Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials

Ronco, Guglielmo; Dillner, Joakim; Elfström, K. Miriam; Tùnesi, Sara; Snijders, Peter J.F.; Arbyn, Marc; Kitchener, Henry C; Segnan, Nereo; Gilham, Clare; Rossi, Paolo Giorgi; Berkhof, Johannes; Peto, Julian; Meijer, Chris J.L.M.

doi:10.1016/s0140-6736(13)62218-7

Cited by 1,436 publications

(1,446 citation statements)

References 25 publications

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“…In several countries, including The Netherlands, hrHPV testing is replacing cytology as primary screening method. Compared to cytology, hrHPV testing has a higher sensitivity for CIN2+ detection [45,46]. However, its 3–5% lower specificity makes triage testing of hrHPV-positive women necessary to prevent over-referral and overtreatment.…”

Section: Discussionmentioning

confidence: 99%

Host-cell DNA methylation patterns during high-risk HPV-induced carcinogenesis reveal a heterogeneous nature of cervical pre-cancer

et al. 2018

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Cervical cancer development following a persistent infection with high-risk human papillomavirus (hrHPV) is driven by additional host-cell changes, such as altered DNA methylation. In previous studies, we have identified 12 methylated host genes associated with cervical cancer and pre-cancer (CIN2/3). This study systematically analyzed the onset and DNA methylation pattern of these genes during hrHPV-induced carcinogenesis using a longitudinal in vitro model of hrHPV-transformed cell lines (n = 14) and hrHPV-positive cervical scrapings (n = 113) covering various stages of cervical carcinogenesis. DNA methylation analysis was performed by quantitative methylation-specific PCR (qMSP) and relative qMSP values were used to analyze the data. The majority of genes displayed a comparable DNA methylation pattern in both cell lines and clinical specimens. DNA methylation onset occurred at early or late immortal passage, and DNA methylation levels gradually increased towards tumorigenic cells. Subsequently, we defined a so-called cancer-like methylation-high pattern based on the DNA methylation levels observed in cervical scrapings from women with cervical cancer. This cancer-like methylation-high pattern was observed in 72% (38/53) of CIN3 and 55% (11/20) of CIN2, whereas it was virtually absent in hrHPV-positive controls (1/26). In conclusion, hrHPV-induced carcinogenesis is characterized by early onset of DNA methylation, typically occurring at the pre-tumorigenic stage and with highest DNA methylation levels at the cancer stage. Host-cell DNA methylation patterns in cervical scrapings from women with CIN2 and CIN3 are heterogeneous, with a subset displaying a cancer-like methylation-high pattern, suggestive for a higher cancer risk.

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Section: Discussionmentioning

confidence: 99%

Host-cell DNA methylation patterns during high-risk HPV-induced carcinogenesis reveal a heterogeneous nature of cervical pre-cancer

et al. 2018

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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. It is, however, not clear if for these genotypes the co‐existing high risk of developing invasive cancer and low risk of having a pre‐cancerous lesion detected depends on a high rate of progression of such lesions to invasion or on the difficulty in detecting them by colposcopy.…”

Section: Discussionmentioning

confidence: 99%

“…Cervical cancer screening based on HPV testing allows earlier diagnosis of persistent high‐grade cervical intraepithelial neoplasia (CIN) than cytology‐based screening1 and is more effective in preventing invasive cervical cancer 2. However, as the specificity of HPV testing for high‐grade CIN is low,1 a triage for selecting which HPV‐positive women are referred to colposcopy is needed.…”

Section: Introductionmentioning

confidence: 99%

“…All randomized controlled trials (RCTs) except one (NTCC, New Technologies for Cervical Cancer) referred to colposcopy only HPV‐positive women with abnormal cytology or persistent HPV infection. This approach, compared to stand alone cytology, increased efficacy without increasing the biopsy rate 2. Nonetheless, short‐term test repeats are needed, which is disturbing for women3 and entail appreciable loss to follow‐up4 so investigating other triage methods is of interest.…”

Section: Introductionmentioning

confidence: 99%

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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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“…Large longitudinal studies have shown that screening can be improved by the introduction of a hrHPV test as a primary screening tool [14][15][16][17][18][19][20][21][22][23][24][25][26]. Compared to primary screening with Pap cytology, a primary hrHPV test has a superior sensitivity for cervical cancer [24] and its high-grade precursor lesions (cervical intraepithelial neoplasia grade 3, CIN3) [14][15][16][17][18][19][20][21]26]. Moreover, a negative hrHPV test has been shown to provide a significantly higher long-term reassurance against the presence or development of CIN3 or cervical cancer (together referred to as ≥CIN3) compared to a normal Pap cytology result [22,23].…”

Section: Introductionmentioning

confidence: 99%

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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Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials

Cited by 1,436 publications

References 25 publications

Host-cell DNA methylation patterns during high-risk HPV-induced carcinogenesis reveal a heterogeneous nature of cervical pre-cancer

Host-cell DNA methylation patterns during high-risk HPV-induced carcinogenesis reveal a heterogeneous nature of cervical pre-cancer

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

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

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