve uptake?
Funder: Department of Health and Social Care

Abstract: Research questionIs urine HPV testing effective as a primary cervical screening test and can its use improve screening uptake?BackgroundCervical cancer is preventable through screening for high-risk human papillomavirus (HPV) infection, which is necessary for its pathogenesis. HPV positive samples are triaged by cytology to identify women at risk of high grade cervical intraepithelial neoplasia (CIN2+), whose treatment prevents cancer. Cervical screening is estimated to save 2,000 lives every year in the UK alone but participation rates are plummeting, with only 71% of eligible women screened last year. Some barriers to participation like embarrassment, fear of speculums and inconvenience may be alleviated by self-sampling. Vaginal self-sampling is effective for CIN2+ detection but return rates are modest at just 6-8%. A urine test may have wider appeal but few studies have tested its effectiveness in a primary screening population. Further, it is not known whether urine testing is acceptable to cervical screening attenders, or whether its use could encourage participation by non-attenders. In a pilot study, I optimised urine collection and processing for high risk HPV using NHS-approved tests, and showed excellent sensitivity for CIN2+ detection in a small colposcopy referral population.This proposal aims1. To estimate the effectiveness of urine HPV testing for CIN2+ detection in a large cohort of women2. To assess the acceptability of urine-based cervical screening3. To determine whether urine testing can improve the uptake of cervical screeningMethodsIn Study 1, clinically annotated matched urine and cervical samples will be tested for high risk HPV using the NHS-approved Roche Cobas test. HPV positive samples will undergo methylation testing in collaboration with Prof Lorincz at QMUL, to establish its effectiveness for molecular colposcopy triage. I will test colposcopy referral (n=400) and primary screening populations (n=1500) to estimate the clinical performance of urine testing for CIN2+ detection. In collaboration with Prof Waller at UCL, I will design a short questionnaire to understand the views and preferences of current cervical screening attendees.In Study 2, in collaboration with Prof Sasieni at KCL, I will cluster randomise 22 GP practices in Greater Manchester to control and opportunistic practices, balancing for age and cervical screening uptake. In opportunistic practices, women who are 6+ months overdue cervical screening will be offered urine testing kits when they attend their GP for any reason. At 18 months, women across all participating practices will be individually randomised to receive no intervention, a urine or vaginal self-sampling kit, posted to their home address. Returned samples will be HPV tested and HPV positive women offered routine screening for cytology triage, as per NHS standards. I will track whether women who do not return kits attend routine screening. A short questionnaire will help me understand more about women who take up urine testing and their barriers to routine screening. Anticipated impact This proposal will establish whether the clinical performance of urine testing is sufficient to recommend its use as a primary cervical screening test, and whether its use could improve uptake by non-attenders.

Lay abstract: BackgroundCervical cancer is caused by chronic infection with human papillomavirus, or HPV. Cervical screening tests for HPV in cells collected from the cervix using a soft brush. If the test is HPV positive, the cells are examined under the microscope by cytology. If cytology shows abnormal cells, the woman is referred to colposcopy, where pre-cancer cells are identified and treated. In this way, cervical screening saves lives from cervical cancer. Yet only 7 in 10 women in the UK attend cervical screening, the lowest rate in 20 years. Reasons include embarrassment, fear of examination and inconvenience, factors that may be overcome by 'self-sampling'. Vaginal self-sampling is an effective way of identifying cervical pre-cancer, but in the UK, only 1 in 10 women return a sample. In a small pilot study, I developed and tested a urine HPV test for cervical pre-cancer. I hypothesise that this urine test will accurately pick up cervical pre-cancer and encourage more women to be screened. Aims1. To see whether a urine test is effective at picking up cervical pre-cancer2. To see whether urine-based cervical screening is acceptable to women3. To see whether a urine test can encourage women to attend for cervical screening MethodsIn Study 1, I will see whether a urine test can accurately identify women with cervical pre-cancer by comparing HPV detection rates in urine and matched cervical samples. I will see whether HPV positive samples can be further distinguished by a methylation test, which measures the impact of HPV on the genetic makeup, or DNA, of cervical cells. I will collect samples from 400 women referred with abnormal cervical screening results, and 1500 women attending primary care for routine screening. Women will be managed according to the NHS Cervical Screening Programme but I will track their clinical outcomes. This large number of women will give us precise estimates regarding the accuracy of urine for picking up pre-cancer (its sensitivity) and for correctly ruling out disease (its specificity). Women will also complete a short questionnaire about what they think of the urine test. In Study 2, I will see whether a urine test can encourage women who have not attended for cervical screening to have a test. In Stage 1, I will computer randomise GP practices in Greater Manchester to control practices, where women who are overdue cervical screening receive standard care (no intervention), and opportunistic practices, where women are offered a urine test when they attend their GP for any reason. Stage 2 will randomise women registered at participating GP practices who are still overdue cervical screening 12 months later, to receive standard care (no intervention), a urine sampling kit or a vaginal self-sampling kit sent to their home address. I will see how many women return self-collected samples or attend routine cervical screening. I will ask women to complete a short questionnaire regarding their preference for the urine test, vaginal self-sampling or routine screening. Patient and public involvement (PPI)Women are at the very heart of this proposal. Their views have informed its strategy through two nationwide surveys and a purpose-built PPI panel. Their input will be instrumental to its design, particularly through review of patient-facing documentation, as well as guiding its management and the dissemination of its findings. DisseminationI will present my results at scientific conferences and publish in open access journals. I will engage with lay audiences through blogs and videos on social media. If a urine test is both accurate at identifying pre-cancer and improves cervical screening uptake, I will campaign for its inclusion in an NHS Cervical Screening Programme implementation pilot.

Research activity codes: 4.3 INFLUENCES AND IMPACT;4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS