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High‐risk HPV (hrHPV)‐based screening has led to many unnecessary colposcopy referrals, mainly because of direct referral after low‐grade cytology (ASC‐US/LSIL). DNA methylation and genotyping tests on ASC‐US/LSIL samples have the potential to significantly improve the efficiency of screening. In this study, 12 triage strategies were constructed from FAM19A4/miR124‐2 or ASCL1/LHX8 methylation, HPV16/18 or HPV16/18/31/33/45 genotyping and 1‐year repeat cytology. The performance was evaluated on 215 hrHPV‐positive ASC‐US/LSIL samples from the IMPROVE trial (NTR5078). Performance was measured by colposcopy referral rate, positive predictive value (PPV) for detecting precancer (CIN3), and negative predictive value (NPV). To evaluate efficiency, strategies were ordered by the cumulative colposcopy referral rate after 1‐year cytology and compared by the marginal PPV to detect one additional CIN3 (mPPV). The most conservative strategy (referral when HPV16/18 and FAM19A4/miR124 methylation results are positive) had a direct referral rate of 5.2%, a cumulative referral rate after 1‐year cytology of 54.1%, and mPPV of 19.3%. Replacing HPV16/18 by HPV16/18/31/33/45 increased the cumulative 1‐year referral rate to 54.6%, and yielded an mPPV of 10.0%. Similar results were obtained for strategies with ASCL1/LHX8 methylation. Of all strategies, referral after an HPV16/18/31/33/45 positive, ASCL1/LHX8 methylation‐positive, and/or 1‐year cytology‐positive result yielded the highest direct and cumulative 1‐year colposcopy referral rates of 64.4% and 79.1%, respectively. The NPVs after 1‐year cytology varied between 98.1% and 99.4%, warranting a return to routine screening. Altogether, DNA methylation‐based triage strategies are recommended as they are discriminative for CIN3 and control the number of immediate colposcopy referrals. [ABSTRACT FROM AUTHOR]

Cervical cancer screening programs, including triage tests, need redesigning as human papillomavirus (HPV)‐vaccinated women are entering the programs. Methylation markers offer a potential solution to reduce false‐positive rates by identifying clinically relevant cervical lesions with progressive potential. In a nested case–control study, 9242 women who received the three‐dose HPV16/18‐vaccine at ages 12–15 or 18 in a community‐randomized trial were included. Subsequently, they were re‐randomized for either frequent or infrequent cervical cancer screening trials. Over a 15‐year post‐vaccination follow‐up until 2022, 17 high‐grade squamous intraepithelial lesion (HSIL) and 15 low‐grade (LSIL) cases were identified at the 25‐year screening round, alongside 371 age and community‐matched HPV16/18‐vaccinated controls. Methylation analyses were performed on cervical samples collected at age 25, preceding histologically confirmed LSIL or HSIL diagnoses. DNA methylation of viral (HPV16/18/31/33) and host‐cell genes (EPB41L3, FAM19A4, and miR124‐2) was measured, along with HPV‐genotyping. No HPV16/18 HSIL cases were observed. The predominant HPV‐genotypes were HPV52 (29.4%), HPV59/HPV51/HPV58 (each 23.5%), and HPV33 (17.7%). Methylation levels were generally low, with no significant differences in mean methylation levels of viral or host‐cell genes between the LSIL/HSIL and controls. However, a significant difference in methylation levels was found between HSIL cases and controls when considering a combination of viral genes and EPB41L3 (p value =.0001). HPV‐vaccinated women with HSIL had HPV infections with uncommon HPV types that very rarely cause cancer and displayed low methylation levels. Further investigation is warranted to understand the likely regressive nature of HSIL among HPV‐vaccinated women and its implications for management. [ABSTRACT FROM AUTHOR]

Author(s): Federica Inturrisi 1,2,*, Lawrence Rozendaal 3, Nienke J. Veldhuijzen 1, Daniëlle A. M. Heideman 3,4, Chris J. L. M. Meijer 3,4, Johannes Berkhof 1,2,* Introduction Human papillomavirus (HPV) causes [...], Background Human papillomavirus (HPV)-based screening programs still use one-size-fits-all protocols but efficiency and efficacy of programs may be improved by stratifying women based on previous screening results. Methods and findings We studied the association between cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) and previous screening results in the Population-Based Screening Study Amsterdam (POBASCAM) trial, performed in the Netherlands in the setting of regular screening, where women aged from 29 to 61 years old were invited to cytology and HPV co-testing at enrolment in year 1999/2002 and at the next round in 2003/2007. We selected 18,448 women (9,293 from the intervention group and 9,155 from the control group) who tested HPV-negative in 2003/2007 and did not have cervical intraepithelial neoplasia grade 2 or worse (CIN2+) or hysterectomy after enrolment. Follow-up was collected until 14 years after the 2003/2007 screen, covering 4 rounds of screening. Risk of CIN3+ and CIN2+ among women with an HPV-negative test, irrespective of previous round results and stratified according to previous round HPV and cytology results, were calculated by the Kaplan-Meier method. During 14 years of follow-up, 62 CIN3+ cases (24 in the intervention group and 38 in the control group) were detected. HPV-negative women had a 14-year CIN3+ risk of 0.48% (95% confidence interval 0.37 to 0.62) and CIN2+ risk of 1.17% (0.99 to 1.38). The CIN3+ risk among HPV-negative women was increased in women with a previous positive HPV test (2.36%, 1.20 to 4.63; p < 0.001) or co-test (1.68%, 0.87 to 3.20; p < 0.001) and, equivalently, decreased in women with a previous negative HPV test (0.43%, 0.33 to 0.57) or a negative co-test (0.43%, 0.33 to 0.57). The CIN3+ risk was not influenced by the previous cytology result. The CIN3+ risk among HPV-negative women was increased after both a previous HPV16-positive test (3.90%, 1.47 to 10.12; p < 0.001) and a previous HPV16-negative/HPVother-positive test (1.91%, 0.76 to 4.74; p = 0.002). For endpoint CIN2+ (147 cases), findings were similar except that the CIN2+ risk was increased after previous abnormal cytology (4.06%, 2.30 to 7.12; p < 0.001). The presented risk estimates were calculated by tracking histological results through the Dutch nationwide pathology archive (PALGA) and were not adjusted for non-compliance with the colposcopy referral advice. Conclusions HPV-negative women had an increased long-term risk of CIN3+ when the HPV test in the previous screening round was positive. This supports the implementation of risk-based intervals that depend on HPV results in the current and previous screening round. Trial registration POBASCAM trial, trial registration number ISRCTN20781131.

Background: High-risk human papillomavirus (hrHPV)-based cervical cancer screening in the Netherlands led to a substantial increase in number of colposcopy referrals and low-grade lesions detected. Genotyping strategies may be employed to lower the screening-related burden. Methods: We evaluated 14 triage strategies with genotyping (HPV16/18 or HPV16/18/31/33/45/52/58) for hrHPV-positive borderlineormilddyskaryosis (BMD)ornormal cytology, usingdata from a population-based hrHPV-based screening trial with 5-year interval (POBASCAM). We considered colposcopy referral at baseline, after 6-month repeat cytology and after 5-year hrHPV testing. Performance was evaluated by one-round positive and negative predictive value (PPVandNPV) for CIN3+ and by two-roundcolposcopy referral rate. To identify efficient strategies, they were ordered by the one-round colposcopy referral rate. Adjacent strategies were compared by the marginal PPV for detecting one additional CIN3+ (mPPV). Results: The most conservative strategy (repeat cytology after BMD and HPV16/18/31/33/45/52/58-positive normal cytology, next round otherwise) yielded an mPPV of 28%, NPV of 98.2%, and two-round colposcopy referral rate of 47.2%. Adding direct referral after BMD or genotype-positive BMD yielded an mPPV = 8.2%, NPV = 98.5% and an increase in colposcopy referral rate of 1.9% to 6.5%. Adding direct referral after HPV16/18-positive normal cytology yielded an mPPV = 3.5%, NPV = 99.5% and an increase in colposcopy referral rate of 13.9%. Conclusions: Direct colposcopy referral of women with BMD or normal cytology is unlikely to be efficient, but genotype-guided direct referral after BMD may be considered because the increase in colposcopies is limited. [ABSTRACT FROM AUTHOR]