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Nicolas Wentzensen - One of the best experts on this subject based on the ideXlab platform.

  • identification of hpv genotypes causing cervical Precancer using tissue based genotyping
    International Journal of Cancer, 2020
    Co-Authors: Rebecca Venetianer, Mark Schiffman, Joan L Walker, Rosemary E Zuna, Megan A Clarke, Jacolien Van Der Marel, Joseph E Tota, Samuel Terence Dunn, Wim Quint, Nicolas Wentzensen
    Abstract:

    Identification of high-risk human papillomavirus genotypes causing cervical Precancer is crucial for informing HPV vaccine development and efficacy studies, and for determining which types to include in next-generation genotyping assays. Co-occurrence of hrHPV infections is common and complicates carcinogenicity assessment; accurate attribution requires tissue-based genotyping of Precancers. We included all women with cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) from the Biopsy Study, an observational study of 690 women enrolled between 2009 and 2012 at the University of Oklahoma. Tissue-based genotyping, including whole tissue sections (WTS) and laser-capture microdissection (LCM), was performed on all Precancers with multiple hrHPV infections detected in cytology, totaling over 1,800 HPV genotyping assays. Genotype attribution was compared to hierarchical and proportional hrHPV-type attribution models. Of 276 women with CIN2+, 122 (44.2%) had multiple hrHPV genotypes in cytology. Of 114 women with genotyping data, 94 had one or more hrHPV detected in tissue. Seventy-one women (75.5%) had a single causal hrHPV genotype, while 23 women had multiple hrHPV genotypes causing CIN2+. Ten women had multiple causal infections in a single biopsy, contrary to the previous notion that each lesion is caused by a single type only. While HPV16 was the predominant causal hrHPV genotype using all approaches, the hierarchical model overattributed HPV16, whereas other causal hrHPV genotypes, particularly HPV18 and HPV35, were underattributed. Understanding true causal genotypes is important for the evaluation of vaccine efficacy, to estimate the extent of unmasking, and for type-specific risk assessment in screening and management.

  • 5 year prospective evaluation of cytology human papillomavirus testing and biomarkers for detection of anal Precancer in human immunodeficiency virus positive men who have sex with men
    Clinical Infectious Diseases, 2019
    Co-Authors: Megan A Clarke, Teresa M Darragh, Philip E Castle, Li C Cheung, Diane Tokugawa, Thomas Lorey, Julia C Gage, Brad Hare, Rebecca Landy, Nicolas Wentzensen
    Abstract:

    Author(s): Clarke, Megan A; Cheung, Li C; Lorey, Thomas; Hare, Brad; Landy, Rebecca; Tokugawa, Diane; Gage, Julia C; Darragh, Teresa M; Castle, Philip E; Wentzensen, Nicolas | Abstract: BackgroundHuman papillomavirus (HPV)-related biomarkers have shown good cross-sectional performance for anal Precancer detection in human immunodeficiency virus-positive (HIV+) men who have sex with men (MSM). However, the long-term performance and risk stratification of these biomarkers are unknown. Here, we prospectively evaluated high-risk (HR) HPV DNA, HPV16/18 genotyping, HPV E6/E7 messenger RNA (mRNA), and p16/Ki-67 dual stain in a population of HIV+ MSM.MethodsWe enrolled 363 HIV+ MSM between 2009-2010, with passive follow-up through 2015. All had anal cytology and a high-resolution anoscopy at baseline. For each biomarker, we calculated the baseline sensitivity and specificity for a combined endpoint of high-grade squamous intraepithelial lesion (HSIL) and anal intraepithelial neoplasia grade 2 or more severe diagnoses (HSIL/AIN2+), and we estimated the 2- and 5-year cumulative risks of HSIL/AIN2+ using logistic and Cox regression models.ResultsThere were 129 men diagnosed with HSIL/AIN2+ during the study. HR-HPV testing had the highest positivity and sensitivity of all assays, but the lowest specificity. HPV16/18 and HPV E6/E7 mRNA had high specificity, but lower sensitivity. The 2- and 5-year risks of HSIL/AIN2+ were highest for those testing HPV16/18- or HPV E6/E7 mRNA-positive, followed by those testing dual stain-positive. Those testing HR-HPV- or dual stain-negative had the lowest 2- and 5-year risks of HSIL/AIN2+.ConclusionsHPV-related biomarkers provide long-term risk stratification for anal Precancers. HR-HPV- and dual stain-negativity indicate a low risk of HSIL/AIN2+ for at least 2 years, compared with negative anal cytology; however, the high positivity of HR-HPV in HIV+ MSM may limit its utility for surveillance and management in this population.

  • five year risk of cervical Precancer following p16 ki 67 dual stain triage of hpv positive women
    JAMA Oncology, 2019
    Co-Authors: Megan A Clarke, Mark Schiffman, Philip E Castle, Li C Cheung, Diane Tokugawa, Nancy Poitras, Thomas Lorey, Walter Kinney, Nicolas Wentzensen
    Abstract:

    Importance As cervical cancer screening transitions to primary human papillomavirus (HPV) testing, effective triage and management of HPV-positive women is critical to avoid unnecessary colposcopy referral and associated harms while maintaining high sensitivity for cervical Precancer. Triage with p16/Ki-67 dual-stain (DS) testing has shown high sensitivity and specificity for detection of cervical Precancers; however, longitudinal studies are needed to determine the long-term risk of Precancer following a negative DS result. Objective To evaluate the longitudinal performance of p16/Ki-67 DS triage for detection of cervical Precancer in HPV-positive women over 5 years of follow-up in the context of clinical management thresholds. Design, Setting, and Participants Prospective cohort study of HPV-positive women 30 years or older undergoing routine cervical cancer screening in 2012 with HPV and Papanicolaou (hereinafter “cytology”) co-testing within the Kaiser Permanente Northern California health care system. Follow-up of medical records was conducted through 2017. Exposures All p16/Ki-67 DS testing was performed on residual SurePath material, and slides were evaluated for p16/Ki-67 positivity. Main Outcomes and Measures Histological end points were ascertained from the clinical database through 2017. We estimated 5-year cumulative risks of cervical intraepithelial neoplasia grades of 2 or worse (≥CIN2) or grades 3 or worse (≥CIN3) by baseline DS and cytology at yearly intervals using Logistic Weibull models. Risks were compared with clinical management thresholds for colposcopy referral and a 1-year return interval. Results Among the 1549 HPV-positive women in this study, the mean age at enrollment was 42.2 years, and the median follow-up time was 3.7 years (range, 0.2-5.4 years). Positive DS results were associated with significantly higher cumulative 5-year risks of ≥CIN2 compared with abnormal cytology (31.0%; 95% CI, 27.2%-35.3% vs 25.0%; 95% CI, 21.7%-28.7%;P = .03). Women with DS-negative findings had significantly lower 5-year risks of ≥CIN2 compared with women with normal cytology (8.5%; 95% CI, 6.5%-11.1% vs 12.3%; 95% CI, 9.8%-15.4%;P = .04). In DS-negative women, the risks of both ≥CIN2 and ≥CIN3 remained below the colposcopy referral threshold for all 5 years, crossing the 1-year return threshold at 3 years. Conclusions and Relevance Triage with p16/Ki-67 DS provides better long-term risk stratification than cytology over 5 years. The low risk of cervical Precancer in p16/Ki-67 DS–negative women permits safe extension of follow-up intervals for 3 years.

  • a prospective study of risk based colposcopy demonstrates improved detection of cervical Precancers
    American Journal of Obstetrics and Gynecology, 2018
    Co-Authors: Nicolas Wentzensen, Stewart L Massad, Michelle I Silver, Michael A Gold, Katie M Smith, Joan L Walker, Rosemary E Zuna, Angela Liu, Terence S Dunn, Mark Schiffman
    Abstract:

    Background Sensitivity for detection of Precancers at colposcopy and reassurance provided by a negative colposcopy are in need of systematic study and improvement. Objective We sought to evaluate whether selecting the appropriate women for multiple targeted cervical biopsies based on screening cytology, human papillomavirus testing, and colposcopic impression could improve accuracy and efficiency of cervical Precancer detection. Study Design In all, 690 women aged 18-67 years referred to colposcopy subsequent to abnormal cervical cancer screening results were included in the study (ClinicalTrials.gov: NCT00339989 ). Up to 4 cervical biopsies were taken during colposcopy to evaluate the incremental benefit of multiple biopsies. Cervical cytology, human papillomavirus genotyping, and colposcopy impression were used to establish up to 24 different risk strata. Outcomes for the primary analysis were cervical Precancers, which included p16 + cervical intraepithelial neoplasia 2 and all cervical intraepithelial neoplasia 3 that were detected by colposcopy-guided biopsy during the colposcopy visit. Later outcomes in women without cervical intraepithelial neoplasia 2 + at baseline were abstracted from electronic medical records. Results The risk of detecting Precancer ranged from 2-82% across 24 strata based on colposcopy impression, cytology, and human papillomavirus genotyping. The risk of Precancer in the lowest stratum increased only marginally with multiple biopsies. Women in the highest-risk strata had risks of Precancer consistent with immediate treatment. In other risk strata, multiple biopsies substantially improved detection of cervical Precancer. Among 361 women with cervical intraepithelial neoplasia Conclusion Risk assessment at the colposcopy visit makes identification of cervical Precancers more effective and efficient. Not finding Precancer after a multiple-biopsy protocol provides high reassurance and allows releasing women back to regular screening.

  • epidemiologic evidence that excess body weight increases risk of cervical cancer by decreased detection of Precancer
    Journal of Clinical Oncology, 2018
    Co-Authors: Megan A Clarke, Nicolas Wentzensen, Li C Cheung, Hormuzd A Katki, Barbara Fetterman, Julia C Gage, Brian Befano, Maria Demarco, John Schussler, Walter Kinney
    Abstract:

    PurposeObesity has been inconsistently linked to increased cervical cancer incidence and mortality; however, the effect of obesity on cervical screening has not been explored. We investigated the hypothesis that increased body mass might decrease detection of cervical Precancer and increase risk of cervical cancer even in women undergoing state-of-the-art screening.MethodsWe conducted a retrospective cohort study of 944,227 women age 30 to 64 years who underwent cytology and human papillomavirus DNA testing (ie, cotesting) at Kaiser Permanente Northern California (January 2003 to December 2015). Body mass index was categorized as normal/underweight (< 25 kg/m2), overweight (25 to < 30 kg/m2), or obese (≥ 30 kg/m2). We estimated 5-year cumulative risks of cervical Precancer and cancer by category of body mass index using logistic Weibull survival models.ResultsWe observed lower risk of cervical Precancer (n = 4,489) and higher risk of cervical cancer (n = 490) with increasing body mass index. Specifically,...

Philip E Castle - One of the best experts on this subject based on the ideXlab platform.

  • genetic and epigenetic variations of hpv52 in cervical Precancer
    International Journal of Molecular Sciences, 2021
    Co-Authors: Katharine J Bee, Mark Schiffman, Philip E Castle, Ariana Harari, Zigui Chen, Tina Rainebennett, Ana Gradissimo, Megan A Clarke
    Abstract:

    The goal of this study was to identify human papillomavirus (HPV) type 52 genetic and epigenetic changes associated with high-grade cervical Precancer and cancer. Patients were selected from the HPV Persistence and Progression (PaP) cohort, a cervical cancer screening program at Kaiser Permanente Northern California (KPNC). We performed a nested case-control study of 89 HPV52-positive women, including 50 cases with predominantly cervical intraepithelial neoplasia grade 3 (CIN3) and 39 controls without evidence of abnormalities. We conducted methylation analyses using Illumina sequencing and viral whole genome Sanger sequencing. Of the 24 CpG sites examined, increased methylation at CpG site 5615 in HPV52 L1 region was the most significantly associated with CIN3, with a difference in median methylation of 17.9% (odds ratio (OR) = 4.8, 95% confidence interval (CI) = 1.9-11.8) and an area under the curve of 0.73 (AUC; 95% CI = 0.62-0.83). Complete genomic sequencing of HPV52 isolates revealed associations between SNPs present in sublineage C2 and a higher risk of CIN3, with ORs ranging from 2.8 to 3.3. This study identified genetic and epigenetic HPV52 variants associated with high risk for cervical Precancer, improving the potential for early diagnosis of cervical neoplasia caused by HPV52.

  • 5 year prospective evaluation of cytology human papillomavirus testing and biomarkers for detection of anal Precancer in human immunodeficiency virus positive men who have sex with men
    Clinical Infectious Diseases, 2019
    Co-Authors: Megan A Clarke, Teresa M Darragh, Philip E Castle, Li C Cheung, Diane Tokugawa, Thomas Lorey, Julia C Gage, Brad Hare, Rebecca Landy, Nicolas Wentzensen
    Abstract:

    Author(s): Clarke, Megan A; Cheung, Li C; Lorey, Thomas; Hare, Brad; Landy, Rebecca; Tokugawa, Diane; Gage, Julia C; Darragh, Teresa M; Castle, Philip E; Wentzensen, Nicolas | Abstract: BackgroundHuman papillomavirus (HPV)-related biomarkers have shown good cross-sectional performance for anal Precancer detection in human immunodeficiency virus-positive (HIV+) men who have sex with men (MSM). However, the long-term performance and risk stratification of these biomarkers are unknown. Here, we prospectively evaluated high-risk (HR) HPV DNA, HPV16/18 genotyping, HPV E6/E7 messenger RNA (mRNA), and p16/Ki-67 dual stain in a population of HIV+ MSM.MethodsWe enrolled 363 HIV+ MSM between 2009-2010, with passive follow-up through 2015. All had anal cytology and a high-resolution anoscopy at baseline. For each biomarker, we calculated the baseline sensitivity and specificity for a combined endpoint of high-grade squamous intraepithelial lesion (HSIL) and anal intraepithelial neoplasia grade 2 or more severe diagnoses (HSIL/AIN2+), and we estimated the 2- and 5-year cumulative risks of HSIL/AIN2+ using logistic and Cox regression models.ResultsThere were 129 men diagnosed with HSIL/AIN2+ during the study. HR-HPV testing had the highest positivity and sensitivity of all assays, but the lowest specificity. HPV16/18 and HPV E6/E7 mRNA had high specificity, but lower sensitivity. The 2- and 5-year risks of HSIL/AIN2+ were highest for those testing HPV16/18- or HPV E6/E7 mRNA-positive, followed by those testing dual stain-positive. Those testing HR-HPV- or dual stain-negative had the lowest 2- and 5-year risks of HSIL/AIN2+.ConclusionsHPV-related biomarkers provide long-term risk stratification for anal Precancers. HR-HPV- and dual stain-negativity indicate a low risk of HSIL/AIN2+ for at least 2 years, compared with negative anal cytology; however, the high positivity of HR-HPV in HIV+ MSM may limit its utility for surveillance and management in this population.

  • five year risk of cervical Precancer following p16 ki 67 dual stain triage of hpv positive women
    JAMA Oncology, 2019
    Co-Authors: Megan A Clarke, Mark Schiffman, Philip E Castle, Li C Cheung, Diane Tokugawa, Nancy Poitras, Thomas Lorey, Walter Kinney, Nicolas Wentzensen
    Abstract:

    Importance As cervical cancer screening transitions to primary human papillomavirus (HPV) testing, effective triage and management of HPV-positive women is critical to avoid unnecessary colposcopy referral and associated harms while maintaining high sensitivity for cervical Precancer. Triage with p16/Ki-67 dual-stain (DS) testing has shown high sensitivity and specificity for detection of cervical Precancers; however, longitudinal studies are needed to determine the long-term risk of Precancer following a negative DS result. Objective To evaluate the longitudinal performance of p16/Ki-67 DS triage for detection of cervical Precancer in HPV-positive women over 5 years of follow-up in the context of clinical management thresholds. Design, Setting, and Participants Prospective cohort study of HPV-positive women 30 years or older undergoing routine cervical cancer screening in 2012 with HPV and Papanicolaou (hereinafter “cytology”) co-testing within the Kaiser Permanente Northern California health care system. Follow-up of medical records was conducted through 2017. Exposures All p16/Ki-67 DS testing was performed on residual SurePath material, and slides were evaluated for p16/Ki-67 positivity. Main Outcomes and Measures Histological end points were ascertained from the clinical database through 2017. We estimated 5-year cumulative risks of cervical intraepithelial neoplasia grades of 2 or worse (≥CIN2) or grades 3 or worse (≥CIN3) by baseline DS and cytology at yearly intervals using Logistic Weibull models. Risks were compared with clinical management thresholds for colposcopy referral and a 1-year return interval. Results Among the 1549 HPV-positive women in this study, the mean age at enrollment was 42.2 years, and the median follow-up time was 3.7 years (range, 0.2-5.4 years). Positive DS results were associated with significantly higher cumulative 5-year risks of ≥CIN2 compared with abnormal cytology (31.0%; 95% CI, 27.2%-35.3% vs 25.0%; 95% CI, 21.7%-28.7%;P = .03). Women with DS-negative findings had significantly lower 5-year risks of ≥CIN2 compared with women with normal cytology (8.5%; 95% CI, 6.5%-11.1% vs 12.3%; 95% CI, 9.8%-15.4%;P = .04). In DS-negative women, the risks of both ≥CIN2 and ≥CIN3 remained below the colposcopy referral threshold for all 5 years, crossing the 1-year return threshold at 3 years. Conclusions and Relevance Triage with p16/Ki-67 DS provides better long-term risk stratification than cytology over 5 years. The low risk of cervical Precancer in p16/Ki-67 DS–negative women permits safe extension of follow-up intervals for 3 years.

  • human papillomavirus dna methylation as a biomarker for cervical Precancer consistency across 12 genotypes and potential impact on management of hpv positive women
    Clinical Cancer Research, 2018
    Co-Authors: Megan A Clarke, Mark Schiffman, Nancy Poitras, Thomas Lorey, Barbara Fetterman, Tina Rainebennett, Ana Gradissimo, Jessica Lam, Christopher C Sollecito, Philip E Castle
    Abstract:

    Purpose: Human papillomavirus (HPV) DNA methylation testing is a promising triage option for women testing HPV positive during cervical cancer screening. However, the extent to which methylation indicates Precancer for all 12 carcinogenic HPV types has not been evaluated.Experimental Design: In this nested case-control study, we tested up to 30 cases of Precancer [cervical intraepithelial neoplasia grade 3 (CIN3)/adenocarcinoma in situ (AIS)] and 30 normal controls for each carcinogenic type (single infections with 16/18/31/33/35/39/45/51/52/56/58/59). Next-generation bisulfite sequencing was performed on CpG sites within the L1 and L2 genes. We calculated differences in methylation, ORs, and AUC. Using a fixed sensitivity of 80%, we evaluated the specificity and the risk of CIN3/AIS for best performing CpG sites, and compared the performance of an explorative multi-type methylation assay with current triage strategies.Results: Methylation was positively associated with CIN3/AIS across all 12 types. AUCs for the top sites ranged from 0.71 (HPV51 and HPV56) to 0.86 (HPV18). A combined 12-type methylation assay had the highest Youden index (0.46), compared with cytology (0.31) and a 5-type methylation assay, including only previously described types (0.26). The 12-type methylation assay had higher sensitivity (80% vs. 76.6%) and lower test positivity compared with cytology (38.5% vs. 48.7%). The risk of CIN3/AIS was highest for methylation positives and lowest for cytology or HPV16/18 positives.Conclusions: HPV DNA methylation is a general phenomenon marking the transition from HPV infection to Precancer for all 12 carcinogenic types. Development of a combined multitype methylation assay may serve as a triage test for HPV-positive women. Clin Cancer Res; 24(9); 2194-202. ©2018 AACR.

  • the population impact of human papillomavirus cytology cervical cotesting at 3 year intervals reduced cervical cancer risk and decreased yield of Precancer per screen
    Cancer, 2016
    Co-Authors: Michelle I Silver, Mark Schiffman, Nicolas Wentzensen, Thomas Lorey, Walter Kinney, Barbara Fetterman, Julia C Gage, Nancy E Poitras, Philip E Castle
    Abstract:

    BACKGROUND The objective of cervical screening is to detect and treat Precancer to prevent cervical cancer mortality and morbidity while minimizing overtreatment of benign human papillomavirus (HPV) infections and related minor abnormalities. HPV/cytology cotesting at extended 5-year intervals currently is a recommended screening strategy in the United States, but the interval extension is controversial. In the current study, the authors examined the impact of a decade of an alternative, 3-year cotesting, on rates of Precancer and cancer at Kaiser Permanente Northern California. The effect on screening efficiency, defined as numbers of cotests/colposcopy visits needed to detect a Precancer, also was considered. METHODS Two cohorts were defined. The “open cohort” included all women screened at least once during the study period; > 1 million cotests were performed. In a fixed “long-term screening cohort,” the authors considered the cumulative impact of repeated screening at 3-year intervals by restricting the cohort to women first cotested in 2003 through 2004 (ie, no women entering screening later were added to this group). RESULTS Detection of cervical intraepithelial neoplasia 3/adenocarcinoma in situ (CIN3/AIS) increased in the open cohort (2004-2006: 82.0/100,000 women screened; 2007-2009: 140.6/100,000 women screened; and 2010-2012: 126.0/100,000 women screened); cancer diagnoses were unchanged. In the long-term screening cohort, the detection of CIN3/AIS increased and then decreased to the original level (2004-2006: 80.5/100,000 women screened; 2007-2009: 118.6/100,000 women screened; and 2010-2012: 84.9./100,000 women screened). The number of cancer diagnoses was found to decrease. When viewed in terms of screening efficiency, the number of colposcopies performed to detect a single case of CIN3/AIS increased in the cohort with repeat screening. CONCLUSIONS Repeated cotesting at a 3-year interval eventually lowers population rates of Precancer and cancer. However, a greater number of colposcopies are required to detect a single Precancer. Cancer 2016. © 2016 American Cancer Society.

Mark Schiffman - One of the best experts on this subject based on the ideXlab platform.

  • genetic and epigenetic variations of hpv52 in cervical Precancer
    International Journal of Molecular Sciences, 2021
    Co-Authors: Katharine J Bee, Mark Schiffman, Philip E Castle, Ariana Harari, Zigui Chen, Tina Rainebennett, Ana Gradissimo, Megan A Clarke
    Abstract:

    The goal of this study was to identify human papillomavirus (HPV) type 52 genetic and epigenetic changes associated with high-grade cervical Precancer and cancer. Patients were selected from the HPV Persistence and Progression (PaP) cohort, a cervical cancer screening program at Kaiser Permanente Northern California (KPNC). We performed a nested case-control study of 89 HPV52-positive women, including 50 cases with predominantly cervical intraepithelial neoplasia grade 3 (CIN3) and 39 controls without evidence of abnormalities. We conducted methylation analyses using Illumina sequencing and viral whole genome Sanger sequencing. Of the 24 CpG sites examined, increased methylation at CpG site 5615 in HPV52 L1 region was the most significantly associated with CIN3, with a difference in median methylation of 17.9% (odds ratio (OR) = 4.8, 95% confidence interval (CI) = 1.9-11.8) and an area under the curve of 0.73 (AUC; 95% CI = 0.62-0.83). Complete genomic sequencing of HPV52 isolates revealed associations between SNPs present in sublineage C2 and a higher risk of CIN3, with ORs ranging from 2.8 to 3.3. This study identified genetic and epigenetic HPV52 variants associated with high risk for cervical Precancer, improving the potential for early diagnosis of cervical neoplasia caused by HPV52.

  • identification of hpv genotypes causing cervical Precancer using tissue based genotyping
    International Journal of Cancer, 2020
    Co-Authors: Rebecca Venetianer, Mark Schiffman, Joan L Walker, Rosemary E Zuna, Megan A Clarke, Jacolien Van Der Marel, Joseph E Tota, Samuel Terence Dunn, Wim Quint, Nicolas Wentzensen
    Abstract:

    Identification of high-risk human papillomavirus genotypes causing cervical Precancer is crucial for informing HPV vaccine development and efficacy studies, and for determining which types to include in next-generation genotyping assays. Co-occurrence of hrHPV infections is common and complicates carcinogenicity assessment; accurate attribution requires tissue-based genotyping of Precancers. We included all women with cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) from the Biopsy Study, an observational study of 690 women enrolled between 2009 and 2012 at the University of Oklahoma. Tissue-based genotyping, including whole tissue sections (WTS) and laser-capture microdissection (LCM), was performed on all Precancers with multiple hrHPV infections detected in cytology, totaling over 1,800 HPV genotyping assays. Genotype attribution was compared to hierarchical and proportional hrHPV-type attribution models. Of 276 women with CIN2+, 122 (44.2%) had multiple hrHPV genotypes in cytology. Of 114 women with genotyping data, 94 had one or more hrHPV detected in tissue. Seventy-one women (75.5%) had a single causal hrHPV genotype, while 23 women had multiple hrHPV genotypes causing CIN2+. Ten women had multiple causal infections in a single biopsy, contrary to the previous notion that each lesion is caused by a single type only. While HPV16 was the predominant causal hrHPV genotype using all approaches, the hierarchical model overattributed HPV16, whereas other causal hrHPV genotypes, particularly HPV18 and HPV35, were underattributed. Understanding true causal genotypes is important for the evaluation of vaccine efficacy, to estimate the extent of unmasking, and for type-specific risk assessment in screening and management.

  • five year risk of cervical Precancer following p16 ki 67 dual stain triage of hpv positive women
    JAMA Oncology, 2019
    Co-Authors: Megan A Clarke, Mark Schiffman, Philip E Castle, Li C Cheung, Diane Tokugawa, Nancy Poitras, Thomas Lorey, Walter Kinney, Nicolas Wentzensen
    Abstract:

    Importance As cervical cancer screening transitions to primary human papillomavirus (HPV) testing, effective triage and management of HPV-positive women is critical to avoid unnecessary colposcopy referral and associated harms while maintaining high sensitivity for cervical Precancer. Triage with p16/Ki-67 dual-stain (DS) testing has shown high sensitivity and specificity for detection of cervical Precancers; however, longitudinal studies are needed to determine the long-term risk of Precancer following a negative DS result. Objective To evaluate the longitudinal performance of p16/Ki-67 DS triage for detection of cervical Precancer in HPV-positive women over 5 years of follow-up in the context of clinical management thresholds. Design, Setting, and Participants Prospective cohort study of HPV-positive women 30 years or older undergoing routine cervical cancer screening in 2012 with HPV and Papanicolaou (hereinafter “cytology”) co-testing within the Kaiser Permanente Northern California health care system. Follow-up of medical records was conducted through 2017. Exposures All p16/Ki-67 DS testing was performed on residual SurePath material, and slides were evaluated for p16/Ki-67 positivity. Main Outcomes and Measures Histological end points were ascertained from the clinical database through 2017. We estimated 5-year cumulative risks of cervical intraepithelial neoplasia grades of 2 or worse (≥CIN2) or grades 3 or worse (≥CIN3) by baseline DS and cytology at yearly intervals using Logistic Weibull models. Risks were compared with clinical management thresholds for colposcopy referral and a 1-year return interval. Results Among the 1549 HPV-positive women in this study, the mean age at enrollment was 42.2 years, and the median follow-up time was 3.7 years (range, 0.2-5.4 years). Positive DS results were associated with significantly higher cumulative 5-year risks of ≥CIN2 compared with abnormal cytology (31.0%; 95% CI, 27.2%-35.3% vs 25.0%; 95% CI, 21.7%-28.7%;P = .03). Women with DS-negative findings had significantly lower 5-year risks of ≥CIN2 compared with women with normal cytology (8.5%; 95% CI, 6.5%-11.1% vs 12.3%; 95% CI, 9.8%-15.4%;P = .04). In DS-negative women, the risks of both ≥CIN2 and ≥CIN3 remained below the colposcopy referral threshold for all 5 years, crossing the 1-year return threshold at 3 years. Conclusions and Relevance Triage with p16/Ki-67 DS provides better long-term risk stratification than cytology over 5 years. The low risk of cervical Precancer in p16/Ki-67 DS–negative women permits safe extension of follow-up intervals for 3 years.

  • a prospective study of risk based colposcopy demonstrates improved detection of cervical Precancers
    American Journal of Obstetrics and Gynecology, 2018
    Co-Authors: Nicolas Wentzensen, Stewart L Massad, Michelle I Silver, Michael A Gold, Katie M Smith, Joan L Walker, Rosemary E Zuna, Angela Liu, Terence S Dunn, Mark Schiffman
    Abstract:

    Background Sensitivity for detection of Precancers at colposcopy and reassurance provided by a negative colposcopy are in need of systematic study and improvement. Objective We sought to evaluate whether selecting the appropriate women for multiple targeted cervical biopsies based on screening cytology, human papillomavirus testing, and colposcopic impression could improve accuracy and efficiency of cervical Precancer detection. Study Design In all, 690 women aged 18-67 years referred to colposcopy subsequent to abnormal cervical cancer screening results were included in the study (ClinicalTrials.gov: NCT00339989 ). Up to 4 cervical biopsies were taken during colposcopy to evaluate the incremental benefit of multiple biopsies. Cervical cytology, human papillomavirus genotyping, and colposcopy impression were used to establish up to 24 different risk strata. Outcomes for the primary analysis were cervical Precancers, which included p16 + cervical intraepithelial neoplasia 2 and all cervical intraepithelial neoplasia 3 that were detected by colposcopy-guided biopsy during the colposcopy visit. Later outcomes in women without cervical intraepithelial neoplasia 2 + at baseline were abstracted from electronic medical records. Results The risk of detecting Precancer ranged from 2-82% across 24 strata based on colposcopy impression, cytology, and human papillomavirus genotyping. The risk of Precancer in the lowest stratum increased only marginally with multiple biopsies. Women in the highest-risk strata had risks of Precancer consistent with immediate treatment. In other risk strata, multiple biopsies substantially improved detection of cervical Precancer. Among 361 women with cervical intraepithelial neoplasia Conclusion Risk assessment at the colposcopy visit makes identification of cervical Precancers more effective and efficient. Not finding Precancer after a multiple-biopsy protocol provides high reassurance and allows releasing women back to regular screening.

  • human papillomavirus dna methylation as a biomarker for cervical Precancer consistency across 12 genotypes and potential impact on management of hpv positive women
    Clinical Cancer Research, 2018
    Co-Authors: Megan A Clarke, Mark Schiffman, Nancy Poitras, Thomas Lorey, Barbara Fetterman, Tina Rainebennett, Ana Gradissimo, Jessica Lam, Christopher C Sollecito, Philip E Castle
    Abstract:

    Purpose: Human papillomavirus (HPV) DNA methylation testing is a promising triage option for women testing HPV positive during cervical cancer screening. However, the extent to which methylation indicates Precancer for all 12 carcinogenic HPV types has not been evaluated.Experimental Design: In this nested case-control study, we tested up to 30 cases of Precancer [cervical intraepithelial neoplasia grade 3 (CIN3)/adenocarcinoma in situ (AIS)] and 30 normal controls for each carcinogenic type (single infections with 16/18/31/33/35/39/45/51/52/56/58/59). Next-generation bisulfite sequencing was performed on CpG sites within the L1 and L2 genes. We calculated differences in methylation, ORs, and AUC. Using a fixed sensitivity of 80%, we evaluated the specificity and the risk of CIN3/AIS for best performing CpG sites, and compared the performance of an explorative multi-type methylation assay with current triage strategies.Results: Methylation was positively associated with CIN3/AIS across all 12 types. AUCs for the top sites ranged from 0.71 (HPV51 and HPV56) to 0.86 (HPV18). A combined 12-type methylation assay had the highest Youden index (0.46), compared with cytology (0.31) and a 5-type methylation assay, including only previously described types (0.26). The 12-type methylation assay had higher sensitivity (80% vs. 76.6%) and lower test positivity compared with cytology (38.5% vs. 48.7%). The risk of CIN3/AIS was highest for methylation positives and lowest for cytology or HPV16/18 positives.Conclusions: HPV DNA methylation is a general phenomenon marking the transition from HPV infection to Precancer for all 12 carcinogenic types. Development of a combined multitype methylation assay may serve as a triage test for HPV-positive women. Clin Cancer Res; 24(9); 2194-202. ©2018 AACR.

Megan A Clarke - One of the best experts on this subject based on the ideXlab platform.

  • genetic and epigenetic variations of hpv52 in cervical Precancer
    International Journal of Molecular Sciences, 2021
    Co-Authors: Katharine J Bee, Mark Schiffman, Philip E Castle, Ariana Harari, Zigui Chen, Tina Rainebennett, Ana Gradissimo, Megan A Clarke
    Abstract:

    The goal of this study was to identify human papillomavirus (HPV) type 52 genetic and epigenetic changes associated with high-grade cervical Precancer and cancer. Patients were selected from the HPV Persistence and Progression (PaP) cohort, a cervical cancer screening program at Kaiser Permanente Northern California (KPNC). We performed a nested case-control study of 89 HPV52-positive women, including 50 cases with predominantly cervical intraepithelial neoplasia grade 3 (CIN3) and 39 controls without evidence of abnormalities. We conducted methylation analyses using Illumina sequencing and viral whole genome Sanger sequencing. Of the 24 CpG sites examined, increased methylation at CpG site 5615 in HPV52 L1 region was the most significantly associated with CIN3, with a difference in median methylation of 17.9% (odds ratio (OR) = 4.8, 95% confidence interval (CI) = 1.9-11.8) and an area under the curve of 0.73 (AUC; 95% CI = 0.62-0.83). Complete genomic sequencing of HPV52 isolates revealed associations between SNPs present in sublineage C2 and a higher risk of CIN3, with ORs ranging from 2.8 to 3.3. This study identified genetic and epigenetic HPV52 variants associated with high risk for cervical Precancer, improving the potential for early diagnosis of cervical neoplasia caused by HPV52.

  • identification of hpv genotypes causing cervical Precancer using tissue based genotyping
    International Journal of Cancer, 2020
    Co-Authors: Rebecca Venetianer, Mark Schiffman, Joan L Walker, Rosemary E Zuna, Megan A Clarke, Jacolien Van Der Marel, Joseph E Tota, Samuel Terence Dunn, Wim Quint, Nicolas Wentzensen
    Abstract:

    Identification of high-risk human papillomavirus genotypes causing cervical Precancer is crucial for informing HPV vaccine development and efficacy studies, and for determining which types to include in next-generation genotyping assays. Co-occurrence of hrHPV infections is common and complicates carcinogenicity assessment; accurate attribution requires tissue-based genotyping of Precancers. We included all women with cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) from the Biopsy Study, an observational study of 690 women enrolled between 2009 and 2012 at the University of Oklahoma. Tissue-based genotyping, including whole tissue sections (WTS) and laser-capture microdissection (LCM), was performed on all Precancers with multiple hrHPV infections detected in cytology, totaling over 1,800 HPV genotyping assays. Genotype attribution was compared to hierarchical and proportional hrHPV-type attribution models. Of 276 women with CIN2+, 122 (44.2%) had multiple hrHPV genotypes in cytology. Of 114 women with genotyping data, 94 had one or more hrHPV detected in tissue. Seventy-one women (75.5%) had a single causal hrHPV genotype, while 23 women had multiple hrHPV genotypes causing CIN2+. Ten women had multiple causal infections in a single biopsy, contrary to the previous notion that each lesion is caused by a single type only. While HPV16 was the predominant causal hrHPV genotype using all approaches, the hierarchical model overattributed HPV16, whereas other causal hrHPV genotypes, particularly HPV18 and HPV35, were underattributed. Understanding true causal genotypes is important for the evaluation of vaccine efficacy, to estimate the extent of unmasking, and for type-specific risk assessment in screening and management.

  • 5 year prospective evaluation of cytology human papillomavirus testing and biomarkers for detection of anal Precancer in human immunodeficiency virus positive men who have sex with men
    Clinical Infectious Diseases, 2019
    Co-Authors: Megan A Clarke, Teresa M Darragh, Philip E Castle, Li C Cheung, Diane Tokugawa, Thomas Lorey, Julia C Gage, Brad Hare, Rebecca Landy, Nicolas Wentzensen
    Abstract:

    Author(s): Clarke, Megan A; Cheung, Li C; Lorey, Thomas; Hare, Brad; Landy, Rebecca; Tokugawa, Diane; Gage, Julia C; Darragh, Teresa M; Castle, Philip E; Wentzensen, Nicolas | Abstract: BackgroundHuman papillomavirus (HPV)-related biomarkers have shown good cross-sectional performance for anal Precancer detection in human immunodeficiency virus-positive (HIV+) men who have sex with men (MSM). However, the long-term performance and risk stratification of these biomarkers are unknown. Here, we prospectively evaluated high-risk (HR) HPV DNA, HPV16/18 genotyping, HPV E6/E7 messenger RNA (mRNA), and p16/Ki-67 dual stain in a population of HIV+ MSM.MethodsWe enrolled 363 HIV+ MSM between 2009-2010, with passive follow-up through 2015. All had anal cytology and a high-resolution anoscopy at baseline. For each biomarker, we calculated the baseline sensitivity and specificity for a combined endpoint of high-grade squamous intraepithelial lesion (HSIL) and anal intraepithelial neoplasia grade 2 or more severe diagnoses (HSIL/AIN2+), and we estimated the 2- and 5-year cumulative risks of HSIL/AIN2+ using logistic and Cox regression models.ResultsThere were 129 men diagnosed with HSIL/AIN2+ during the study. HR-HPV testing had the highest positivity and sensitivity of all assays, but the lowest specificity. HPV16/18 and HPV E6/E7 mRNA had high specificity, but lower sensitivity. The 2- and 5-year risks of HSIL/AIN2+ were highest for those testing HPV16/18- or HPV E6/E7 mRNA-positive, followed by those testing dual stain-positive. Those testing HR-HPV- or dual stain-negative had the lowest 2- and 5-year risks of HSIL/AIN2+.ConclusionsHPV-related biomarkers provide long-term risk stratification for anal Precancers. HR-HPV- and dual stain-negativity indicate a low risk of HSIL/AIN2+ for at least 2 years, compared with negative anal cytology; however, the high positivity of HR-HPV in HIV+ MSM may limit its utility for surveillance and management in this population.

  • five year risk of cervical Precancer following p16 ki 67 dual stain triage of hpv positive women
    JAMA Oncology, 2019
    Co-Authors: Megan A Clarke, Mark Schiffman, Philip E Castle, Li C Cheung, Diane Tokugawa, Nancy Poitras, Thomas Lorey, Walter Kinney, Nicolas Wentzensen
    Abstract:

    Importance As cervical cancer screening transitions to primary human papillomavirus (HPV) testing, effective triage and management of HPV-positive women is critical to avoid unnecessary colposcopy referral and associated harms while maintaining high sensitivity for cervical Precancer. Triage with p16/Ki-67 dual-stain (DS) testing has shown high sensitivity and specificity for detection of cervical Precancers; however, longitudinal studies are needed to determine the long-term risk of Precancer following a negative DS result. Objective To evaluate the longitudinal performance of p16/Ki-67 DS triage for detection of cervical Precancer in HPV-positive women over 5 years of follow-up in the context of clinical management thresholds. Design, Setting, and Participants Prospective cohort study of HPV-positive women 30 years or older undergoing routine cervical cancer screening in 2012 with HPV and Papanicolaou (hereinafter “cytology”) co-testing within the Kaiser Permanente Northern California health care system. Follow-up of medical records was conducted through 2017. Exposures All p16/Ki-67 DS testing was performed on residual SurePath material, and slides were evaluated for p16/Ki-67 positivity. Main Outcomes and Measures Histological end points were ascertained from the clinical database through 2017. We estimated 5-year cumulative risks of cervical intraepithelial neoplasia grades of 2 or worse (≥CIN2) or grades 3 or worse (≥CIN3) by baseline DS and cytology at yearly intervals using Logistic Weibull models. Risks were compared with clinical management thresholds for colposcopy referral and a 1-year return interval. Results Among the 1549 HPV-positive women in this study, the mean age at enrollment was 42.2 years, and the median follow-up time was 3.7 years (range, 0.2-5.4 years). Positive DS results were associated with significantly higher cumulative 5-year risks of ≥CIN2 compared with abnormal cytology (31.0%; 95% CI, 27.2%-35.3% vs 25.0%; 95% CI, 21.7%-28.7%;P = .03). Women with DS-negative findings had significantly lower 5-year risks of ≥CIN2 compared with women with normal cytology (8.5%; 95% CI, 6.5%-11.1% vs 12.3%; 95% CI, 9.8%-15.4%;P = .04). In DS-negative women, the risks of both ≥CIN2 and ≥CIN3 remained below the colposcopy referral threshold for all 5 years, crossing the 1-year return threshold at 3 years. Conclusions and Relevance Triage with p16/Ki-67 DS provides better long-term risk stratification than cytology over 5 years. The low risk of cervical Precancer in p16/Ki-67 DS–negative women permits safe extension of follow-up intervals for 3 years.

  • human papillomavirus dna methylation as a biomarker for cervical Precancer consistency across 12 genotypes and potential impact on management of hpv positive women
    Clinical Cancer Research, 2018
    Co-Authors: Megan A Clarke, Mark Schiffman, Nancy Poitras, Thomas Lorey, Barbara Fetterman, Tina Rainebennett, Ana Gradissimo, Jessica Lam, Christopher C Sollecito, Philip E Castle
    Abstract:

    Purpose: Human papillomavirus (HPV) DNA methylation testing is a promising triage option for women testing HPV positive during cervical cancer screening. However, the extent to which methylation indicates Precancer for all 12 carcinogenic HPV types has not been evaluated.Experimental Design: In this nested case-control study, we tested up to 30 cases of Precancer [cervical intraepithelial neoplasia grade 3 (CIN3)/adenocarcinoma in situ (AIS)] and 30 normal controls for each carcinogenic type (single infections with 16/18/31/33/35/39/45/51/52/56/58/59). Next-generation bisulfite sequencing was performed on CpG sites within the L1 and L2 genes. We calculated differences in methylation, ORs, and AUC. Using a fixed sensitivity of 80%, we evaluated the specificity and the risk of CIN3/AIS for best performing CpG sites, and compared the performance of an explorative multi-type methylation assay with current triage strategies.Results: Methylation was positively associated with CIN3/AIS across all 12 types. AUCs for the top sites ranged from 0.71 (HPV51 and HPV56) to 0.86 (HPV18). A combined 12-type methylation assay had the highest Youden index (0.46), compared with cytology (0.31) and a 5-type methylation assay, including only previously described types (0.26). The 12-type methylation assay had higher sensitivity (80% vs. 76.6%) and lower test positivity compared with cytology (38.5% vs. 48.7%). The risk of CIN3/AIS was highest for methylation positives and lowest for cytology or HPV16/18 positives.Conclusions: HPV DNA methylation is a general phenomenon marking the transition from HPV infection to Precancer for all 12 carcinogenic types. Development of a combined multitype methylation assay may serve as a triage test for HPV-positive women. Clin Cancer Res; 24(9); 2194-202. ©2018 AACR.

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  • 5 year prospective evaluation of cytology human papillomavirus testing and biomarkers for detection of anal Precancer in human immunodeficiency virus positive men who have sex with men
    Clinical Infectious Diseases, 2019
    Co-Authors: Megan A Clarke, Teresa M Darragh, Philip E Castle, Li C Cheung, Diane Tokugawa, Thomas Lorey, Julia C Gage, Brad Hare, Rebecca Landy, Nicolas Wentzensen
    Abstract:

    Author(s): Clarke, Megan A; Cheung, Li C; Lorey, Thomas; Hare, Brad; Landy, Rebecca; Tokugawa, Diane; Gage, Julia C; Darragh, Teresa M; Castle, Philip E; Wentzensen, Nicolas | Abstract: BackgroundHuman papillomavirus (HPV)-related biomarkers have shown good cross-sectional performance for anal Precancer detection in human immunodeficiency virus-positive (HIV+) men who have sex with men (MSM). However, the long-term performance and risk stratification of these biomarkers are unknown. Here, we prospectively evaluated high-risk (HR) HPV DNA, HPV16/18 genotyping, HPV E6/E7 messenger RNA (mRNA), and p16/Ki-67 dual stain in a population of HIV+ MSM.MethodsWe enrolled 363 HIV+ MSM between 2009-2010, with passive follow-up through 2015. All had anal cytology and a high-resolution anoscopy at baseline. For each biomarker, we calculated the baseline sensitivity and specificity for a combined endpoint of high-grade squamous intraepithelial lesion (HSIL) and anal intraepithelial neoplasia grade 2 or more severe diagnoses (HSIL/AIN2+), and we estimated the 2- and 5-year cumulative risks of HSIL/AIN2+ using logistic and Cox regression models.ResultsThere were 129 men diagnosed with HSIL/AIN2+ during the study. HR-HPV testing had the highest positivity and sensitivity of all assays, but the lowest specificity. HPV16/18 and HPV E6/E7 mRNA had high specificity, but lower sensitivity. The 2- and 5-year risks of HSIL/AIN2+ were highest for those testing HPV16/18- or HPV E6/E7 mRNA-positive, followed by those testing dual stain-positive. Those testing HR-HPV- or dual stain-negative had the lowest 2- and 5-year risks of HSIL/AIN2+.ConclusionsHPV-related biomarkers provide long-term risk stratification for anal Precancers. HR-HPV- and dual stain-negativity indicate a low risk of HSIL/AIN2+ for at least 2 years, compared with negative anal cytology; however, the high positivity of HR-HPV in HIV+ MSM may limit its utility for surveillance and management in this population.

  • five year risk of cervical Precancer following p16 ki 67 dual stain triage of hpv positive women
    JAMA Oncology, 2019
    Co-Authors: Megan A Clarke, Mark Schiffman, Philip E Castle, Li C Cheung, Diane Tokugawa, Nancy Poitras, Thomas Lorey, Walter Kinney, Nicolas Wentzensen
    Abstract:

    Importance As cervical cancer screening transitions to primary human papillomavirus (HPV) testing, effective triage and management of HPV-positive women is critical to avoid unnecessary colposcopy referral and associated harms while maintaining high sensitivity for cervical Precancer. Triage with p16/Ki-67 dual-stain (DS) testing has shown high sensitivity and specificity for detection of cervical Precancers; however, longitudinal studies are needed to determine the long-term risk of Precancer following a negative DS result. Objective To evaluate the longitudinal performance of p16/Ki-67 DS triage for detection of cervical Precancer in HPV-positive women over 5 years of follow-up in the context of clinical management thresholds. Design, Setting, and Participants Prospective cohort study of HPV-positive women 30 years or older undergoing routine cervical cancer screening in 2012 with HPV and Papanicolaou (hereinafter “cytology”) co-testing within the Kaiser Permanente Northern California health care system. Follow-up of medical records was conducted through 2017. Exposures All p16/Ki-67 DS testing was performed on residual SurePath material, and slides were evaluated for p16/Ki-67 positivity. Main Outcomes and Measures Histological end points were ascertained from the clinical database through 2017. We estimated 5-year cumulative risks of cervical intraepithelial neoplasia grades of 2 or worse (≥CIN2) or grades 3 or worse (≥CIN3) by baseline DS and cytology at yearly intervals using Logistic Weibull models. Risks were compared with clinical management thresholds for colposcopy referral and a 1-year return interval. Results Among the 1549 HPV-positive women in this study, the mean age at enrollment was 42.2 years, and the median follow-up time was 3.7 years (range, 0.2-5.4 years). Positive DS results were associated with significantly higher cumulative 5-year risks of ≥CIN2 compared with abnormal cytology (31.0%; 95% CI, 27.2%-35.3% vs 25.0%; 95% CI, 21.7%-28.7%;P = .03). Women with DS-negative findings had significantly lower 5-year risks of ≥CIN2 compared with women with normal cytology (8.5%; 95% CI, 6.5%-11.1% vs 12.3%; 95% CI, 9.8%-15.4%;P = .04). In DS-negative women, the risks of both ≥CIN2 and ≥CIN3 remained below the colposcopy referral threshold for all 5 years, crossing the 1-year return threshold at 3 years. Conclusions and Relevance Triage with p16/Ki-67 DS provides better long-term risk stratification than cytology over 5 years. The low risk of cervical Precancer in p16/Ki-67 DS–negative women permits safe extension of follow-up intervals for 3 years.

  • human papillomavirus dna methylation as a biomarker for cervical Precancer consistency across 12 genotypes and potential impact on management of hpv positive women
    Clinical Cancer Research, 2018
    Co-Authors: Megan A Clarke, Mark Schiffman, Nancy Poitras, Thomas Lorey, Barbara Fetterman, Tina Rainebennett, Ana Gradissimo, Jessica Lam, Christopher C Sollecito, Philip E Castle
    Abstract:

    Purpose: Human papillomavirus (HPV) DNA methylation testing is a promising triage option for women testing HPV positive during cervical cancer screening. However, the extent to which methylation indicates Precancer for all 12 carcinogenic HPV types has not been evaluated.Experimental Design: In this nested case-control study, we tested up to 30 cases of Precancer [cervical intraepithelial neoplasia grade 3 (CIN3)/adenocarcinoma in situ (AIS)] and 30 normal controls for each carcinogenic type (single infections with 16/18/31/33/35/39/45/51/52/56/58/59). Next-generation bisulfite sequencing was performed on CpG sites within the L1 and L2 genes. We calculated differences in methylation, ORs, and AUC. Using a fixed sensitivity of 80%, we evaluated the specificity and the risk of CIN3/AIS for best performing CpG sites, and compared the performance of an explorative multi-type methylation assay with current triage strategies.Results: Methylation was positively associated with CIN3/AIS across all 12 types. AUCs for the top sites ranged from 0.71 (HPV51 and HPV56) to 0.86 (HPV18). A combined 12-type methylation assay had the highest Youden index (0.46), compared with cytology (0.31) and a 5-type methylation assay, including only previously described types (0.26). The 12-type methylation assay had higher sensitivity (80% vs. 76.6%) and lower test positivity compared with cytology (38.5% vs. 48.7%). The risk of CIN3/AIS was highest for methylation positives and lowest for cytology or HPV16/18 positives.Conclusions: HPV DNA methylation is a general phenomenon marking the transition from HPV infection to Precancer for all 12 carcinogenic types. Development of a combined multitype methylation assay may serve as a triage test for HPV-positive women. Clin Cancer Res; 24(9); 2194-202. ©2018 AACR.

  • the population impact of human papillomavirus cytology cervical cotesting at 3 year intervals reduced cervical cancer risk and decreased yield of Precancer per screen
    Cancer, 2016
    Co-Authors: Michelle I Silver, Mark Schiffman, Nicolas Wentzensen, Thomas Lorey, Walter Kinney, Barbara Fetterman, Julia C Gage, Nancy E Poitras, Philip E Castle
    Abstract:

    BACKGROUND The objective of cervical screening is to detect and treat Precancer to prevent cervical cancer mortality and morbidity while minimizing overtreatment of benign human papillomavirus (HPV) infections and related minor abnormalities. HPV/cytology cotesting at extended 5-year intervals currently is a recommended screening strategy in the United States, but the interval extension is controversial. In the current study, the authors examined the impact of a decade of an alternative, 3-year cotesting, on rates of Precancer and cancer at Kaiser Permanente Northern California. The effect on screening efficiency, defined as numbers of cotests/colposcopy visits needed to detect a Precancer, also was considered. METHODS Two cohorts were defined. The “open cohort” included all women screened at least once during the study period; > 1 million cotests were performed. In a fixed “long-term screening cohort,” the authors considered the cumulative impact of repeated screening at 3-year intervals by restricting the cohort to women first cotested in 2003 through 2004 (ie, no women entering screening later were added to this group). RESULTS Detection of cervical intraepithelial neoplasia 3/adenocarcinoma in situ (CIN3/AIS) increased in the open cohort (2004-2006: 82.0/100,000 women screened; 2007-2009: 140.6/100,000 women screened; and 2010-2012: 126.0/100,000 women screened); cancer diagnoses were unchanged. In the long-term screening cohort, the detection of CIN3/AIS increased and then decreased to the original level (2004-2006: 80.5/100,000 women screened; 2007-2009: 118.6/100,000 women screened; and 2010-2012: 84.9./100,000 women screened). The number of cancer diagnoses was found to decrease. When viewed in terms of screening efficiency, the number of colposcopies performed to detect a single case of CIN3/AIS increased in the cohort with repeat screening. CONCLUSIONS Repeated cotesting at a 3-year interval eventually lowers population rates of Precancer and cancer. However, a greater number of colposcopies are required to detect a single Precancer. Cancer 2016. © 2016 American Cancer Society.

  • p16 ki 67 dual stain cytology for detection of cervical Precancer in hpv positive women
    Journal of the National Cancer Institute, 2015
    Co-Authors: Nicolas Wentzensen, Mark Schiffman, Philip E Castle, Diane Tokugawa, Nancy Poitras, Barbara Fetterman, Shannon N Wood, Eric Stiemerling, Clara Bodelon, Thomas Lorey
    Abstract:

    BACKGROUND: Human papillomavirus (HPV)-based cervical cancer screening requires triage markers to decide who should be referred to colposcopy. p16/Ki-67 dual stain cytology has been proposed as a biomarker for cervical Precancers. We evaluated the dual stain in a large population of HPV-positive women. METHODS: One thousand five hundred and nine HPV-positive women screened with HPV/cytology cotesting at Kaiser Permanente California were enrolled into a prospective observational study in 2012. Dual stain cytology was performed on residual Surepath material, and slides were evaluated for dual stain-positive cells. Disease endpoints were ascertained from the clinical database at KPNC. We evaluated the clinical performance of the assay among all HPV-positive women and among HPV-positive, cytology-negative women. We used internal benchmarks for clinical management to evaluate the clinical relevance of the dual stain assay. We evaluated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the dual stain compared with Pap cytology. All statistical tests were two-sided. RESULTS: The dual stain had lower positivity (45.9%) compared with cytology at an ASC-US threshold (53.4%). For detection of CIN2+, the dual stain had similar sensitivity (83.4% vs 76.6%, P = .1), and statistically higher specificity (58.9% vs 49.6%, P < .001), PPV (21.0% vs 16.6%, P < .001), and NPV (96.4% vs 94.2%, P = .01) compared with cytology. Similar patterns were observed for CIN3+. Women with a positive test had high enough risk for referral to colposcopy, while the risk for women with negative tests was below a one-year return threshold based on current US management guidelines. CONCLUSION: Dual stain cytology showed good risk stratification for all HPV-positive women and for HPV-positive women with normal cytology. Additional follow-up is needed to determine how long dual stain negative women remain at low risk of Precancer.

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