p16/ki67 and E6/E7 mRNA Accuracy and Prognostic Value in Triaging HPV DNA-Positive Women

Abstract

Background The study presents cross-sectional accuracy of E6/E7 mRNA detection and p16/ki67 dual staining, alone or in combination with cytology and HPV16/18 genotyping, as triage test in HPV DNA-positive women and their impact on CIN2+ overdiagnosis. Methods Women aged 25-64 were recruited. HPV DNA-positives were triaged with cytology and tested for E6/E7 mRNA and p16/ki67. Cytology positives were referred to colposcopy, while negatives were randomised to immediate colposcopy or to one-year HPV retesting. Lesions found within 24 months since recruitment were included. All p-values were two-sided. Results 40,509 women were recruited and 3147 (7.8%) tested HPV DNA-positive; 174 CIN2+ were found: sensitivity was 61.0% (95% CI = 53.6 to 68.0), 94.4% (95% CI = 89.1 to 97.3), and 75.2% (95% CI = 68.1 to 81.6) for cytology, E6/E7 mRNA, and p16/ki67, respectively. Immediate referral was 25.6%, 66.8%, and 28.3%, respectively. Overall referral was 65.3%, 78.3%, and 63.3%. Cytology or p16/ki67 when combined with HPV16/18 typing reached higher sensitivity with a small impact on referral. Among the 2306 HPV DNA-positive/cytology-negative women, relative CIN2+ detection in those randomized at 1-year retesting vs. immediate colposcopy suggests a -28% CIN2+ regression (95% CI = -57% to + 20%); regression was higher in E6/E7 mRNA-negatives (pinteraction =.29). HPV clearance at 1 year in E6/E7 mRNA and in p16/ki67 negatives was about 2 times higher than in positive women (Pinteraction < .001 for both). Conclusions p16/ki67 showed good performance as triage test. E6/E7 mRNA showed the highest sensitivity, at the price of too high a positivity rate to be efficient for triage. However, when negative, it showed a good prognostic value for clearance and CIN2+ regression.

Is Primary HPV with Secondary p16/Ki67 Dual-Stain an Alternative HSIL-Risk Detection Strategy in Cervical Cancer Screening for Women under 30 Years?

“…Our study results are essentially consistent with the data from other reports on the evaluation of the diagnostic performance of p16/Ki67 dual-stained cytology for triaging HPV-positive cases [15,20,21,24]. All comparator studies involved groups of women <30 years, and most of them included women aged 21-24, as was designed in our investigation.…”

“…Similarities with several studies in the sensitivity levels for detection HSIL (CIN2+) obtained in our screening model 1 were noted, including the study of the New Technologies for Cervical Cancer Screening group [24] (81.8%), the report of the Wentzensen et al [20] (86.8%) in a comparable to our size study and the ATHENA sub-study trial-similarities with our results were observed only in the group with p16/Ki67 triaging N16/N18 HPVpositive test results (82.8%) [15]. A difference was found with the ATHENA study in the specificity for HSIL (CIN2+) detection (75.6% reported in the ATHENA).…”

HPV Infection Leaves a DNA Methylation Signature in Oropharyngeal Cancer Affecting Both Coding Genes and Transposable Elements

“…In a recent meta-analysis, its sensitivity and specificity to detect cervical intraepithelial neoplasia of grade 2 (CIN2 + ), 3 or worse (CIN3 + ) ranged from 82–86% and 49–71%, respectively [ 41 ]. When combined with Ki67 IHC, p16 showed a sensitivity of 75.2% to detected CIN2 + , compared to 61.0% achieved by cytology alone [ 42 ]. In HNSCC, p16 IHC sensitivity to detect HPV-positive cases is high (92%, 95% CI 82–97%), while its specificity seems to be moderate (72%, 95% CI 45–89%) [ 43 ].…”

A Framework for Cervical Cancer Elimination in Low-and-Middle-Income Countries: A Scoping Review and Roadmap for Interventions and Research Priorities

“…Tests for E6/E7 oncoproteins present a promising option for triaging screen-positive women given high positive predictive value and limited laboratory equipment ( 145 ). However, more than 60% of HPV positive women were also E6/E7 mRNA positive ( 146 ), which would present a challenge in identifying women with precancerous lesions. A systematic review of three types of HPV E6/E7 mRNA tests (Aptima, Quantivirus, and PreTect Proofer) found that while the tests have diagnostic relevance to detect CIN2-3, the higher specificity of some tests is due to the limited number of HPV types it detects ( 147 ).…”