Triage Of hrHPV-positive Women Research Articles

PCDHGB7 hypermethylation-based Cervical cancer Methylation (CerMe) detection for the triage of high-risk human papillomavirus-positive women: a prospective cohort study

BackgroundImplementation of high-risk human papillomavirus (hrHPV) screening has greatly reduced the incidence and mortality of cervical cancer. However, a triage strategy that is effective, noninvasive, and independent from the subjective interpretation of pathologists is urgently required to decrease unnecessary colposcopy referrals in hrHPV-positive women.MethodsA total of 3251 hrHPV-positive women aged 30–82 years (median = 41 years) from International Peace Maternity and Child Health Hospital were included in the training set (n = 2116) and the validation set (n = 1135) to establish Cervical cancer Methylation (CerMe) detection. The performance of CerMe as a triage for hrHPV-positive women was evaluated.ResultsCerMe detection efficiently distinguished cervical intraepithelial neoplasia grade 2 or worse (CIN2 +) from cervical intraepithelial neoplasia grade 1 or normal (CIN1 −) women with excellent sensitivity of 82.4% (95% CI = 72.6 ~ 89.8%) and specificity of 91.1% (95% CI = 89.2 ~ 92.7%). Importantly, CerMe showed improved specificity (92.1% vs. 74.9%) in other 12 hrHPV type-positive women as well as superior sensitivity (80.8% vs. 61.5%) and specificity (88.9% vs. 75.3%) in HPV16/18 type-positive women compared with cytology testing. CerMe performed well in the triage of hrHPV-positive women with ASC-US (sensitivity = 74.4%, specificity = 87.5%) or LSIL cytology (sensitivity = 84.4%, specificity = 83.9%).ConclusionsPCDHGB7 hypermethylation-based CerMe detection can be used as a triage strategy for hrHPV-positive women to reduce unnecessary over-referrals.Trial registrationChiCTR2100048972. Registered on 19 July 2021.

Acceptability of risk-based triage in cervical cancer screening: A focus group study.

Compared to the previous cytology-based program, the introduction of primary high-risk human papillomavirus (hrHPV) based screening in 2017 has led to an increased number of referrals. To counter this, triage of hrHPV-positive women in cervical cancer screening can potentially be optimized by taking sociodemographic and lifestyle risk factors for cervical abnormalities into account. Therefore, it is essential to gain knowledge of the views of women (30-60 years) eligible for cervical cancer screening. The main goal of this qualitative study was to gain insight in the aspects that influence acceptability of risk-based triage in cervical cancer screening. A focus group study in which participants were recruited via four general medical practices, and purposive sampling was used to maximize heterogeneity with regards to age, education level, and cervical cancer screening experiences. The focus group discussions were transcribed verbatim and analyzed using reflexive thematic analysis. A total of 28 women (average age: 45.2 years) eligible for cervical cancer screening in The Netherlands participated in seven online focus group discussions. Half of the participants was higher educated, and the participants differed in previous cervical cancer screening participation and screening result. In total, 5 main themes and 17 subthemes were identified that determine the acceptability of risk-stratified triage. The main themes are: 1) adequacy of the screening program: an evidence-based program that is able to minimize cancer incidence and reduce unnecessary referrals; 2) personal information (e.g., sensitive topics and stigma); 3) emotional impact: fear and reassurance; 4) communication (e.g., transparency); and 5) autonomy (e.g., prevention). The current study highlights several challenges regarding the development and implementation of risk-based triage that need attention in order to be accepted by the target group. These challenges include dealing with sensitive topics and a transparent communication strategy.

Prikaz HPV testiranja kao primarnog skrininga raka grlića materice

Cytology-based cervical cancer screening achieved undisputable success in reducing the incidence and mortality of cervical cancer in many countries of the world, especially high-income countries. However, in lowand middle-income countries substantial reductions in cervical cancer incidence rates have not been achieved, mainly due to the difficulties in realization of complex conditions for implementing high quality cytology-based cervical cancer screening programs. Most international guidelines, including the World Health Organisation (WHO) Global Strategy, now recommend high-risk human papillomavirus (hrHPV) testing as the preferred cervical screening test, for several reasons, primarily due to its sensitivity, less subjectivity in diagnosis and possibility of easier program organization and implementation. The advantages of primary hrHPV screening include higher sensitivity of technology compared to cytology based examinations, and increased specificity in populations where large proportions of women have been vaccinated against the human papillomavirus (HPV), while the high-negative predictive value enables prolongation of screening intervals to 7 to 10 years, which increases the cost effectiveness of the screening programme, when applied at population level. Also, primary hrHPV screening for cervical cancer can be carried out by self-taken samples which increases the feasibility of such cervical cancer screening programme. However, implementing primary hrHPV cervical cancer screening requires at the same time organised system of monitoring the implementation of the program, coordination and quality assurance of all processes within the implementation of cervical cancer screening.Effective hrHPV primary cervical cancer screening programme requires the triage of hrHPV positive women to maximise the detection of clinically relevant cervical lesions for further investigation. Most of the countries that introduced hrHPV primary cervical cancer screening use visual inspection with acetic acid (VIA), cytology based examination or HPV geno-typing with cytology for triage testing. The choice of triage strategy depends on various factors, including availability of resources, effectiveness and cost of procedures to recall women for triage testing as well as the capacity and quality of existing health services to deliver the triage tests. Implementation of self-sampling also requires a number of issues to be addressed, including communication to motivate participation and to inform women about the self-sampling procedure, delivery of the self-sampling kits and return of the samples to the laboratories, laboratory procedures, communication of results, recalling screen-positive women for further examination and triage and motivating them to attend for follow-up and treatment. Finally, the introduction primary screening for HPV on the mucous membrane of the cervix should be accompanied by awareness-raising programs to improve the information and knowledge of women and the entire population about the importance of the cervical cancer screening, which would improve the results of population based cervical cancer screening programs and increase the women's participation.

DNA methylation marker for the triage of hrHPV positive women in cervical cancer screening: Real-world evidence in Taiwan

ObjectiveHuman papillomavirus (HPV) testing as the primary cervical cancer screening followed by reflex cytology if high-risk HPV is present (hrHPV+) is recently adopted in some countries. However, reflex cytology's sensitivity is variable, and a suitable triage approach for hrHPV+ remains controversial. Here, we compared the performance of three triage tools in hrHPV+ women. MethodsThree triage tools—cytology, HPV16/18 genotyping, and DNA methylation biomarker PAX1m—were analyzed for their clinical performance in hrHPV+ women. In addition, women without cervical cancer at enrollment were followed for histologically confirmed high-grade cervical intraepithelial neoplasia or worse (CIN3+) annually using Papanicolaou smear. ResultsOf 4762 women aged ≥20 years enrolled, 502 (10.5%) were hrHPV+. PAX1m and cytology demonstrated similar accuracy (>90%), sensitivity (>78%), and specificity (>92%) as triage tools in 429 hrHPV+ women aged 30–64 years. PAX1m had better accuracy and specificity (91.6% and 92.5%, respectively) than HPV16/18 (76.9% and 76.8%, respectively). The incidence of CIN3+ among hrHPV+ women was 10.7 cases/1000 person-years. The incidence was significantly greater in PAX1m-positive women than in PAX1m-negative women. ConclusionsPAX1m has comparable clinical performance to cytology and better accuracy and specificity than HPV16/18 as the triage tool for detecting CIN3+ in hrHPV+ women. The PAX1m assay is thus a promising molecular-based triage tool for early detection of CIN and predicting disease progression in hrHPV+ women. It can be especially useful in countries where adequate cytology-based infrastructure is lacking, such as some Southeast Asian countries, for cervical cancer screening and prevention.

Abstract LB-165: Risk factor prediction models for triage of HR-HPV positive women: The Estampa study

Abstract Background: Cervical cancer remains an important public health problem worldwide, being the 4th most common cancer in women globally. HPV testing has been proposed for primary cervical cancer screening, given its higher sensitivity compared to cytology to detect cervical cancer precursors. However, HPV testing may lead to costly and unnecessary increases in follow-ups and/or treatments for transiently HPV positive women. Thus, triage methods are needed for HR-HPV positive women to determine optimal management. This study aims to construct and validate a risk prediction model for cervical pre-cancer based on demographics, clinical, and lifestyle characteristics among HR-HPV positive women. Methods: This analysis from the Multicentric study of cervical cancer screening and triage with HPV testing (ESTAMPA) included HR-HPV positive women aged 30-65 recruited on nine countries in Latin America from 2012 to 2019 (n=4565). The outcomes were: (1) cervical intraepithelial neoplasia grade 2 or more severe disease (CIN2+), and (2) CIN grade 3 or more severe disease (CIN3+) before final pathology review. Covariates included demographic characteristics and cervical cancer risk factors. Univariate logistic regression models were used to assess potential predictors of CIN2+ and CIN3+, controlling for the effect of the country of residence, using a multilevel approach. A multivariate logistic regression model was used to predict outcomes. After computing the probability of CIN2+ and CIN3+ among participants, we categorized these probabilities in deciles, to set the scale boundaries. Receiver-operating curves (ROC) and the Area under the Curves (AUC) were constructed. Sensitivity, specificity and predictive values were used to summarize the performance of the scoring system. Results: The prevalence of CIN2+ and CIN3+ in the study population were 14.7% and 9.7%, respectively. Age at recruitment, history of last Pap test, number of pregnancies, use of oral contraceptives, cigarette use and age at first sexual intercourse were significantly associated (p<0.05) with having CIN2+ and CIN3+. The AUC for the risk factor prediction model was 0.66 for CIN2+ and 0.69 for CIN3+. The optimal cutpoint selected by the Youden's statistic was the 5th decile for CIN2+ and 6th decile for CIN3+. This optimal point was for women with probabilities of CIN2+ greater than 13% and greater than 10% for CIN3+. Thus, in these deciles the number of referrals to colposcopy decreased from 100% to 60% for CIN2+ (100% to 49% for CIN3+), and the sensitivity and specificity obtained in this decile was 80% and 43% for CIN2+, respectively (73% and 54% for CIN3+). Conclusions: Our risk prediction model demonstrated a close to acceptable discrimination. This risk prediction model has the potential to reduce the number of HR-HPV positive women who are referred to colposcopy or treatment unnecessarily, reducing the burden for the patient and the healthcare system. Further analyses after pathology review are underway. Citation Format: Marievelisse Soto-Salgado, Maribel Almonte, Ana Patricia Ortiz, Erick L. Suarez, Luis R. Pericchi, Armando Baena, Rolando Herrero. Risk factor prediction models for triage of HR-HPV positive women: The Estampa study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-165.

Triage of high-risk HPV-positive women in population-based screening by miRNA expression analysis in cervical scrapes; a feasibility study

BackgroundPrimary testing for high-risk HPV (hrHPV) is increasingly implemented in cervical cancer screening programs. Many hrHPV-positive women, however, harbor clinically irrelevant infections, demanding additional disease markers to prevent over-referral and over-treatment. Most promising biomarkers reflect molecular events relevant to the disease process that can be measured objectively in small amounts of clinical material, such as miRNAs. We previously identified eight miRNAs with altered expression in cervical precancer and cancer due to either methylation-mediated silencing or chromosomal alterations. In this study, we evaluated the clinical value of these eight miRNAs on cervical scrapes to triage hrHPV-positive women in cervical screening.ResultsExpression levels of the eight candidate miRNAs in cervical tissue samples (n = 58) and hrHPV-positive cervical scrapes from a screening population (n = 187) and cancer patients (n = 38) were verified by quantitative RT-PCR. In tissue samples, all miRNAs were significantly differentially expressed (p < 0.05) between normal, high-grade precancerous lesions (CIN3), and/or cancer. Expression patterns detected in cervical tissue samples were reflected in cervical scrapes, with five miRNAs showing significantly differential expression between controls and women with CIN3 and cancer. Using logistic regression analysis, a miRNA classifier was built for optimal detection of CIN3 in hrHPV-positive cervical scrapes from the screening population and its performance was evaluated using leave-one-out cross-validation. This miRNA classifier consisted of miR-15b-5p and miR-375 and detected a major subset of CIN3 as well as all carcinomas at a specificity of 70%. The CIN3 detection rate was further improved by combining the two miRNAs with HPV16/18 genotyping. Interestingly, both miRNAs affected the viability of cervical cancer cells in vitro.ConclusionsThis study shows that miRNA expression analysis in cervical scrapes is feasible and enables the early detection of cervical cancer, thus underlining the potential of miRNA expression analysis for triage of hrHPV-positive women in cervical cancer screening.

The Value of a Novel Panel of Cervical Cancer Biomarkers for Triage of HPV Positive Patients and for Detecting Disease Progression.

In the era of primary vaccination against HPV and at the beginning of the low prevalence of cervical lesions, introduction of screening methods that can distinguish between low- and high-grade lesions is necessary in order to maintain the positive predictive value of screening. This case-control study included 562 women who attended cervical screening or were referred for colposcopy and 140 disease free controls, confirmed by histology and/or cytology. The cases were stratified by age. Using routine exfoliated liquid based cytological samples RT-PCR measurements of biomarker genes, high-risk HPV testing and liquid based cytology were performed and used to evaluate different testing protocols including sets of genes/tests with different test cut-offs for the diagnostic panels. Three new panels of cellular biomarkers for improved triage of hrHPV positive women (diagnostic panel) and for prognostic assessment of CIN lesions were proposed. The diagnostic panel (PIK3AP1, TP63 and DSG3) has the potential to distinguish cytologically normal hrHPV+ women from hrHPV+ women with CIN2+. The prognostic gene panels (KRT78, MUC5AC, BPIFB1 and CXCL13, TP63, DSG3) have the ability to differentiate hrHPV+ CIN1 and carcinoma cases. The diagnostic triage panel showed good likelihood ratios for all age groups. The panel showed age-unrelated performance and even better diagnostic value under age 30, a unique feature among the established cervical triage tests. The prognostic gene-panels demonstrated good discriminatory power and oncogenic, anti-oncogenic grouping of genes. The study highlights the potential for the gene expression panels to be used for diagnostic triage and lesion prognostics in cervical cancer screening.

Triage of high-risk human papillomavirus-positive women by methylated POU4F3.

BackgroundInsufficient specificity of the high-risk human papillomavirus (hrHPV) assay in primary cervical cancer screening results in unnecessary referral. Additional assays to triage hrHPV-positive women are needed to improve molecular cervical cancer screening. DNA methylation is a promising biomarker in cervical cancer. We evaluated the clinical performance of potentially methylated genes as a triage assay for hrHPV-positive women.ResultsWe conducted a retrospective hospital-based case–control study in Taiwan. Cervical scrapings were collected before colposcopy for hrHPV testing and quantitative methylation-specific PCR (QMSP) of 16 genes. Five genes, POU4F3, HS3ST2, AJAP1, PAX1, and SOX1, were prioritized for the clinical performance to triage hrHPV-positive women. Two hundred cervical scrapings were randomly classified into a training set (n = 111) and testing set (n = 89). All samples were tested for hrHPV using a Hybrid Capture II (HCII) assay. HrHPV-positive women were subjected to DNA methylation analysis by QMSP. In the training set, the receiver operating characteristic (ROC) curves defined the optimal methylation index (M-index) cutoff values for discriminating CIN3+ from CIN1/normal, which then were applied to the testing set. Among the five genes, POU4F3 revealed the highest area under the ROC curve (AUC) (0.86; 95 % CI, 0.78–0.95) in detecting CIN3+. In the testing set, POU4F3 revealed the best clinical performance in triage of hrHPV-positive women with a sensitivity of 74 % and specificity of 89 % for detecting CIN3+.ConclusionsPOU4F3 methylation analysis is a potential molecular tool for triage in detecting CIN3+ in hrHPV-positive women. The combined use of broad-spectrum HPV assay and POU4F3 methylation analysis as a new generation of molecular cervical cancer screening warrants further population-based study.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0122-0) contains supplementary material, which is available to authorized users.

Primary hrHPV DNA Testing in Cervical Cancer Screening: How to Manage Screen-Positive Women? A POBASCAM Trial Substudy

High-risk human papillomavirus (hrHPV) testing has higher sensitivity but lower specificity than cytology for cervical (pre)-cancerous lesions. Therefore, triage of hrHPV-positive women is needed in cervical cancer screening. A cohort of 1,100 hrHPV-positive women, from a population-based screening trial (POBASCAM: n = 44,938; 29-61 years), was used to evaluate 10 triage strategies, involving testing at baseline and six months with combinations of cytology, HPV16/18 genotyping, and/or repeat hrHPV testing. Clinical endpoint was cervical intraepithelial neoplasia grade 3 or worse (CIN3(+)) detected within four years; results were adjusted for women not attending repeat testing. A triage strategy was considered acceptable, when the probability of no CIN3(+) after negative triage (negative predictive value, NPV) was at least 98%, and the CIN3(+) risk after positive triage (positive predictive value, PPV) was at least 20%. Triage at baseline with cytology only yielded an NPV of 94.3% [95% confidence interval (CI), 92.0-96.0] and a PPV of 39.7% (95% CI, 34.0-45.6). An increase in NPV, against a modest decrease in PPV, was obtained by triaging women with negative baseline cytology by repeat cytology (NPV 98.5% and PPV 34.0%) or by baseline HPV16/18 genotyping (NPV 98.8% and PPV 28.5%). The inclusion of both HPV16/18 genotyping at baseline and repeat cytology testing provided a high NPV (99.6%) and a moderately high PPV (25.6%). Triaging hrHPV-positive women by cytology at baseline and after 6 to 12 months, possibly in combination with baseline HPV16/18 genotyping, seems acceptable for cervical cancer screening. Implementable triage strategies are provided for primary hrHPV screening in an organized setting.