Primary hrHPV Testing Research Articles

Primary HPV screening compared with other cervical cancer screening strategies in women with HIV: a cost-effectiveness study.

To compare the model-predicted benefits, harms, and cost-effectiveness of cytology, cotesting, and primary HPV screening in U.S. women living with HIV (WLWH). We adapted a previously published Markov decision model to simulate a cohort of U.S. WLWH. United States. A hypothetical inception cohort of WLWH. We simulated five screening strategies all assumed the same strategy of cytology with HPV triage for ASCUS for women aged 21 to 29 years. The different strategies noted are for women aged 30 and older as the following: continue cytology with HPV triage, cotesting with repeat cotesting triage, cotesting with HPV16/18 genotyping triage, primary hrHPV testing with cytology triage, and primary hrHPV testing with HPV16/18 genotyping triage. The outcomes include colposcopies, false-positive results, treatments, cancers, cancer deaths, life-years and costs, and lifetime quality-adjusted life-years. Compared with no screening, screening was cost-saving, and > 96% of cervical cancers and deaths could be prevented. Cytology with HPV triage dominated primary HPV screening and cotesting. At willingness-to-pay thresholds under $250,000, probabilistic sensitivity analyses indicated that primary HPV testing was more cost-effective than cotesting in over 98% of the iterations. Our study suggests the current cytology-based screening recommendation is cost-effective, but that primary HPV screening could be a cost-effective alternative to cotesting. To improve the cost-effectiveness of HPV-based screening, increased acceptance of the HPV test among targeted women is needed, as are alternative follow-up recommendations to limit the harms of high false-positive testing.

Comparing Cervical Cancer Screening Strategies in an Incarcerated Population.

Objective: To describe the prevalence of cervical intraepithelial neoplasia (CIN), high-risk human papillomavirus (hrHPV) infection, and cervical cancer in a high-risk, underscreened incarcerated population and to evaluate the performance of current cervical cancer screening options to detect cervical precancer (CIN 2/3) in this population. Study Design: Deidentified data were obtained from all cytological, hrHPV DNA, and histopathological testing of cervical biopsies performed on people incarcerated at the North Carolina Correctional Institute for Women between January 1, 2013, and December 31, 2020. These were linked to corresponding demographic data. The proportions of histopathological diagnoses of CIN2+ and CIN3+ immediately preceded by abnormal cytology testing or hrHPV testing were determined, and prevalence differences and 95% confidence intervals were calculated. Results: A total of 15,319 individuals incarcerated at the North Carolina Correctional Institute for Women had at least one cytology result during 2013-2020. Of these, 2,829 (18%) had abnormal cervical cytology, and 3,724 (24.3%) had positive hrHPV testing. The detection of CIN2+ was 95.9% by preceding abnormal cervical cytology, 89.9% by preceding positive hrHPV testing (p = 0.03), and 96.5% by preceding positive co-testing. The detection rate of CIN3+ was 96.6% by preceding abnormal cervical cytology, 90.8% by preceding positive hrHPV testing (p = 0.12), and 96.6% by positive co-testing. Conclusion: In our sample, primary cytology and co-testing detected CIN2+ at higher rates when compared with primary hrHPV testing. This reinforces that incarcerated populations do not fall into average-risk populations for which current cervical cancer screening options are designed, which should be considered when performing screening in this population.

Acceptability of human papillomavirus self-collection and the role of telehealth: a prospective, randomized study stratified by menopausal status

ObjectiveWe investigated the utility of telehealth instruction versus mail-based written instruction in facilitating high-risk human papillomavirus (hrHPV) self-collection among post-menopausal patients compared with pre-menopausal patients, as well as the impact...

Comparative accuracy of cervical cancer screening strategies in healthy asymptomatic women: a systematic review and network meta-analysis

To compare all available accuracy data on screening strategies for identifying cervical intraepithelial neoplasia grade ≥ 2 in healthy asymptomatic women, we performed a systematic review and network meta-analysis. MEDLINE and EMBASE were searched up to October 2020 for paired-design studies of cytology and testing for high-risk genotypes of human papillomavirus (hrHPV). The methods used included a duplicate assessment of eligibility, double extraction of quantitative data, validity assessment, random-effects network meta-analysis of test accuracy, and GRADE rating. Twenty-seven prospective studies (185,269 subjects) were included. The combination of cytology (atypical squamous cells of undetermined significance or higher grades) and hrHPV testing (excepting genotyping for HPV 16 or 18 [HPV16/18]) with the either-positive criterion (OR rule) was the most sensitive/least specific, whereas the same combination with the both-positive criterion (AND rule) was the most specific/least sensitive. Compared with standalone cytology, non-HPV16/18 hrHPV assays were more sensitive/less specific. Two algorithms proposed for primary cytological testing or primary hrHPV testing were ranked in the middle as more sensitive/less specific than standalone cytology and the AND rule combinations but more specific/less sensitive than standalone hrHPV testing and the OR rule combination. Further research is needed to assess these results in population-relevant outcomes at the program level.

Cost Savings of HPV Testing Alone Versus Co-Testing for Cervical Cancer Screening at a Student-Run Free Clinic

Background: Primary high-risk human papillomavirus (hrHPV) testing is an approved alternative method of cervical cancer screening by the United States Preventative Services Task Force. The University of South Florida BRIDGE (Building Relationships and Initiatives Dedicated to Gaining Equality) Clinic is a student-run free clinic with limited screening resources, serving patients below the poverty line. This study aimed to determine the potential cost benefit of primary hrHPV testing in this population.
 Methods: A retrospective observational study of clinic invoices and patient charts from January 2014 to December 2018 of women receiving cervical cancer screening by co-testing was performed. 
 Results: BRIDGE spent $29,122.37 on screening over the five-year period for 128 patients. By elimi-nating cervical cytology, the clinic would have saved $11,594.34. Fifteen patients had abnormal results, ten of which were hrHPV-positive.
 Conclusions: The $11,594 saved would allow BRIDGE to screen 110 more patients by primary hrHPV testing and another three by eliminating follow-up for atypical squamous cells of undetermined significance, hrHPV-negative results. One patient with low-grade squamous intraepithelial lesion and negative hrHPV represents a 0.8% risk of missing precancerous lesions the clinic would assume by adopting primary hrHPV testing.

Two-stage Cervical Cancer Screening Algorithms Using Primary hrHPV Testing in Botswana

Two-stage Cervical Cancer Screening Algorithms Using Primary hrHPV Testing in Botswana

Estimated Quality of Life and Economic Outcomes Associated With 12 Cervical Cancer Screening Strategies

Many cervical cancer screening strategies are now recommended in the United States, but the benefits, harms, and costs of each option are unclear. To estimate the cost-effectiveness of 12 cervical cancer screening strategies. The cross-sectional portion of this study enrolled a convenience sample of 451 English-speaking or Spanish-speaking women aged 21 to 65 years from September 22, 2014, to June 16, 2016, identified at women's health clinics in San Francisco. In this group, utilities (preferences) were measured for 23 cervical cancer screening-associated health states and were applied to a decision model of type-specific high-risk human papillomavirus (hrHPV)-induced cervical carcinogenesis. Test accuracy estimates were abstracted from systematic reviews. The evaluated strategies were cytologic testing every 3 years for women aged 21 to 65 years with either repeat cytologic testing in 1 year or immediate hrHPV triage for atypical squamous cells of undetermined significance (ASC-US), cytologic testing every 3 years for women age 21 to 29 years followed by cytologic testing plus hrHPV testing (cotesting), or primary hrHPV testing alone for women aged 30 to 65 years. Screening frequency, abnormal test result management, and the age to switch from cytologic testing to hrHPV testing (25 or 30 years) were varied. Analyses were conducted from both the societal and health care sector perspectives. Utilities for 23 cervical cancer screening-associated health states (cross-sectional study) and quality-adjusted life-years (QALYs) and total costs for each strategy. Utilities were measured in a sociodemographically diverse group of 451 women (mean [SD] age, 38.2 [10.7] years; 258 nonwhite [57.2%]). Cytologic testing every 3 years with repeat cytologic testing for ASC-US yielded the most lifetime QALYs and conferred more QALYs at higher costs ($2166 per QALY) than the lowest-cost strategy (cytologic testing every 3 years with hrHPV triage of ASC-US). All cytologic testing plus hrHPV testing (cotesting) and primary hrHPV testing strategies provided fewer QALYs at higher costs. Adding indirect costs did not change the conclusions. In sensitivity analyses, hrHPV testing every 5 years with genotyping triage beginning at age 30 years was the lowest-cost strategy when hrHPV test sensitivity was markedly higher than cytologic test sensitivity or when hrHPV test cost was equated to the lowest reported cytologic test cost ($14). Cytologic testing every 3 years for women aged 21 to 29 years with either continued cytologic testing every 3 years or switching to a low-cost hrHPV test every 5 years confers a reasonable balance of benefits, harms, and costs. Comparative modeling is needed to confirm the association of these novel utilities with cost-effectiveness.

Cervical cancer detection by DNA methylation analysis in urine

Urine samples provide a potential alternative to physician-taken or self-collected cervical samples for cervical screening. Screening by primary hrHPV testing requires additional risk assessment (so-called triage) of hrHPV-positive women. Molecular markers, such as DNA methylation, have proven most valuable for triage when applied to cervical specimens. This study was set out to compare hrHPV and DNA methylation results in paired urine and cervical scrapes, and to evaluate the feasibility of DNA methylation analysis in urine to detect cervical cancer. Urine samples (n = 41; native and sediment) and paired cervical scrapes (n = 38) from cervical cancer patients, and urine from 44 female controls, were tested for hrHPV and 6 methylation markers. Results on native urine and sediment were highly comparable. A strong agreement was found between hrHPV testing on urine and scrapes (kappa = 0.79). Also, methylation levels in urine were moderately to strongly correlated to those detected in scrapes (r = 0.508–0.717). All markers were significantly increased in urine from cervical cancer patients compared to controls and showed a good discriminatory power for cervical cancer (AUC = 0.744–0.887). Our results show a good agreement of urine-based molecular analysis with reference cervical samples, and suggest that urine-based DNA methylation testing may provide a promising strategy for cervical cancer detection.

Implementation of HPV-based cervical cancer screening in an organised regional screening programme: 3years of experience.

The aim of this study was to evaluate the performance of human papillomavirus (HPV)-based screening in the framework of an organised cervical cancer screening programme. A total of 46708 women aged 35-60years invited to the regional cervical cancer screening programme from 1 January 2012, to 31 December 2014, were enrolled. Overall, 17770 women were screened by the Abbot RealTime hrHPV test with cytology triage and 15605 were screened by conventional (Papanicolaou, Pap) cytology. In both groups, women with at least low-grade squamous intraepithelial lesions were referred directly for colposcopy, whereas HPV-positive women with borderline or normal cytology were invited to intensified screening in the following year. In the Pap group, the indication for intensified follow-up was borderline cytology. The attendance rate was similar in the HPV and Pap groups (72% and 71%, respectively). Overall, 6.0% of women in the HPV group vs 6.4% in the Pap group were referred to intensified follow-up (relative risk 0.94, 95% confidence interval [CI]: 0.87-1.03). At the index screening years, the relative sensitivity of the HPV test with cytology triage vs conventional screening was 1.64 (95% CI: 1.05-2.55) for CIN2+ and 2.06 (95% CI: 1.17-3.41) for CIN3+. The specificity of the hrHPV test with cytology triage for CIN2+ and CIN3+ was equal to that of the Pap screening (99.2% vs 99.2% for CIN2+ and 99.1% vs 99.1% for CIN3+). Due to its high sensitivity and specificity, primary hrHPV testing with cytology triage seems to be acceptable for cervical cancer screening in an organised setting.

History of high‐risk HPV and Pap test results in a large cohort of patients with invasive cervical carcinoma: Experience from the largest women's hospital in China

Current cervical cancer screening guidelines recommend screening with a Papanicolaou (Pap) test or by cotesting (Pap and human papillomavirus [HPV]). Given the importance of high-risk HPV (hrHPV) infection in the development of cervical cancer, some studies are now suggesting the use of primary hrHPV testing as a possible screening modality. To gain further insight into the role of both Pap testing and hrHPV testing, the authors examined prior screening results in a population of Chinese patients with invasive cervical carcinoma. Cases with a histologic diagnosis of invasive cervical carcinoma were retrieved from the Obstetrics and Gynecology Hospital of Fudan University from January 2011 to October 2014. Prior hrHPV testing and Pap test results within 3 years before the cancer diagnosis were recorded. Of 3714 patients with invasive cervical carcinoma, over a 46-month period, 525 had prior hrHPV testing using Hybrid Capture 2 within 3 years and 238 patients had Pap cytology testing within 1 year before the histological diagnosis. Within the 1-year period before diagnosis, the overall hrHPV-negative rate was 15.5% (74 of 477 patients) and the Pap-negative rate was also 15.5% (37 of 238 patients). Only 9 of 231 patients with both hrHPV testing and Pap testing (3.9%) had a double-negative result. Compared with squamous cell carcinoma, adenocarcinoma has significantly higher rates of prior negative results with both hrHPV and Pap cytology. The results of the current study demonstrated prior results of hrHPV testing and Pap cytology in a population of women in China who had not undergone intensive prior screening. Both hrHPV testing and Pap cytology were found to have similar negative rates in this population and, not surprisingly, there were fewer women who had negative testing results using both testing modalities.

Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance.

In 2011, the American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology updated screening guidelines for the early detection of cervical cancer and its precursors. Recommended screening strategies were cytology or cotesting (cytology in combination with high-risk HPV (hrHPV) testing). These guidelines also addressed the use of hrHPV testing alone as a primary screening approach, which was not recommended for use at that time. There is now a growing body of evidence for screening with primary hrHPV testing, including a prospective US-based registration study. Thirteen experts including representatives from the Society of Gynecologic Oncology, American Society for Colposcopy and Cervical Pathology, American College of Obstetricians and Gynecologists, American Cancer Society, American Society of Cytopathology, College of American Pathologists, and the American Society for Clinical Pathology, convened to provide interim guidance for primary hrHPV screening. This guidance panel was specifically triggered by an application to the FDA for a currently marketed HPV test to be labeled for the additional indication of primary cervical cancer screening. Guidance was based on literature review and review of data from the FDA registration study, supplemented by expert opinion. This document aims to provide information for health care providers who are interested in primary hrHPV testing and an overview of the potential advantages and disadvantages of this strategy for screening as well as to highlight areas in need of further investigation.

Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance.

In 2011, the American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology updated screening guidelines for the early detection of cervical cancer and its precursors. Recommended screening strategies were cytology or cotesting (cytology in combination with high-risk human papillomavirus [hrHPV] testing). These guidelines also addressed the use of hrHPV testing alone as a primary screening approach, which was not recommended for use at that time. There is now a growing body of evidence for screening with primary hrHPV testing, including a prospective U.S.-based registration study. Thirteen experts, including representatives from the Society of Gynecologic Oncology, the American Society for Colposcopy and Cervical Pathology, the American College of Obstetricians and Gynecologists, the American Cancer Society, the American Society of Cytopathology, the College of American Pathologists, and the American Society for Clinical Pathology, convened to provide interim guidance for primary hrHPV screening. This guidance panel was specifically triggered by an application to the U.S. Food and Drug Administration (FDA) for a currently marketed HPV test to be labeled for the additional indication of primary cervical cancer screening. Guidance was based on literature review and review of data from the FDA registration study, supplemented by expert opinion. This document aims to provide information for health care providers who are interested in primary hrHPV testing and an overview of the potential advantages and disadvantages of this strategy for screening as well as to highlight areas in need of further investigation.

Abstract 1360: DNA methylation analysis in self-sampled material as a triage test in hrHPV positive women

Abstract Background: Primary hrHPV testing in cervical cancer screening shows relatively low specificity. To decrease the number of unnecessary referrals for colposcopy, triage testing is necessary. In this study, DNA methylation analysis was compared with routine cytology for triage testing in hrHPV positive women. Moreover, feasibility of DNA methylation analysis directly on original brush-based self-sampled specimens was assessed. Methods: Non-responding women from population-based screening were invited to self-collect a cervico-vaginal specimen for hrHPV testing; hrHPV positive women were referred to a physician for liquid-based sampling. For this pilot study, DNA methylation analysis was performed on 128 triage samples and on 50 matched Evalyn brush self-samples with QMSP for C13ORF18, EPB41L3, JAM3 and TERT. Results: In the physician-taken triage material, DNA methylation analysis of JAM3 showed the highest specificity (88%) combined with a high sensitivity (82%) for detection of CIN3+, whereas cytology showed a specificity of 48% and a sensitivity of 91%. Out of 39 women with abnormal cytology and normal histology (false positive by cytology), 87% were negative for JAM3 and 90% for C13ORF18 methylation. The agreement for DNA methylation analysis performed directly on the matched self-sampled material and the physician-taken samples was 90% for C13ORF18 (κ=0.77; p<0.001) and 88% for JAM3 (κ=0.75, p<0.001). Conclusion: DNA methylation analysis as a triage test in hrHPV positive women outperformed cytology due to higher specificity without losing its sensitivity and is also feasible to be performed directly on Evalyn Brush self-samplers. This might result in more correct referrals to the gynecologist and eliminate the need for a new scraping taken by a medical professional thereby offering great logistic and financial advantages. This study was financed by the Dutch Cancer Society (RUG-NKB2009-4577). Citation Format: Aniek Boers, Remko P. Bosgraaf, Roland W. van Leeuwen, Ed Schuuring, Leon FAG Massuger, Johan Bulten, Willem JG Melchers, Ate GJ van der Zee, Ruud LM Bekkers, Bea Wisman. DNA methylation analysis in self-sampled material as a triage test in hrHPV positive women. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1360. doi:10.1158/1538-7445.AM2014-1360

A Promising DNA Methylation Signature for the Triage of High-Risk Human Papillomavirus DNA-Positive Women

High-risk human papillomavirus (hrHPV)-DNA testing is frequently performed parallel to cytology for the detection of high-grade dysplasia and cervical cancer particularly in women above 30 years of age. Although highly sensitive, hrHPV testing cannot distinguish between HPV-positive women with or without clinically relevant lesions. However, in principle discrimination is possible on the basis of DNA methylation markers.In order to identify novel DNA regions which allow an effective triage of hrHPV-positive cases, hypermethylated DNA enriched from cervical cancers was compared with that from cervical scrapes of HPV16-positive cases with no evidence for disease by CpG island microarray hybridization. The most promising marker regions were validated by quantitative methylation-specific PCR (qMSP) using DNA from archived cervical tissues and cervical scrapes. The performance of these markers was then determined in an independent set of 217 hrHPV-positive cervical scrapes from outpatients with histopathological verification.A methylation signature comprising the 5′ regions of the genes DLX1, ITGA4, RXFP3, SOX17 and ZNF671 specific for CIN3 and cervical cancer (termed CIN3+) was identified and validated. A high detection rate of CIN3+ was obtained if at least 2 of the 5 markers were methylated. In the subsequent cross-sectional study all cervical carcinomas (n = 19) and 56% (13/23) of CIN3 were identified by this algorithm. Only 10% (11/105) of hrHPV-positive women without histological evidence of cervical disease were scored positive by the methylation assay. Of note is that the detection rate of CIN3 differed between age groups. Eight of nine CIN3 were detected among women ≥30 years of age but only five of fourteen among <30 year old group (p = 0.03). The specificity for CIN3+ in the older age group was 76.6% (95% CI 65.6–85.5%). Clinical validation studies are required to determine the usefulness of these novel markers for triage after primary hrHPV testing in a cervical cancer screening setting.

O10.1 Age Specific Round 1 Results of a Cervical Cancer Screening Trial: HPV FOCAL

BackgroundHPV FOCAL Study is a randomised trial evaluating the efficacy of high risk-HPV DNA (hr-HPV) testing, with Liquid Based Cytology (LBC) triage testing of hr-HPV positives, compared to LBC testing...

A four‐gene methylation marker panel as triage test in high‐risk human papillomavirus positive patients

Cervical neoplasia-specific biomarkers, e.g. DNA methylation markers, with high sensitivity and specificity are urgently needed to improve current population-based screening on (pre)malignant cervical neoplasia. We aimed to identify new cervical neoplasia-specific DNA methylation markers and to design and validate a methylation marker panel for triage of high-risk human papillomavirus (hr-HPV) positive patients. First, high-throughput quantitative methylation-specific PCRs (QMSP) on a novel OpenArray™ platform, representing 424 primers of 213 cancer specific methylated genes, were performed on frozen tissue samples from 84 cervical cancer patients and 106 normal cervices. Second, the top 20 discriminating methylation markers were validated by LightCycler® MSP on frozen tissue from 27 cervical cancer patients and 20 normal cervices and ROCs and test characteristics were assessed. Three new methylation markers were identified (JAM3, EPB41L3 and TERT), which were subsequently combined with C13ORF18 in our four-gene methylation panel. In a third step, our methylation panel detected in cervical scrapings 94% (70/74) of cervical cancers, while in a fourth step 82% (32/39) cervical intraepithelial neoplasia grade 3 or higher (CIN3+) and 65% (44/68) CIN2+ were detected, with 21% positive cases for ≤CIN1 (16/75). Finally, hypothetical scenario analysis showed that primary hr-HPV testing combined with our four-gene methylation panel as a triage test resulted in a higher identification of CIN3 and cervical cancers and a higher percentage of correct referrals compared to hr-HPV testing in combination with conventional cytology. In conclusion, our four-gene methylation panel might provide an alternative triage test after primary hr-HPV testing.

BD-ProExC as Adjunct Molecular Marker for Improved Detection of CIN2+ after HPV Primary Screening

We investigated the efficacy of 8 cervical cancer screening strategies relative to cytology with emphasis on immunocytochemical detection of high-risk human papillomavirus (hrHPV)-induced cell transformation (BD-ProExC) as a tool of triage following primary cytology or hrHPV testing. 3,126 women were tested with BD-SurePath liquid-based cytology, hrHPV PCR genotyping and BD-ProExC immunostaining, and colposcopy verification to calculate sensitivity and positive predictive value (PPV) in detecting cervical intraepithelial neoplasia (CIN2(+)). Compared to cytology screening, double testing with cytology and hrHPV resulted in the same sensitivity with a significant increase in the PPV (relative PPV: 1.83). However, twice as many tests were needed. Cytology with atypical squamous cells of undetermined significance (ASC-US) triage and hrHPV testing showed comparative results to double testing requiring only a small increase in number of tests. Screening for hrHPV subtypes 16/18, and ASC-US triage with hrHPV16/18 resulted in significant reductions in sensitivity (ratio: 0.74 and 0.96, respectively). Primary hrHPV/BD-ProExC screening was significantly more sensitive (ratio: 1.63/1.33), but had a significantly lower PPV (ratio: 0.64/0.88). ASC-US triage by BD-ProExC increased the PPV (ratio: 1.90) but decreased the sensitivity (ratio: 0.96). Primary hrHPV screening followed by BD-ProExC triage, led to significant increases in sensitivity (ratio: 1.30) and PPV (ratio: 2.89), and resulted in 55% fewer referrals for colposcopy. From the investigated screening strategies, primary hrHPV DNA-based screening followed by BD-ProExC triage was determined to be the best screening strategy. Immunocytological triage could be used to perfect hrHPV primary screening.

Abstract 4917: A four-gene methylation marker panel as triage test in hr-HPV positive patients

Abstract Objective: Currently no cervical neoplasia specific methylation markers with high sensitivity and specificity are available for use in population-based screening on (pre)malignant cervical neoplasia. Aim of the study was to identify new methylation markers and to design and validate a methylation marker panel for triage of hr-HPV positive patients. Methods: Quantitative methylation specific PCRs (MSP) on OpenArray™ platform, representing 424 primers of 213 cancer specific methylated genes, were performed on frozen tissue samples from 84 cervical cancer patients and 106 normal cervices. The top 20 of ranked methylation markers were validated by LightCycler® MSP experiments. Then the top 3 methylation markers based on ROC analysis were selected for further clinical validation in combination with C13ORF18 (previously identified by our group), on cervical scrapings from 74 cervical cancer patients, 69 normal cervices and 148 patients referred with an abnormal Pap smear. Finally, a scenario analysis for population based screening program was performed to compare the diagnostic performance of our methylation panel to conventional liquid based cytology after primary hr-HPV testing. Results: Three cervical neoplasia specific methylation markers (JAM3, EPB41L3 and TERT) discriminated strongly between cervical scrapings from cervical cancer patients and healthy controls (p&amp;lt;0.0001). Our methylation panel (JAM3, EPB4lL3, TERT and C13ORF18) detected 94% of cervical cancers, 82% CIN3+ and 65% CIN2+, while specificity was 79% for CIN0/1 lesions. Scenario analysis showed that primary hr-HPV testing combined with our methylation marker panel as a triage test resulted in a higher identification of CIN3 and cervical cancers, a higher percentage of correct referrals and less patient-doctor contacts compared to hr-HPV testing in combination with liquid based cytology. Conclusion: Our study resulted in the discovery of three new cervical neoplasia specific methylation markers. Our methylation panel comprising 4 genes might be an alternative triage test after primary hr-HPV testing and its possible application deserves to be further explored in large population-based screening programs for cervical neoplasia. This study was supported by OncoMethylome Sciences S.A., Liège, Belgium, by the Dutch Cancer Society (NKB) (project-number RUG 2004-3161) and by the “Direction générale des Technologies, de la Recherche et de l'Énergie” of the Walloon Region of Belgium. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4917.

Routine cervical screening with primary HPV testing and cytology triage protocol in a randomised setting

The role of high-risk human papillomavirus (hrHPV) testing in primary cervical screening has not been established. We generated a randomised evaluation design ultimately to clarify whether primary hrHPV testing implemented into routine screening can bring increase in the programme effectiveness. The aim of the present report on first-year results was to assess the cross-sectional relative validity parameters for routine hrHPV screening, in comparison with conventional screening. An equal number of women invited to routine screening was randomly allocated to primary hrHPV screening (n=7060) and to cytological screening (n=7089). In the hrHPV screening arm, after a single positive hrHPV test result, the need of colposcopy referral was determined by a cytological triage test. Compared with the conventional arm, more colposcopy referrals were made in the hrHPV screening arm (relative risk 1.51, confidence interval 95% 1.03–2.22). Specificity of the primary screening with sole hrHPV test (91.5–92.1%) was much lower than that with the cytology triage (98.7–99.3%), which was not quite as specific as screening with conventional cytology (99.2–99.6%). Compared with conventional cytology, primary screening with hrHPV test results in increased cross-sectional relative sensitivity at the level of all positive lesions at the cost of substantial loss in specificity. With cytology triage, the specificity improves to the level of conventional cytology.