Biomarkers Predictive for Cervical Intraepithelial Neoplasia Grade 2 (CIN2) Evolvement

NCT05049252 | Unknown

• 1 other identifier: CIN2-E4
• Study Type: observational
• Target: 500
• Locations: 1 country
• Sites: 1

Brief Summary

Introduction Cervical intraepithelial neoplasia CIN1 (low grade), CIN2 (moderate grade), CIN3 (severe grade) defines cervical precancer lesions derived from the squamous epithelial cell line. CIN2, represents a heterogenic phenotype expression of both CIN1-like and CIN3-like evolving lesions with different risk of progression. The CIN2 diagnosis has low reproducibility, and current diagnostic tools do not allow for risk-stratification of CIN2. Risk-profiling is important, to enable targeted management of women with CIN2 at first incidence (surgery or active surveillance) and to avoid risk of over- or undertreatment. Preliminary studies show, that the novel tissue biomarker HPV E4 has potential to discriminate CIN1-like (HPV E4 positive) from CIN3-like (HPV E4 negative) evolving CIN2 lesions, suggesting that the biomarker could be vauable for risk-stratification of CIN2. Aim To examine the potential of the HPV E4 biomarker in predicting risk of CIN2 evolvement. Materials and Methods Design: Historical cohort study. Study population: N=500 women, 23-40 years of age with a record of incidental CIN2 diagnosis between \[2000-2010\] in the Danish Pathology Data Bank at Aarhus University Hospital, Region of Central Denmark. All women are defined as managed by active surveillance (i.e. no surgical treatment within 4 months after first CIN2 diagnosis). Exposure: HPV E4 positive vs HPV E4 negative intraepithelial reaction. Outcome: Regression (normal, CIN1) vs non-regression (CIN2, CIN3, cervical cancer). Statistical model: Linear regression model (RR (95%CI)). Perspectives: HPV E4 may act as significant predictor for CIN2 evolvement, and reliable marker for risk-assessment of CIN2. This will be valuable in the clinical management of women with CIN2, enabling to discriminate women, who would most likely regress and could be manged by active surveillance vs women in risk of progression or persistence, who could benefit of immediate surgical treatment.

Conditions

Cervical Intraepithelial Neoplasia Grade 2 (CIN2)

Keywords

CIN2, p16INK4a, HPV E4, molecular biomarker, risk stratification

Outcome Measures

Primary Outcomes (1)

• Regression: Community diagnosis for normal cells or CIN1 (atypical or dysplasia grade 1) based on pathologists microscopy of tissue of cells (visual examination of cell formation, growth and differentation entailing the epithelial layer).

  Regression is identified through the records of community diagnosis of cervical lesion in the Danish Pathology Databank defined by SNOMED codes for normal cervical epithelial cells or CIN1 (atypical or dysplastic cells entailing up to 1/3 of the epithelial layer).

  Time frame is defined from date of index community CIN2 diagnosis to record of last and worst cervical histological diagnosis registred in the Danish Pathology Databank (i.e. 4 months - two years after index CIN2).

Eligibility Criteria

• Age: 23 Years - 40 Years
• Gender Eligibility Details: Gynecological disease.
• Healthy Volunteers: No
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

N=500 women 23-40 years of age with a record of CIN2 in the Danish Pathology Data Bank, at the Department of Pathology, Aarhus University Hospital, managed by active surveillance.

You may qualify if:

• Women
• years of age
• First record of CIN2 verified diagnosis (M74B09, T83110)
• Managed by active surveillance (i.e. no surgical treatment within 4 months after index CIN2 diagnosis)
• Record of CIN2 diagnosis during 2000-2010 and at least one record of cervix histological sample during follow-up.

You may not qualify if:

• Prior record of CIN2+ (i.e. CIN2, CIN3, cervical cancer), hysterectomy or cervical excisional cone biopsy.
• No record of cervical histological sample (cervical punch biopsy of cervical excisional biopsy) within two years after index CIN2 diagnosis.

Sponsors & Collaborators

• University of Aarhus: lead
• University of Southern Denmark: collaborator
• DDL Diagnostic Laboratory: collaborator
• University of Cambridge: collaborator
• National Cancer Institute (NCI): collaborator
• University of Virginia: collaborator

Study Sites (1)

Department of Gynecology and Obstetrics, Herning Regional Hospital

Herning, Region of Central Jutland, 7400, Denmark

Location

Related Publications (12)

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• Chaturvedi AK, Kleinerman RA, Hildesheim A, Gilbert ES, Storm H, Lynch CF, Hall P, Langmark F, Pukkala E, Kaijser M, Andersson M, Fossa SD, Joensuu H, Travis LB, Engels EA. Second cancers after squamous cell carcinoma and adenocarcinoma of the cervix. J Clin Oncol. 2009 Feb 20;27(6):967-73. doi: 10.1200/JCO.2008.18.4549. Epub 2008 Dec 29.

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• Lee MH, Finlayson SJ, Gukova K, Hanley G, Miller D, Sadownik LA. Outcomes of Conservative Management of High Grade Squamous Intraepithelial Lesions in Young Women. J Low Genit Tract Dis. 2018 Jul;22(3):212-218. doi: 10.1097/LGT.0000000000000399.

  PMID: 29762428 BACKGROUND

• van Baars R, Griffin H, Wu Z, Soneji YJ, van de Sandt M, Arora R, van der Marel J, Ter Harmsel B, Jach R, Okon K, Huras H, Jenkins D, Quint W, Doorbar J. Investigating Diagnostic Problems of CIN1 and CIN2 Associated With High-risk HPV by Combining the Novel Molecular Biomarker PanHPVE4 With P16INK4a. Am J Surg Pathol. 2015 Nov;39(11):1518-1528. doi: 10.1097/PAS.0000000000000498.

  PMID: 26379150 BACKGROUND

• Bruinsma FJ, Quinn MA. The risk of preterm birth following treatment for precancerous changes in the cervix: a systematic review and meta-analysis. BJOG. 2011 Aug;118(9):1031-41. doi: 10.1111/j.1471-0528.2011.02944.x. Epub 2011 Mar 30.

  PMID: 21449928 BACKGROUND

• Darragh TM, Colgan TJ, Thomas Cox J, Heller DS, Henry MR, Luff RD, McCalmont T, Nayar R, Palefsky JM, Stoler MH, Wilkinson EJ, Zaino RJ, Wilbur DC; Members of the LAST Project Work Groups. The Lower Anogenital Squamous Terminology Standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Int J Gynecol Pathol. 2013 Jan;32(1):76-115. doi: 10.1097/PGP.0b013e31826916c7.

  PMID: 23202792 BACKGROUND

• Xing Y, Wang C, Wu J. Expression of geminin, p16, and Ki67 in cervical intraepithelial neoplasm and normal tissues. Medicine (Baltimore). 2017 Jun;96(26):e7302. doi: 10.1097/MD.0000000000007302.

  PMID: 28658133 BACKGROUND

• Cuschieri KS, Cubie HA, Whitley MW, Gilkison G, Arends MJ, Graham C, McGoogan E. Persistent high risk HPV infection associated with development of cervical neoplasia in a prospective population study. J Clin Pathol. 2005 Sep;58(9):946-50. doi: 10.1136/jcp.2004.022863.

  PMID: 16126875 BACKGROUND

• Griffin H, Soneji Y, Van Baars R, Arora R, Jenkins D, van de Sandt M, Wu Z, Quint W, Jach R, Okon K, Huras H, Singer A, Doorbar J. Stratification of HPV-induced cervical pathology using the virally encoded molecular marker E4 in combination with p16 or MCM. Mod Pathol. 2015 Jul;28(7):977-93. doi: 10.1038/modpathol.2015.52. Epub 2015 May 8.

  PMID: 25953390 BACKGROUND

• Griffin H, Wu Z, Marnane R, Dewar V, Molijn A, Quint W, Van Hoof C, Struyf F, Colau B, Jenkins D, Doorbar J. E4 antibodies facilitate detection and type-assignment of active HPV infection in cervical disease. PLoS One. 2012;7(12):e49974. doi: 10.1371/journal.pone.0049974. Epub 2012 Dec 3.

  PMID: 23226504 BACKGROUND

• Damgaard RK, Jenkins D, de Koning MN, Quint WG, Stoler MH, Doorbar J, Kahlert J, Gravitt PE, Steiniche T, Petersen LK, Hammer A. Performance of HPV E4 and p16INK4a biomarkers in predicting regression of cervical intraepithelial neoplasia grade 2 (CIN2): protocol for a historical cohort study. BMJ Open. 2022 Jul 6;12(7):e059593. doi: 10.1136/bmjopen-2021-059593.

  PMID: 35793925 DERIVED

Biospecimen

Retention: SAMPLES WITHOUT DNA

Slides from formalin fixed paraffine embedded cervical biopsies.

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 31, 2021
• First Posted: September 20, 2021
• Study Start: June 1, 2020
• Primary Completion: December 31, 2023
• Study Completion: December 31, 2023
• Last Updated: December 7, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)