Cervical Cancer Prevention: From DNA to mRNA? - New Technologies for Cervical Cancer Screening 2

Study Overview
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Brief Summary
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In industrialized countries, cervical cancer is a well controlled disease thanks to the diffusion of Pap test and, in particular, to organized screening programs, which are able to detect and treat pre-invasive lesions (cervical intraepithelial neoplasia, CIN). The human papilloma virus (HPV) has been recognised as the necessary, but not sufficient, cause of cervical cancer, so a new screening test based on the identification of high risk (HR) HPV types has been developed(HPV DNA test). This test has demonstrated to be more effective than cytology in reducing the incidence and the mortality of cervical cancer, but it is less specific, so the use of a test triage is necessary to reduce the number of colposcopies and the risk of over-diagnosis (due to the potential regressivity of pre-invasive lesions). Until now, the triage test used is the cytology (Pap test). Recently specific biomarkers (mRNA and p16 tests) have been introduced for high grade CIN, targeting the molecular alterations strictly associated to transformation rather than simply detecting HR-HPV infections. These tests are more specific than HPV DNA test with a modest reduction of sensitivity for high-grade lesions. This is a multicenter randomised trial nested into some Italian screening programs based on the use of HPV DNA test as primary test. All women with positive HPV DNA test will be tested for cytology and also for mRNA and p16. Women with positive cytology will be referred to colposcopy, while women with negative cytology will be randomized into two arms. This study aims to evaluate if mRNA and p16 could be used as test of triage of HPV DNA or as a primary screening test with direct sending in colposcopy. In particular the main objectives are: Measuring the cumulative detection rate of CIN2+ in the five years following a HPV DNA positive test and mRNA or p16 negative. Measuring the potential reduction of overdiagnosis of using mRNA or p16 test instead of DNA, with direct sending in colposcopy Measuring the reduction of overdiagnosis of cytological triage or triage with mRNA or p16 compared to the direct sending in colposcopy in women with HPV DNA test positive. Secondary objectives are: to assess the feasibility of mRNA testing in primary screening to validate the sample techniques for the new tests to standardize quality controls for the the new tests

Detailed Description
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Individual data about the following study steps are collected according a fixed format: recruited women HPV DNA result cytology and randomization results p16 result mRNA result colposcopies (with relative cytology and histologies) results Women excluded after informed consent Interventions During the first year of recruitment, there will be two semi-annual sending of data, then each year. To analyze the study progress in each center, summary tables will periodically send to the PI. All CIN lesions and cancers found in the study will be be blindly reviewed. A set of quality assurance procedures will be implemented for both the molecular tests, including the use of controls provided by the manufacturers with known HPV DNA or mRNA content and the circulation of clinical samples prepared by the laboratories participating in the study.

Official Title
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HPV as Primary Screening Test in Cervical Cancer Prevention: From DNA to mRNA? A Randomised Controlled Trial Nested in a Double Testing Study With Long Term Follow up

Conditions
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Precancerous Conditions, Neoplasms

Intervention / Treatment
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* Procedure: Experimental: immediate colposcopy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: women invited for a new screening round based on HPV DNA test Exclusion Criteria: women not resident in the screening area, or pregnant, or with treated CIN in the 5 previous years, or in post-colposcopy follow up, or in repetition for unsatisfactory cytology.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 59 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Screening
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: one year follow up<br>A random sample of HPV positive women with negative cytology will be invited to repeat HPV DNA test and biomarkers after a year, as recommended by the current screening protocols based on HPV DNA | |
| Experimental: direct sending in colposcopy<br>Experimental: immediate colposcopy. A random sample of HPV positive women with negative cytology will be sent to immediate colposcopy | Procedure: Experimental: immediate colposcopy<br>* A immediate colposcopy in this arm may detect potentially spontaneous regressive cervical lesions, so may determine an over diagnosis and over treatment, which the study want to estimate<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cumulative incidence of CIN2+ in women with positive DNA and negative mRNA or p16 | Sum of CIN2+ detected in women with positive DNA and negative mRNA or p16 tests during the entire period (5 years) divided by the total number of CIN2+ found in the study. The HPV DNA test will be the final follow-up test, since it is the most sensitive test among the candidates for screening, so it is the one that allows to estimate more accurately the prevalence of lesions. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| comparison between CIN2+ detection rates in the two arms in women with p16 or mRNA negative | proportion of CIN2+, HPV DNA positive and p16 or mRNA negative, which regress in a year | 1 year | 
| comparison between CIN2+ detection rates in the two arms in women with negative cytology | measure of how much the cytological triage can reduce overdiagnosis compared to HPV DNA with direct sending to colposcopy | 1 year | 
| comparison between CIN2+ detection rate in the two arms in women with p16 or mRNA positive | direct comparison of the effectiveness between a screening based on the HPV mRNA or p16 test followed by cytological triage and a screening with direct sending to colposcopy | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cervical cancer screening, CIN, cervical cancer, biomarkers, sensitivity and specificity