Use of the HPV DNA test for cervical cancer screening

Okužba z onkogenimi tipi humanih papilomavirusov (HPV) je potreben pogoj za razvoj raka materničnega vratu. Zaradi dolgoletne uporabe citoloških brisov se je incidenca tega raka zmanjšala, a kljub temu bi bilo treba najti nov presejalni test, ki bi bil občutljivejši za progresivne predrakave spremembe, cervikalno intraepitelialno neoplazijo (CIN). Med te teste spadajo testi HPV DNK. V tem članku so opisane njihove značilnosti, kakor jih je mogoče presoditi na podlagi vseh 8 randomiziranih kontroliranih raziskav z objavljenimi podatki, ki so primerjale uporabo testov HPV s citološkimi brisi za primarno presejanje. Te raziskave so potrdile, da je mogoče na podlagi testov HPV diagnosticirati večje število ≥ CIN 3 kot na podlagi citoloških brisov, čeprav razlika v nekaterih od raziskav, tudi zaradi njihove velikosti, ni bila statistično značilna. Razveseljivo je, da večja občutljivost za ≥ CIN 3 verjetno pomeni tudi boljšo zaščito pred rakom materničnega vratu, čeprav ocena temelji na majhnem številu opazovanih primerov v vsaki izmed raziskav. Pri uporabi testov HPV bo večji izziv omejiti njihove neželene učinke. To so predvsem pogostejši napačno pozitivni testi (ki jih definiramo kot pozitivne presejalne teste brez diagnoze ≥ CIN 3 ali ≥ CIN 2) ter pogostejše diagnoze in morebitno zdravljenje manj nevarnih stopenj CIN (predvsem CIN 1, deloma tudi CIN 2). V tem članku so kritično ovrednoteni 3 pristopi k zmanjšanju bremena testov HPV v primerjavi s citološkimi brisi, in sicer uporaba triažnih testov pri ženskah s pozitivnimi presejalnimi testi HPV, omejitev uporabe testov HPV pri mlajših ženskah in sprememba mejne vrednosti, pri kateri se test HPV odčita kot pozitiven. Vsi ti pristopi imajo svoje prednosti in slabosti.An infection with oncogenic types of Human Papillomavirus (HPV) is a necessary condition for development of cervical cancer. The incidence of cervical cancer has decreased over the years in line with the use of cytology screening. Nevertheless, cytology is not an optimally sensitive screening test for cervical intraepithelial neoplasia (CIN), and a more sensitive test would be beneficial. The aim of this paper was to describe the characteristics of HPV DNA tests as observed in all eight randomized controlled trials with published data that compared HPV tests and cytology in primary screening. These trials showed that the sensitivity of HPV tests for ≥CIN3 is higher than the sensitivity of cytology. In several trials, the higher sensitivity in the baseline screening rounds led to fewer diagnoses of cervical cancer by the subsequent screening round than was the case with cytology, although these observations were based on few cases per trial. It will be a greater challenge to limit the amount of extra unwanted side effects of HPV testing compared with cytology. These are predominantly false-positive tests, i.e. positive screening tests without a subsequent diagnosis of ≥CIN3, and extra diagnoses of CIN grades with a low probability of progression to cervical cancer, i.e. CIN1 and to some degree also CIN2. The three most widely discussed approaches to reducing the burden of the extra unwanted effects were discussed in this paper: the use of triage tests in women with positive HPV screening tests, the use of HPV tests from the age of 30 years onwards only, and a change in the threshold value for a positive HPV test. Each of these approaches is associated with distinct advantages and disadvantages

Recent Developments in the Dutch Cervical Cancer Screening Programme

Worldwide, cervical cancer is the second most common female malignancy, diagnosed in 500,000 women each year, while 275,000 die from it. Without prevention, the peak incidence occurs at a relatively young age, between 40-55 years, when women are still active on the labour market and have young children. While cervical cancer is the leading cancer-related cause of death and the second most common cancer in women in developing countries (incidence rates ≥30 per 100,000), it became much less common in developed countries in the recent decades. In the Netherlands, the incidence and mortality have been decreasing for decades (Figure 1-1). In 2003, cervical cancer was newly diagnosed in 584 women (World standardized incidence rate (WSR): 4.9 per 100,000 women) and 214 women died from it (WSR: 1.4 per 100,000 women). Inter-country differences in cervical cancer incidence are caused by differences in determinants and in access to preventive measures. The prevalence of the Human Papillomavirus (HPV) infection, the necessary factor in the development of cervical cancer, is generally higher in developing countries. Differences in the host factor, e.g. more common malnourishment and the prevalence of other infections in the developing countries, may also play a role. These countries typically do not offer population-wide cervical cancer screening facilities, which require a high level of organization and adequate health care resources

Human papillomavirus testing in primary cervical screening and the cut-off level for hybrid capture 2 tests: systematic review

Objective To determine the trade-off between the sensitivity and the specificity for high grade cervical intraepithelial neoplasia at hybrid capture 2 cut-off values above the standard ≥1 relative light units/cut-off level (rlu/co)

Cross-reactivity profiles of hybrid capture II, cobas, and APTIMA human papillomavirus assays:split-sample study

BACKGROUND: High-risk Human Papillomavirus (HPV) testing is replacing cytology in cervical cancer screening as it is more sensitive for preinvasive cervical lesions. However, the bottleneck of HPV testing is the many false positive test results (positive tests without cervical lesions). Here, we evaluated to what extent these can be explained by cross-reactivity, i.e. positive test results without evidence of high-risk HPV genotypes. The patterns of cross-reactivity have been thoroughly studied for hybrid capture II (HC2) but not yet for newer HPV assays although the manufacturers claimed no or limited frequency of cross-reactivity. In this independent study we evaluated the frequency of cross-reactivity for HC2, cobas, and APTIMA assays. METHODS: Consecutive routine cervical screening samples from 5022 Danish women, including 2859 from women attending primary screening, were tested with the three evaluated DNA and mRNA HPV assays. Genotyping was undertaken using CLART HPV2 assay, individually detecting 35 genotypes. The presence or absence of cervical lesions was determined with histological examinations; women with abnormal cytology were managed as per routine recommendations; those with normal cytology and positive high-risk HPV test results were invited for repeated testing in 18 months. RESULTS: Cross-reactivity to low-risk genotypes was detected in 109 (2.2 %) out of 5022 samples on HC2, 62 (1.2 %) on cobas, and 35 (0.7 %) on APTIMA with only 10 of the samples cross-reacting on all 3 assays. None of the 35 genotypes was detected in 49 (1.0 %), 162 (3.2 %), and 56 (1.1 %) samples, respectively. In primary screening at age 30 to 65 years (n = 2859), samples of 72 (25 %) out of 289 with high-risk infections on HC2 and < CIN2 histology were due to cross-reactivity. On cobas, this was 106 (26 %) out of 415, and on APTIMA 48 (21 %) out of 224. CONCLUSIONS: Despite manufacturer claims, all three assays showed cross-reactivity. In primary cervical screening at age ≥30 years, cross-reactivity accounted for about one quarter of false positive test results regardless of the assay. Cross-reactivity should be addressed in EU tenders, as this primarily technical shortcoming imposes additional costs on the screening programmes

Incidence of cervical cancer after several negative smear results by age 50: prospective observational study

Objective To determine the incidence of cervical cancer after several negative cervical smear tests at different ages

Cervical screening during the COVID-19 pandemic: optimising recovery strategies

Disruptions to cancer screening services have been experienced in most settings as a consequence of the COVID-19 pandemic. Ideally, programmes would resolve backlogs by temporarily expanding capacity; however, in practice, this is often not possible. We aim to inform the deliberations of decision makers in high-income settings regarding their cervical cancer screening policy response. We caution against performance measures that rely solely on restoring testing volumes to pre-pandemic levels because they will be less effective at mitigating excess cancer diagnoses than will targeted measures. These measures might exacerbate pre-existing inequalities in accessing cervical screening by disregarding the risk profile of the individuals attending. Modelling of cervical screening outcomes before and during the pandemic supports risk-based strategies as the most effective way for screening services to recover. The degree to which screening is organised will determine the feasibility of deploying some risk-based strategies, but implementation of age-based risk stratification should be universally feasible.Health Research BoardNational Health and Medical Research Council AustraliaCancer Research UKCancer Institute NSWNational Institutes of Health USANorwegian Cancer SocietyNational Cancer Centre Japa

Risk of cervical cancer after completed post-treatment follow-up of cervical intraepithelial neoplasia: Population based cohort study

Abstract Objective To compare the risk of cervical cancer in women with histologically confirmed cervical intraepithelial neoplasia who returned to routine screening after having completed post-treatment follow-up with consecutive normal smear test results with women with a normal primary smear test result. Design Population based cohort study using data from a nationwide pathology register. Setting The Netherlands, 1994 to 2006. Population 38 956 women with histologically confirmed intraepithelial neoplasia grades 1 to 3 with completed follow-up after treatment. Intervention Routine post-treatment follow-up of cervical intraepithelial neoplasia, recommending smear tests at six, 12, and 24 months. Main outcome measure Incidence of cervical cancer in the period from completed follow-up with negative test results after cervical intraepithelial neoplasia to the next primary test. 10-year hazard ratios were compared with periods after normal results for the primary smear test, adjusted for year in follow-up. Results 20 cervical cancers were diagnosed during 56 956 woman years after completed follow-up of cervical intraepithelial neoplasia, whereas 1613 cervical cancers were diagnosed during 25 020 697 woman years after a normal primary smear test result. The incidence of 35.1 (95% confidence interval 21.4 to 54.2) per 100 000 woman years and 6.4 (6.1 to 6.8) per 100 000 woman years, respectively, led to an adjusted hazard ratio of 4.2 (95% confidence interval 2.7 to 6.5) for periods after completed follow-up compared with periods after normal primary smear test results. This hazard ratio was increased for all ages. No significant difference in risk of cervical cancer was observed by grade of cervical intraepithelial neoplasia. Conclusions An excess risk

Cervical cancer incidence after normal cytological sample in routine screening using SurePath, ThinPrep, and conventional cytology: population based study

#### Objective To compare the cumulative incidence of cervical cancer diagnosed within 72 months after a normal screening sample between conventional cytology and liquid based cytology tests SurePath and ThinPrep. #### Design Retrospective population based cohort study. #### Setting Nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA), January 2000 to March 2013. #### Population Women with 5924474 normal screening samples (23833123 person years). #### Exposure Use of SurePath or ThinPrep versus conventional cytology as screening test. #### Main outcome measure 72 month cumulative incidence of invasive cervical cancer after a normal screening sample for each screening test. Cox regression analyses assessed the hazard ratios, adjusted for calendar time, age, screening history, and socioeconomic status and including laboratories as random effects. #### Results The 72 month cumulative cancer incidence was 58.5 (95% confidence interval 54.6 to 62.7) per 100000 normal conventional cytology samples, compared with 66.8 (56.7 to 78.7) for ThinPrep and 44.6 (37.8 to 52.6) for SurePath. Compared with conventional cytology, the hazard of invasive cancer was 19% lower (hazard ratio 0.81, 95% confidence interval 0.66 to 0.99) for SurePath, mainly caused by a 27% lower hazard (0.73, 0.57 to 0.93) of a clinically detected cancer. For ThinPrep, the hazard was on average 15% higher (hazard ratio 1.15, 0.95 to 1.38), mainly caused by a 56% higher hazard of a screen detected cancer (1.56, 1.17 to 2.08). #### Conclusions These findings should provoke reconsideration of the assumed similarity in sensitivity to detect progressive cervical intraepithelial neoplasia between different types of liquid based cy