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
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 入组人数
- 500
- 试验地点
- 1
- 主要终点
- 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).
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Retrospective
入排标准
- 年龄范围
- 23 Years 至 40 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
结局指标
主要结局
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).
时间窗: 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).
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).
次要结局
未报告次要终点