Self-sampling could increase detection of cervical pre-cancer

A non-invasive test to detect cervical pre-cancer has been developed through a study led by the director of the Wolfson Institute of Preventive Medicine at Queen Mary, in the hopes of increasing the participation rates in cervical cancer screening programs. The test analyzes urine and vaginal samples collected by women at home.

Cervical pre-cancer, also called cervical intraepithelial neoplasia (CIN), refers to the development of abnormal growths on the surface of the cervix that can grow into cancerous cells. Pre-cancer develops over three stages, CIN1, CIN2, and CIN3, with each stage seeing pre-cancer cells become more likely to develop into cancerous cells.

Approximately 1 in 20 women have abnormal changes that could progress to cervical cancer and are referred to undergo a colposcopy, where the cervix is examined under magnification in order to detected, sampled, and treated before the risk of cancer can increase. As such, researchers aimed to assess whether they could identify women with CIN3 pre-cancer using urine and vaginal samples.

The test focused on the methylation classifier S5, looking at DNA methylation (a chemical change to one of the four DNA base letters constituting the human genetic code) of the four types of the human papillomavirus (HPV) that are most strongly linked with cervical cancer: HPV16, HPV18, HPV31, and HPV33. The S5 test also looked at the human gene EPB41L3 to score the level of risk, with a score above a certain cut-off point suggesting an increased risk of a pre-cancer lesion, with higher scores indicating higher levels of cancer risk.

Women attending the colposcopy clinic at the Royal London Hospital after abnormal cells had been detected through a smear test or they had been tested positive for the human papillomavirus (HPV) were invited to take part in the study that included vaginal and urine samples. The women were able to collect both samples themselves, using swabs for the vaginal samples. After 620 women provided vaginal samples with 503 of the women also providing a urine sample, the researchers extracted and analyzed DNA and generated S5 scores.

Presenting the research at the 2019 NCRI Cancer Conference today, Dr. Belinda Nedjai, a senior research fellow and director of the Molecular Epidemiology Lab at Queen Mary, University of London, UK, said that women preferred the self-sampling tests to attend a screening appointment at a doctor’s surgery.

The initial use of self-sampling is likely to be for women who do not attend clinic after a screening invitation and countries without a cervical cancer screening programme. In the longer term, self-sampling could become the standard method for all screening tests. The study indicated that women much preferred doing a test at home than attending a doctor’s surgery.”
Dr. Belinda Nedjai, senior research fellow and director of the Molecular Epedimiology Lab, Queen Mary University of London

In previous research Nedjai and her research team at Queen Mary had found that the S5 test was 100 percent accurate when detecting invasive cervical cancer using cervical samples and 93 percent accurate when detecting pre-cancer in HPV-positive patients.

"We found that S5 classier with or without HPV testing worked well in both urine and vaginal samples," Dr. Nedjai said. "It distinguished between women who had no pre-cancerous lesions and those who had CIN3 or higher lesions.

“We evaluated two distinct ways that S5 could be used. We first tested S5 as a secondary test on HPV positive women to limit the number of patients sent to colposcopy. In urine, S5 was better at correctly identifying women who did have pre-cancer lesions than testing for the presence of HPV16 or 18; 96 percent of true CIN3 were identified with S5 compared to 73 percent with an HPV16 or 18 test. Secondly, we evaluated S5 as a stand-alone test, without first doing HPV testing. We adjusted the cut-offs to identify at least 85 percent of true positives. Urine performed as well as self-collected vaginal samples.”

She continued:

"We are currently working on new markers to try to improve the accuracy of the classifier even further, but these findings represent an advance in cervical cancer screening, especially for women who do not attend the clinic, such as older women, or women who find the smear test too painful or who do not have access to a screening programme in their country. We think it's promising."
In the future, samples for both HPV and methylation analysis could be collected at home, circumventing the need to attend a clinic at all.

Dr. Manuel Rodriguez-Justo, a consultant pathologist at University College London (UK) and a member of the NCRI’s sub-committee on early detection and prevention, who was not involved in the study, gave his opinion on this promising research.

“This is exciting research that shows it’s possible to detect cervical pre-cancer that is at high risk of developing into invasive cancer in urine and vaginal samples collected by women in the comfort and privacy of their own homes. This has the potential to revolutionize the way a positive HPV test is followed up, as well as making it easier for women in countries with no cervical cancer screening program to be tested.”

He explained that although the UK cervical cancer screening program in the UK has been successful, there has been a decline in uptake in certain areas of the country and in particular ethnic groups. With validation through further testing in a wide range of ethnic groups, the S5 test and the implementation of self-sample urine and vaginal tests could increase the numbers of women being tested and reduce the costs of running screening programs, while also maintaining the high levels of sensitivity current smear tests achieve to detect pre-cancer lesions.

With cervical cancer being the fourth most frequently occurring cancer in women worldwide, it is important that more and more women go through regular screening tests and attend follow-up appointments. In 2018 alone there were approximately 570,000 new cases of cervical cancer with 310,000 women dying from the disease.

HPV infection accounts for the majority of cervical cancer cases, with over 25 types of HPV being sexually transmitted, 12 of which carry a high risk of cancer through their ability to deactivate tumor-suppressing proteins. This is true of HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 68.

Dr. Nedjai concluded:

“HPV testing is rapidly becoming the primary screening method for cervical cancer worldwide. It is a very sensitive method, very good at detecting true positives, but lacks specificity - in other words, a second test is needed to exclude HPV positive women that are not at increased risk of developing cancer. The choice of an appropriate strategy for high-risk HPV positive women is a key issue.

“We expect the self-sampling test to improve acceptance rates for cervical cancer screening, as well as reducing costs to health services and improving the performance of screening programmes.”

EurekAlert! Science News. Cervical Pre-Cancer Can Be Detected in Self-Collected Urine or Vaginal Samples. (2019). https://www.eurekalert.org/emb_releases/2019-11/ncri-cpc110119.php.