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VALID-SCREEN Report Summary

Project ID: 666800

Periodic Reporting for period 1 - VALID-SCREEN (Validation of PreCursor-M for enhanced Cervical (Pre)Cancer detection)

Reporting period: 2015-07-01 to 2016-06-30

Summary of the context and overall objectives of the project

With an estimated 528,000 new cases and 266,000 deaths in 2012 worldwide, cervical cancer is the fourth most common type of cancer in women, and second cause of death in women 15-45 years. Cervical cancer is preventable with regular screening tests and follow-up, and curable if found and treated early. In many countries, cytology-based screening programs are in place, which have resulted in a marked decrease in cervical cancer incidence. The effects of current screening methods however has levelled off, asking for innovations.
Cervical cancer is caused by an infection with the human papillomavirus (HPV). Women can be screened for the presence of a cervical HPV infection. HPV testing will replace cytology as primary screening test given better protection from cervical (pre-)cancer to screened women than the current standard of cytology. Most HPV infections, however, clear spontaneously without leading to clinically relevant disease or cervical cancer. Thereby, a drawback as stand-alone screening test, is the relative low specificity of HPV testing, causing overreferral, overdiagnosis and overtreatment. Triage of HPV-positive women is essential to maintain a sustainable and cost-effective screening program. Such a triage test will distinguish the subgroup of HPV-positive women having a high risk of cervical (pre)cancer in need of further gynecologic examination. At the same time, the use of a triage test reduces overdiagnosis, and unnecessary follow-up of women without clinically meaningful HPV infections.
Molecular changes known as hyper-methylation of promoter regions of host-cell genes are involved in cervical carcinogenesis. Methylation-based disease markers can well serve as a triage test for HPV-positive women to identify those at risk for cervical (pre)cancer. Self-screen developed a CE-IVD methylation assay consisting of two biomarkers combined with a reference in one multiplex assay. Supplementing HPV screening with this methylation assay will enable physicians to assess whether the HPV infection is progressing toward cancer; a valuable insight that will provide guidance to follow-up procedures, reducing overdiagnosis and overtreatment. The markers have been separately validated in clinical settings, and the combined marker panel has been validated in laboratory and small-scale clinical settings with desired clinical sensitivity and specificity. Divided over six work packages, the Valid-screen project will test and validate the clinical performance of the methylation assay in HPV-positive women. Independent subcontractors from different European countries will test and validate the assay in historical, prospectively collected screening cohorts and gynaecological outpatient referral populations with known clinical follow up. The project will furthermore tackle important market implementation aspects. Altogether, the study will provide essential clinical performance data of the methylation assay in European screening and gynaecologic outpatient setting, and deliver a key diagnostic tool in the cancer detection area to advance women’s health.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

To validate the clinical performance of the methylation assay in different, well characterised clinical cohorts from European countries, partnerships with five European institutes were established. Participating institutes were subcontracted on the availability of unique well-documented clinical cohorts suitable for performing validation studies as detailed in the project. An ethics advisory boards was set up to control for the ethical aspects associated with testing of human materials. To start of the laboratory testing, each institute was trained for methylation testing on-site by personnel of Self-screen. Following successful implementation of methylation testing at each laboratory site, the analysis of inter-laboratory agreement of the methylation assay is currently ongoing, with positive interim results. Meanwhile, active engagement with potential commercial diagnostic partners to explore interest in further co-development projects and marketing activities led to strategic partnering with Qiagen, a company with a major worldwide market in women’s health. Strategic partnering with Qiagen allows to further develop the market of the methylation assay, and co-educate clinicians and other users of the assay. The CE-IVD assay was launched and promoted at the Eurogin 2016 congress (14-18 June 2016, Salzburg, Austria).

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The DNA methylation analysis test represents a paradigm shift in human healthcare that is happening now.
Precursor lesions of cervical cancer, named cervical intraepithelial neoplasia (CIN), are classically divided into CIN1, CIN 2, and CIN3, of which CIN3 is considered the most advanced precursor lesion of cervical cancer. Common practice is that CIN2 and CIN3 are treated to prevent cancer development. However, it is well known in the field that many of these CIN2 and some of the CIN3 lesions could spontaneously regress, making treatment actually unwarranted. Current CIN classification is not able to identify which lesions will progress or regress. The present treatment approach thereby leads to considerable overtreatment and cervical morbidity, including frequent preterm birth and cervical insufficiency in women at fertile age.
DNA methylation analysis of genes involved in cervical cancer development represents an important change in the concept of treatment of CIN2 and CIN3 lesions. A positive methylation test can be used as a biomarker for the detection of advanced cervical precursor lesions (i.e., part of the CIN2 and most CIN3 lesions with a duration of existence of >5years and with many chromosomal abnormalities) with a high short-term risk of progression to cervical cancer in need of treatment (Steenbergen et al. Nat Rev Cancer 2014). This concept fits well with knowledge in the field that most CIN2/3 lesions at young age (<30 years) will not develop into cancer and mainly regress, and that CIN2/3 lesions are heterogeneous with respect to (epi)genetic alterations. This means that the methylation-negative CIN2 and CIN3 lesions, which are detected by current cytology and/or HPV testing, are in fact early lesions with a low chance of progression and may not need treatment within 1-2 years. In this way, DNA methylation analysis can also reduce overdiagnosis and overtreatment.
To translate this new view - which can be seen as a paradigm shift in the treatment of CIN lesions - to profound benefits to patients and for the economics of healthcare, the Valid-screen project is important. The project enables the collaboration with laboratory sites with well-documented clinical specimens to perform the necessary clinical validation studies to support the new concept and enforce the paradigm shift. Strategic partnering with Qiagen allows to further develop the market of the methylation assay and co-educate clinicians and customers.

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