Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study

Castle, Philip E.; Stoler, Mark H.; Wright, Thomas; Sharma, Abha; Wright, Teresa L.; Behrens, Catherine M.

doi:10.1016/s1470-2045(11)70188-7

Cited by 454 publications

(417 citation statements)

References 44 publications

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“…This discrepancy, already observed in many studies having high‐grade CIN as the endpoint,6, 10, 33, 34 could result from a different natural history of cell transformation induced by HPV18 and 45. In fact, these genotypes are over‐represented in adenocarcinomas and early onset cancers35, 36, 37 and are rarely prevented through cytological screening 2, 38, 39.…”

Section: Discussionmentioning

confidence: 92%

Human papilloma virus genotyping for the cross‐sectional and longitudinal probability of developing cervical intraepithelial neoplasia grade 2 or more

Mistro

Adcock

Carozzi

et al. 2018

Intl Journal of Cancer

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Human papilloma virus (HPV) testing is more sensitive but less specific than cytology. We evaluated stand‐alone genotyping as a possible triage method. During a multicentre randomised controlled trial comparing HPV testing to conventional cytology, HPV‐positive women were referred to colposcopy and followed up if no high‐grade lesion was detected. HPV‐positive samples were genotyped by GP5+/GP6+ primed polymerase chain reaction followed by reverse line blot. Genotypes were hierarchically ordered by positive predictive value (PPV) for CIN grade 2 or more (CIN2+), and grouped by cluster analysis into three groups (A, B and C in decreasing order). Receiver operating characteristic curves were computed. Among 2,255 HPV‐positive women with genotyping, 239 CIN2+ (including 113 CIN3+) were detected at baseline or during a 3‐year follow‐up. HPV33 had the highest PPV with CIN2+ and CIN3+ as the endpoint and when considering lesions detected at baseline or also during follow‐up. HPV16 and HPV35 were the second and third, respectively. Cross‐sectional sensitivity for CIN2+ at baseline was 67.3% (95% CI 59.7–74.2), 91.8% (95% CI 86.6–95.5) and 94.7% (95% CI 90.2–97.6), respectively, when considering as “positive” any of the HPV types in group A (33, 16 and 35), A or B (31, 52, 18, 59 and 58) and A or B or C (39, 51, 56, 45 and 68). The corresponding cross‐sectional PPVs for CIN2+ were 15.8% 95% (CI 13.2–18.7), 12.0% (95% CI 10.3–13.9) and 9.6% (95% CI 8.2–11.1), respectively. HPV33, 16 and 35 confer a high probability of CIN2+ but this rapidly decreases when adding other genotypes.

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Section: Discussionmentioning

confidence: 92%

Human papilloma virus genotyping for the cross‐sectional and longitudinal probability of developing cervical intraepithelial neoplasia grade 2 or more

Mistro

Adcock

Carozzi

et al. 2018

Intl Journal of Cancer

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“…Various studies have evaluated triage strategies for HPV‐positive women in screening cohorts, including virus‐ and host cell‐based strategies, such as HPV16/18 genotyping,4, 5 HPV E7 mRNA analysis,6, 7 cytology,8, 9 p16/ki67 dual staining,10, 11 epigenetic changes in the host and/or viral genome,12, 13 and combinations thereof 8, 9. At present, reflex cytology testing, which has been adopted in the Dutch HPV‐based screening program, is considered an appropriate triage test,1, 4, 8, 9, 14 although a short‐term repeat cytology is needed to assure a sufficiently low risk of cervical cancer for triage test‐negative women. Furthermore, cytology is subjective and prior knowledge of HPV presence, as is the case in the setting of primary HPV screening, will likely increase the false‐positivity rate 15.…”

Section: Introductionmentioning

confidence: 99%

Cervical cancer risk in HPV‐positive women after a negative FAM19A4/mir124‐2 methylation test: A post hoc analysis in the POBASCAM trial with 14 year follow‐up

Strooper

Berkhof

Steenbergen

et al. 2018

Intl Journal of Cancer

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DNA methylation analysis of cervical scrapes using FAM19A4 and mir124‐2 genes has shown a good clinical performance in detecting cervical cancer and advanced CIN lesions in need of treatment in HPV‐positive women. To date, longitudinal data on the cancer risk of methylation test‐negative women are lacking. In our study, we assessed the longitudinal outcome of FAM19A4/mir124‐2 methylation analysis in an HPV‐positive screening cohort with 14 years of follow‐up. Archived HPV‐positive cervical scrapes of 1,040 women (age 29–61 years), who were enrolled in the POBASCAM screening trial (ISRCTN20781131) were tested for FAM19A4/mir124‐2 methylation. By linkage with the nationwide network and registry of histo‐ and cytopathology in the Netherlands (PALGA), 35 cervical cancers were identified during 14 years of follow‐up comprising three screens (baseline, and after 5 and 10 years). The baseline scrape of 36.1% (n = 375) women tested positive for FAM19A4/mir124‐2 methylation, including 24 women with cervical cancer in follow‐up, and 30.6% (n = 318) had abnormal cytology (threshold borderline dyskaryosis or ASCUS), including 14 women with cervical cancer in follow‐up. Within screening round capability of FAM19A4/mir124‐2 methylation to detect cervical cancer was 100% (11/11, 95% CI: 71.5–100). Kaplan–Meier estimate of 14‐year cumulative cervical cancer incidence was 1.7% (95% CI: 0.66–3.0) among baseline methylation‐negative and 2.4% (95% CI: 1.4–3.6) among baseline cytology‐negative women (risk difference: 0.71% [95% CI: 0.16–1.4]). In conclusion, a negative FAM19A4/mir124‐2 methylation test provides a low cervical cancer risk in HPV‐positive women of 30 years and older. FAM19A4/mir124‐2 methylation testing merits consideration as an objective triage test in HPV‐based cervical screening programs.

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“…In a hrHPV-positive gynecologic outpatient population, a sensitivity of 80.8% and a specificity of 63.3% of Pap cytology were found [51]. The reported PPVs of a single Pap cytology test for triage of hrHPV-positive women range between 14.1% and 42.2% in screening populations [39,40,47]. Longitudinal studies in screening populations have shown that a single negative Pap cytology result in a hrHPV-positive woman yields insufficient reassurance against ≥CIN3 (NPV 94.3-95.1%) [39,40] to justify direct dismissal from further follow-up, as the required NPV threshold of 98% [38] is not met.…”

Section: Pap Cytologymentioning

confidence: 96%

“…The main limitation of Pap cytology is its subjective nature, which results in a suboptimal sensitivity for ≥CIN3. In large population-based screening studies (ATHENA n = 4275; VUSA-screen n = 1303, POBASCAM n = 1100), triage of hrHPV-positive women by a single Pap cytology test had a sensitivity for ≥CIN3 varying between 52.8% and 75.4%, with a corresponding specificity of 78.0-85.6% [39,40,47]. Of note, these estimates were obtained in study settings where cytologists were blinded to hrHPV-test results.…”

Section: Pap Cytologymentioning

confidence: 99%

“…Inherent to the genotype restriction, the use of HPV16/18 genotyping for triage of hrHPV-positive women has a limited ≥CIN3 sensitivity, which has been estimated at 59.5-65.4% in population-based screening studies [39,47]. In relatively highrisk populations, comprising screening non-attendees or gynecology patients, HPV16/18 genotyping had a ≥CIN3 sensitivity of 72.2-74.8% [51,79].…”

Section: Molecular Triage Strategiesmentioning

confidence: 99%

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Management of high-risk HPV-positive women for detection of cervical (pre)cancer

Luttmer

Strooper

Steenbergen

et al. 2016

Expert Review of Molecular Diagnostics

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Introduction: Primary HPV-testing has been shown to provide a superior detection of women at risk of cervical (pre)cancer compared to cytology-based screening. However, as most high-risk HPV infections are harmless, additional triage testing of HPV-positive women is necessary to identify those with cervical (pre)cancer. In this paper, we compare the performance, advantages and limitations of clinically relevant available triage strategies for HPV-positive women. Areas covered: Many different colposcopy triage strategies, comprising both microscopy-based and molecular (virus/host-related) markers, have been suggested: Pap cytology, p16/Ki-67 dual-stained cytology, HPV16/18 genotyping, viral DNA methylation and host cell DNA methylation. Literature search was limited to triage strategies that have achieved at least phase 2 of the five-phase framework for biomarker development and studies including large cohorts (≥100 hrHPV-positive women). Triage markers were stratified by sample type (cervical scrape, self-collected sample) and by study population (screening, non-attendee, referral). Expert commentary: At present, repeat Pap cytology and Pap cytology combined with HPV16/18 genotyping are the only triage strategies that have been robustly shown to be ready for implementation. Other strategies such as p16/Ki-67 dual-stained cytology and host cell DNA methylation analysis, with or without additional HPV16/18 genotyping, are attractive options for the near future. ARTICLE HISTORY

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Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study

Cited by 454 publications

References 44 publications

Human papilloma virus genotyping for the cross‐sectional and longitudinal probability of developing cervical intraepithelial neoplasia grade 2 or more

Human papilloma virus genotyping for the cross‐sectional and longitudinal probability of developing cervical intraepithelial neoplasia grade 2 or more

Cervical cancer risk in HPV‐positive women after a negative FAM19A4/mir124‐2 methylation test: A post hoc analysis in the POBASCAM trial with 14 year follow‐up

Management of high-risk HPV-positive women for detection of cervical (pre)cancer

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