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

NCT01837693 | Completed

• 1 other identifier: cervicalscreening_mRNA_p16
• Study Type: interventional
• Target: 41,127
• Locations: 1 country
• Sites: 5

Brief Summary

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

Conditions

Precancerous Conditions; Neoplasms

Keywords

cervical cancer screening; CIN; cervical cancer; biomarkers; sensitivity and specificity

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• comparison between CIN2+ detection rates in the two arms in women with p16 or mRNA negative

  1 year

• comparison between CIN2+ detection rates in the two arms in women with negative cytology

  1 year

• comparison between CIN2+ detection rate in the two arms in women with p16 or mRNA positive

  1 year

Study Arms (2)

one year follow up

NO INTERVENTION

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

direct sending in colposcopy

EXPERIMENTAL

Experimental: immediate colposcopy. A random sample of HPV positive women with negative cytology will be sent to immediate colposcopy

Procedure: Experimental: immediate colposcopy

Interventions

Experimental: immediate colposcopy PROCEDURE

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

direct sending in colposcopy

Eligibility Criteria

• Age: 25 Years - 59 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• women invited for a new screening round based on HPV DNA test

You may not qualify if:

• 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.

Sponsors & Collaborators

• Azienda USL Reggio Emilia - IRCCS: lead

Study Sites (5)

Unità Locale Socio-Sanitaria 17 Este Monselice

Este, Italy

Location

Istituto per lo Studio e la Prevenzione Oncologica

Florence, Italy

Location

Azienda Sanitaria Locale 2- Regione Umbria

Perugia, Italy

Location

Azienda Sanitaria della Provincia Autonoma di Trento

Trento, Italy

Location

Centro per la Prevenzione Oncologica del Piemonte

Turin, Italy

Location

Related Publications (3)

• Del Mistro A, Mancuso P, Carozzi F, De Marco L, Bisanzi S, Pompeo G, Ronco G, Gori S, Allia E, Gustinucci D, Frayle H, Iossa A, Cesarini E, Bulletti S, Passamonti B, Viti J, Toniolo L, Venturelli F, Giorgi Rossi P, Benevolo M; NTCC2 Working Group. Impact of differentiating between persistent and new infections on colposcopy referral in HPV-positive triage-negative women: results from the NTCC2 study. Infect Agent Cancer. 2025 Nov 20;20(1):84. doi: 10.1186/s13027-025-00713-8.

  PMID: 41261407 DERIVED

• De Marco L, Bisanzi S, Ronco G, Mancuso P, Carozzi F, Allia E, Rizzolo R, Gustinucci D, Frayle H, Viti J, Iossa A, Cesarini E, Bulletti S, Passamonti B, Gori S, Toniolo L, Venturelli F, Del Mistro A, Giorgi Rossi P, Benevolo M; NTCC2 Working Group. Extended HPV genotyping by the BD Onclarity assay: concordance with screening HPV-DNA assays, triage biomarkers, and histopathology in women from the NTCC2 study. Microbiol Spectr. 2025 Jan 7;13(1):e0089724. doi: 10.1128/spectrum.00897-24. Epub 2024 Nov 22.

  PMID: 39576120 DERIVED

• Benevolo M, Mancuso P, Allia E, Gustinucci D, Bulletti S, Cesarini E, Carozzi FM, Confortini M, Bisanzi S, Rubino T, Rollo F, Marchi N, Farruggio A, Pusiol T, Venturelli F, Giorgi Rossi P; New Technologies for Cervical Cancer 2 (NTCC2) Working Group. Determinants of p16/Ki-67 adequacy and positivity in HPV-positive women from a screening population. Cancer Cytopathol. 2021 May;129(5):383-393. doi: 10.1002/cncy.22385. Epub 2020 Nov 3.

  PMID: 33142029 DERIVED

MeSH Terms

Conditions

Precancerous Conditions; Neoplasms; Uterine Cervical Neoplasms; Hypersensitivity

Condition Hierarchy (Ancestors)

Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Immune System Diseases

Study Officials

• Paolo Giorgi Rossi, PhD

  Epidemiology Service, Local Health Authority of Reggio Emilia, Italy

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: SCREENING
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 18, 2013
• First Posted: April 23, 2013
• Study Start: June 1, 2013
• Primary Completion: January 1, 2017
• Study Completion: January 1, 2017
• Last Updated: June 26, 2025

Record last verified: 2017-06

Data Sharing

• IPD Sharing: Will not share

Locations

IT (5)