Prognostic Value of HPV E6/E7 mRNA Assay in Women with Negative Colposcopy or CIN1 Histology Result: A Follow-Up Study

Abstract

Pap test, and especially HPV DNA test, identify a large group of women who do not have any clinically relevant lesions, i.e., CIN2+ (Cervical Intraepithelial Neoplasia grade 2 or worse), but who are at greater risk of getting lesions in the future. The follow up of these women needs new biomarkers with prognostic value. The objective of this study is to evaluate the prognostic value of E6/E7 mRNA over-expression assay (PreTect HPV-Proofer, Norchip) for 5 HR-HPV types (16, 18, 31, 33, and 45) for progression to CIN2+ after a negative colposcopy. This prospective study, conducted at four Italian centres, enrolled 673 women with either a negative colposcopy or a negative or CIN1 histology. The clinical end-point was histological confirmation of CIN2+. Women were classified at baseline according to mRNA results and managed according to local colposcopy protocols. At least one conclusive follow-up test was obtained for 347 women (25 months average lapse since recruitment, range 5–74). Only seven CIN2+ were detected during follow up, three among the 82 women positive for mRNA at baseline, two among the 250 negative (Fisher exact test, p = 0.02), and two among the 12 with an invalid test. Absolute CIN2+ risk was 6.7/1,000 person/years in the whole cohort. The absolute CIN2+ risk was 18.4/1,000 person/years and 3.6/1,000 person/years in mRNA-positive and mRNA-negative women, respectively. In conclusion, E6/E7 mRNA over-expression appears to be a good candidate as a prognostic biomarker to manage HR-HPV DNA-positive women with negative colposcopy or histology, particularly in order to decrease follow-up intensity in those who are negative.

MiRNA detection in cervical exfoliated cells for missed high-grade lesions in women with LSIL/CIN1 diagnosis after colposcopy-guided biopsy

“…Therefore, in our study, Pap test diagnosis was compared with the miRNAs expression for detecting missed high-grade lesions. Compared with previous literature data, the accuracy of our Pap test is slightly lower than that observed in cohort studies in which the gold standard was determined through follow up [51, 52]. This could be due to ascertainment biases in follow up studies or to lower progression of high grade lesion found in low grade cytology than those in high grade cytology or to low sensitivity of local cytology (at least in the distinction between low and high grade).…”

Separate analysis of human papillomavirus E6 and E7 messenger RNAs to predict cervical neoplasia progression

“…The presence of both E6 and E7 mRNAs showed significant associations with the occurrence of upgraded abnormal cytology, the presence of E7 mRNA showed association without statistical significance, while positive E6 mRNA, HR-HPV DNA, or HPV 16/18 DNA showed no such trends ( Fig 4 ). Regarding follow-up study of HPV mRNA tests, the longitudinal studies have reported that positive mRNA at baseline is an excellent predictor for future development of CIN2+ or CIN3+ in referral or post-treatment populations [ 20 – 26 ]. Moreover, a recent longitudinal screening study has reported that the Aptima HPV test, which collectively detects E6/E7 mRNAs from 14 types of HR-HPV, has a similar sensitivity for detection of CIN2+ or CIN3+ and a significantly higher specificity than the HC2 test [ 27 ].…”

Analytic and Diagnostic Performances of Human Papillomavirus E6/E7 mRNA Test on up-to 11-Year-Old Liquid-Based Cervical Samples. A Biobank-Based Longitudinal Study

“…The rationale for detecting E6/E7 transcripts from oncogenic HPV types is to reduce the prevalence of clinically irrelevant lesions (thus implementing the specificity of cervical cancer screening), at the same time increasing the positive predictive value of DNA testing [ 17 ]. In summary, an E6/E7 -based test should be able to stratify the risk [ 18 ].…”