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

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Brief Title

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

Official Title

Performance of HPV E4 and p16INK4a Biomarkers in Predicting Risk of Regression Among Women Diagnosed With Cervical Intraepithelial Neoplasia Grade 2 (CIN2): a Historical Cohort Study

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.
    

Detailed Description

      Introduction Persistent infection with high-risk human papillomavirus (hrHPV) is a causative
      source of cervical cancer [1]. Cervical intraepitehelial neoplasia CIN1 (low), CIN2
      (moderate), CIN3 (severe) defines cervical precancer lesions evolved from the squamous
      epithelium cell line [3]. CIN1 and CIN2 lesions are associated with lower progression rates
      for cervical cancer than CIN3 [4]. CIN2 poses a major challenge clinically, due to the
      heterogenic expression of both CIN1-like and CIN3-like evolving lesions, which current
      diagnostic tools do not enable to stratify in risk of progression [5]. Risk-stratification of
      CIN2 is highly important for clinical management of CIN2 and to avoid risk of over- or
      undertreatment. Historically, CIN2 has been the threshold for surgical mangement (cone
      excisional biopsy). However, since regressions rates of CIN2 lesions are high, and cone
      excisional biopy is associated with reproductive harm, such as preterm birth, many countries
      such as Denmark has adopted a more conservative approach in the management of young women
      with CIN2 (i.e. active surveillance: colposcopy, cervical punch biopsies for every 4-6 monhts
      up to two years follow-up without any surgical procedure) [6,7]. In the Central Region of
      Denmark, active surveillance has been recommended for young women since 1995.

      The p16 protein plays an important role as inhibitor in cellular regulation and
      differentiation. p16 is a common surrogat marker for hrHPV E6/E7 oncogenic activity and
      cellular transformation associated with cancer evolvement. The intrapeithelial expression
      level of p16 is positively associated with grade of CIN lesion, and may be detected by the
      p16INK4a immuno-histo-chemical biomarker [7, 8]. Although, the p16INK4a biomarker has added
      value to diagnostics and grading of cervical precancer lesions, the biomarker is not robust
      for risk-stratification of CIN2 [9].

      Recent studies show, that the novel biomarker HPV E4 may potentially distinguish CIN2 in
      CIN1-like vs CIN3-like resembling lesions. Suggesting that HPV E4 could be a potential
      biomarker for risk-stratification of CIN2 [10-12].

      However, knowledge is lacking on HPV E4 as predictor for CIN2 evolvement.

      Aim To explore whether the HPV E4 biomarker can predict risk of CIN2 evolvement.

      Materials and methods Study design: Historical cohort study. Study population: N=500 women
      23-40 years of age, with a record of CIN2 in the Danish Patological Data Bank [2000-2010], at
      the Department of Pathology, Aarhus University Hospital. All women are defined as managed by
      active surveillance (i.e. colposcopy and cervical punch biopsies for every 4-6 months up to
      two years follow-up).

      Selection: Eligible women with a record of incidental CIN2 diagnosis will be identified in
      the Danish Pathology Databank among all women with a record of CIN2 diagnosis during
      2000-2010.

      Laboratory analysis: Formalin-fixed paraffin-embedded (FFPE) tissue samples will be compiled
      from the archives, at the Department of Pathology, Aarhus University Hospital.

      FFPE blocks will be sectioned for morphology analysis (hematoxylin & eosin (H&E) and for
      immuno-histo-chemistry analysis (IHC). We will apply the sandwich technique for the p16INK4a
      and HPV E4 IHC analysis, using the CINtec® Histology Kit (Roche) and the SILgrade E4 assay
      (LBP). Subsequently, the stained slides will be evaluated by an expert panel within
      gynecological pathology (2 from Denmark, 1 from UK and 1 from the US respectively).

      Exposure will be defined as expressing a HPV E4 positive (CIN1-like) vs HPV E4 negative
      (CIN3-like) intraepithelial reaction.

      Statistical analysis: Linear regression model, effect measure; relative risk (RR) (95% CI).

      Power calculations: At a sample size of N=500 women, a statistical power of 89% is expected,
      at the significance level 0.05 (alpha). Among women who progress or persist during
      surveillance, a prevalence of 50% CIN2 HPV E4 positive lesions and 70% p16INK4a positive CIN2
      lesions is expected.

      Settings and collaborators The project will be carried out at the Department of Gynecology
      and Obstetrics at Gødstrup Hospital in close collaboration with the Department of Pathology,
      Aarhus University Hospital including DDL Diagnostic Laboratory; University of Virginia;
      University of Cambridge and University of Maryland School of Medicine.

      Main research group in Denmark

        1. Associate professor, MD, Anne Hammer Lauridsen, Department of Gynecology and Obstetrics,
           Gødstrup Hospital, Central Region of Denmark & Department of Clinical medicine, Aarhus
           University

        2. Professor, MD, Lone Kjeld Pedersen, Department of Gynecology and Obstetrics, Odense
           University Hospital & OPEN, University of Southern Denmark.

        3. Professor, MD, Torben Steiniche, Professor, Department of Pathology, Aarhus University
           Hospital & Department of Clinical medicine, Aarhus University.

        4. Ph.d-student, Msch Health Science, Rikke Damgaard, Department of Gynecology and
           Obstetrics, Gødstrup Hospital, Central Region of Denmark & Department of Clinical
           medicine, Aarhus University.

      Ethical statement The study is appoved by the Regional Committee on Health Research Ethics,
      Central Region of Denmark and registered at the Legal Department, Faculty of Health, Aarhus
      University as required by Danish law.

      Perspectives Biomarkers reliable for risk-stratification of CIN2 lesions is important for
      clinical counseling of women, this will enable a more specific and personalized follow-up
      strategy to avoid risk of over- or undertreatment. As other countries are moving toward a
      more conservative approach (active surveillance) with respect to management of young women
      with CIN2 our results may be valauble in an international perspective as well.
    


Study Type

Observational


Primary Outcome

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).


Condition

Cervical Intraepithelial Neoplasia Grade 2 (CIN2)



Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

500

Start Date

June 1, 2020

Completion Date

July 11, 2023

Primary Completion Date

July 11, 2023

Eligibility Criteria

        Inclusion Criteria:

          -  Women

          -  23-40 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.

        Exclusion Criteria:

          -  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.
      

Gender

Female

Ages

23 Years - 40 Years

Accepts Healthy Volunteers

No

Contacts

, , 

Location Countries

Denmark

Location Countries

Denmark

Administrative Informations


NCT ID

NCT05049252

Organization ID

CIN2-E4


Responsible Party

Sponsor

Study Sponsor

University of Aarhus

Collaborators

 University of Southern Denmark

Study Sponsor

, , 


Verification Date

May 2021