Timely follow-up of positive cancer screening results: A systematic review and recommendations from the PROSPR Consortium.

Timely follow-up for positive cancer screening results remains suboptimal, and the evidence base to inform decisions on optimizing the timeliness of diagnostic testing is unclear. This systematic review evaluated published studies regarding time to follow-up after a positive screening for breast, cervical, colorectal, and lung cancers. The quality of available evidence was very low or low across cancers, with potential attenuated or reversed associations from confounding by indication in most studies. Overall, evidence suggested that the risk for poorer cancer outcomes rises with longer wait times that vary within and across cancer types, which supports performing diagnostic testing as soon as feasible after the positive result, but evidence for specific time targets is limited. Within these limitations, we provide our opinion on cancer-specific recommendations for times to follow-up and how existing guidelines relate to the current evidence. Thresholds set should consider patient worry, potential for loss to follow-up with prolonged wait times, and available resources. Research is needed to better guide the timeliness of diagnostic follow-up, including considerations for patient preferences and existing barriers, while addressing methodological weaknesses. Research is also needed to identify effective interventions for reducing wait times for diagnostic testing, particularly in underserved or low-resource settings. CA Cancer J Clin 2018;68:199-216. © 2018 American Cancer Society.

Comparing the performance of 2 human papillomavirus assays for a new use indication: a real-world evidence-based evaluation in the United States.

BACKGROUND: The US Food and Drug Administration supports innovations to facilitate new indications for high-risk human papillomavirus testing. This report describes the retrospective testing of stored specimens and analysis of existing data to efficiently and cost-effectively support a new indication for the Onclarity human papillomavirus assay (Becton, Dickinson and Company, BD Life Sciences - Integrated Diagnostic Solutions, Sparks, MD). The performance of this index test was compared with that of a predicate test, the cobas human papillomavirus assay (Roche Diagnostics, Indianapolis, IN). Both human papillomavirus assays are based on real-time polymerase chain reaction platforms that detect the presence of 14 high-risk human papillomavirus genotypes. The predicate assay reports human papillomavirus types 16 and 18 as individual results and the other 12 human papillomavirus genotypes as 1 pooled result. The index assay reports 9 independent results (human papillomavirus types 16, 18, 31, 33/58, 35/39/68, 45, 51, 52, and 56/59/66). Both the index and predicate assays are approved by the Food and Drug Administration for cervical cancer screening, but at the time that this study was initiated, the index human papillomavirus assay was not approved for use with cervical specimens collected in PreservCyt (Hologic, Inc, San Diego, CA) liquid-based cytology media. OBJECTIVE: The performance of the index human papillomavirus assay was compared with that of the predicate human papillomavirus assay for the detection of cervical intraepithelial neoplasia grades 2 or greater and 3 or greater (≥CIN2 or ≥CIN3) using PreservCyt liquid-based cytology specimens collected from women aged 21 to 65 years. In addition, the ability of the index test's extended genotyping to stratify ≥CIN2 and ≥CIN3 risks, using these specimens, was evaluated. STUDY DESIGN: The New Mexico HPV Pap Registry was used to select an age- and cytology-stratified random sample of 19,879 women undergoing opportunistic cervical screening and follow-up in routine clinical practice across New Mexico. A subset (n = 4820) of PreservCyt specimens was selected from 19,879 women for paired testing by the index and predicate human papillomavirus assays within age and cytology strata and included women with or without cervical biopsy follow-up. Point estimate differences and ratios were calculated for cervical disease detection and positivity rates, respectively, with 95% confidence intervals to determine statistical significance. The cumulative risk of ≥CIN2 or ≥CIN3, with up to 5-year follow-up, was estimated for the index assay using Kaplan-Meier methods. RESULTS: The 5-year cumulative ≥CIN3 detection rates were 5.6% for the index assay and 4.6% for the predicate assay (difference, 1.0%; 95% confidence interval, 0.5%-1.5%). The ≥CIN3 positivity rates within <1 year were 95.3% for the index assay and 94.5% for the predicate assay (ratio, 1.01; 95% confidence interval, 0.98-1.06). The ≥CIN3 cumulative positivity rates for the index and predicate assays were also similar at 5 years. Among cases of ≥CIN3, the positive agreement rates between the index and predicate assays for human papillomavirus types 16 and 18 were 100.0% (95% confidence interval, 95.0%-100.0%) and 90.9% (95% confidence interval, 62.3%-98.4%), respectively. Human papillomavirus type 16 carried the highest ≥CIN2 or ≥CIN3 risk, followed by human papillomavirus types 18/31/33/58/52/45 and human papillomavirus types 35/56/59/51/56/59/66. CONCLUSION: The index and predicate human papillomavirus assays demonstrated equivalent performance, and extended human papillomavirus genotyping, using the index assay, provided effective ≥CIN2 and ≥CIN3 risk stratification, supporting a new indication for use of the index assay with PreservCyt.

Impact of HPV testing in opportunistic cervical screening: Support for primary HPV screening in the United States.

Human papillomavirus (HPV) testing for cervical screening increases diagnosis of precancer and reduces the incidence of cervical cancer more than cytology alone. However, real-world evidence from diverse practice settings is lacking for the United States (U.S.) to support clinician adoption of primary HPV screening. Using a population-based registry, which captures all cervical cytology (with or without HPV testing) and all cervical biopsies, we conducted a real-world evidence study of screening in women aged 30 to 64 years across the entire state of New Mexico. Negative cytology was used to distinguish cotests from reflex HPV tests. A total of 264 198 cervical screening tests (with exclusions based on clinical history) were recorded as the first screening test between 2014 and 2017. Diagnoses of cervical intraepithelial neoplasia grades 2 or 3 or greater (CIN2+, CIN3+) from 2014 to 2019 were the main outcomes. Of cytology-negative screens, 165 595 (67.1%) were cotests and 4.8% of these led to biopsy within 2 years vs 3.2% in the cytology-only group. Among cytology-negative, HPV tested women, 347 of 398 (87.2%) CIN2+ cases were diagnosed in HPV-positive women, as were 147 of 164 (89.6%) CIN3+ cases. Only 29/921 (3.2%) CIN3+ and 67/1964 (3.4%) CIN2+ cases were diagnosed in HPV-negative, cytology-positive women with biopsies. Under U.S. opportunistic screening, across a diversity of health care delivery practices, and in a population suffering multiple disparities, we show adding HPV testing to cytology substantially increased the yield of CIN2+ and CIN3+. CIN3+ was rarely diagnosed in HPV-negative women with abnormal cytology, supporting U.S. primary HPV-only screening.

Provider- and Facility-Level Variation in Precancerous Cervical Biopsy Diagnoses.

OBJECTIVES: Reproducibility of cervical biopsy diagnoses is low and may vary based on where the diagnostic test is performed and by whom. Our objective was to measure multilevel variation in diagnoses across colposcopists, pathologists, and laboratory facilities. METHODS: We cross-sectionally examined variation in cervical biopsy diagnoses within the 5 sites of the Population-Based Research Optimizing Screening through Personalized Regimens (PROSPR I) consortium within levels defined by colposcopists, pathologists, and laboratory facilities. Patients aged 18 to 65 years with a colposcopy with biopsy performed were included, with diagnoses categorized as normal, cervical intraepithelial neoplasia grade 1 (CIN1), grade 2 (CIN2), and grade 3 (CIN3). Using Markov Chain Monte-Carlo methods, we fit mixed-effects logistic regression models for biopsy diagnoses and presented median odds ratios (MORs), which reflect the variability within each level. Median odds ratios can be interpreted as the average increased odds a patient would have for a given outcome (e.g., CIN2 or CIN3 vs normal or CIN1) when switching to a provider with higher odds of diagnosing that outcome. The MOR is always 1 or greater, and a value of 1 indicates no variation in outcome for that level, with higher values indicating greater variation. RESULTS: A total of 130,110 patients were included who received care across 82 laboratory facilities, 2,620 colposcopists, and 489 pathologists. Substantial variation in biopsy diagnoses was found at each level, with the most occurring between laboratory facilities, followed by pathologists and colposcopists. Substantial variation in biopsy diagnoses of CIN2 or CIN3 (vs normal or CIN1) was present between laboratory facilities (MOR: 1.26; 95% credible interval = 1.19-1.36). CONCLUSIONS: Improving consistency in cervical biopsy diagnoses is needed to reduce underdiagnosis, overdiagnosis, and unnecessary treatment resulting from variation in cervical biopsy diagnoses.

DNA methylation testing with S5 for triage of high-risk HPV positive women.

Methylation of host and viral genes is promising for triage of women with high-risk human papillomavirus infections (hrHPV). Using a population-based sample of hrHPV positive women with cervical biopsies within 12 months after cervical screening, the clinical value of the S5 methylation classifier (S5), HPV genotyping and cytology were compared as potential triage tests, for outcomes of cervical intraepithelial neoplasia (CIN) grade 3 or greater (CIN3+), CIN2+ and CIN2, and the area under the curve (AUC) calculated. S5 scores increased with histopathology severity (Ptrend < .001). For CIN3+, the AUC was 0.780 suggesting S5 provides good discrimination between

Clinical performance of methylation as a biomarker for cervical carcinoma in situ and cancer diagnosis: A worldwide study.

The shift towards primary human papillomavirus (HPV)-based screening has necessitated the search for a secondary triage test that provides sufficient sensitivity to detect high-grade cervical intraepithelial neoplasia (CIN) and cancer, but also brings an improved specificity to avoid unnecessary clinical work and colposcopy referrals. We evaluated the performance of the previously described DNA-methylation test (S5) in detecting CIN3 and cancers from diverse geographic settings in high-, medium- and low-income countries, using the cut-off of 0.80 and exploratory cut-offs of 2.62 and 3.70. Assays were performed using exfoliated cervical specimens (n = 808) and formalin-fixed biopsies (n = 166) from women diagnosed with cytology-negative results (n = 220), CIN3 (n = 204) and cancer stages I (n = 245), II (n = 249), III (n = 28) and IV (n = 22). Methylation increased proportionally with disease severity (Cuzick test for trend, P < .0001). S5 accurately separated women with negative-histology from CIN3 or cancer (P < .0001). At the 0.80 cut-off, 543/544 cancers were correctly identified as S5 positive (99.81%). At cut-off 3.70, S5 showed a sensitivity of 95.77% with improved specificity. The S5 odds ratios of women negative for cervical disease vs CIN3+ were significantly higher than for HPV16/18 genotyping at all cut-offs (all P < .0001). At S5 cut-off 0.80, 96.15% of consistently high-risk human papillomavirus (hrHPV)-negative cancers (tested with multiple hrHPV-genotyping assay) were positive by S5. These cancers may have been missed in current primary hrHPV-screening programmes. The S5 test can accurately detect CIN3 and malignancy irrespective of geographic context and setting. The test can be used as a screening and triage tool. Adjustment of the S5 cut-off can be performed considering the relative importance given to sensitivity vs specificity.

Efficacy of AS04-Adjuvanted Vaccine Against Human Papillomavirus (HPV) Types 16 and 18 in Clearing Incident HPV Infections: Pooled Analysis of Data From the Costa Rica Vaccine Trial and the PATRICIA Study.

Clinical trial data and real-world evidence suggest that the AS04-adjuvanted vaccine targeting human papillomavirus types 16 and 18 (AS04-HPV-16/18) vaccine provides nearly 90% protection against cervical intraepithelial neoplasia grade 3 or higher irrespective of type, among women vaccinated before sexual debut. This high efficacy is not fully explained by cross-protection. Although AS04-HPV-16/18 vaccination does not affect clearance of prevalent infections, it may accelerate clearance of newly acquired infections. We pooled data from 2 large-scale randomized controlled trials to evaluate efficacy of the AS04-HPV-16/18 vaccine against clearance of nontargeted incident infections. Results of our analysis do not suggest an effect in expediting clearance of incident infections.

Adjunctive testing by cytology, p16/Ki-67 dual-stained cytology or HPV16/18 E6 oncoprotein for the management of HPV16/18 screen-positive women.

High-risk human papillomavirus type 16/18 (HPV16/18) genotyping is unable to accurately discriminate nonprogressive infections from those that will progress to cervical cancer. Our study aimed to assesses if additional testing either with liquid-based cytology (LBC) or the putative progression markers p16/Ki-67 and HPV16/18 E6 oncoprotein (E6) can improve the efficiency of HPV16/18 genotyping for triaging high-risk HPV (hrHPV)-positive women through better cancer risk stratification. Women attending colposcopy after positive HPV16/18 genotyping results within the Forwarding Research for Improved Detection and Access for Cervical Cancer Screening and Triage (FRIDA) hrHPV-based screening study in Tlaxcala, Mexico, underwent further testing with LBC, p16/Ki-67 dual-stained (DS) cytology and E6. We calculated measures of test performance for detecting histologically confirmed cervical intraepithelial neoplasia grade 2 or higher (CIN2+) and grade 3 or higher (CIN3+). A number of 475 (64.3%) of 739 HPV16/18-positive women had complete results for all tests. Triage positivity rates were 14.1%, 18.5% and 24.4%, for LBC, E6 and DS, respectively. Compared with LBC, DS had higher sensitivity (24.4% vs 60.0%) although lower specificity (87.0% vs 79.3%) for CIN3+ (P < .001), whereas E6 had a sensitivity of 37.8% and a specificity of 83.5%. No invasive cancer was missed by DS or E6, but 75% were in normal cytology. DS test was associated with nearly 75% reduction of colposcopy referrals compared with the direct referral of all HPV16/18-positive women, giving the least number of colposcopies (n = 4.3) per CIN3+ detected. We show that adjunctive testing of HPV16/18-positive women with DS may greatly reduce unnecessary colposcopy referrals within HPV-based screening employing HPV16/18 genotyping while retaining acceptable sensitivity for CIN2+ and CIN3+.

Burden of Mycoplasma genitalium and Bacterial Coinfections in a Population-Based Sample in New Mexico.

ABSTRACT: In this population-based US study, the overall prevalence of Mycoplasma genitalium was 1.95% (95% confidence interval [CI], 1.62%-2.34%), declining from 6.12% (95% CI, 4.72%-7.92%) in women aged 21 to 24 years to 0.48% (95% CI, 0.25%-0.94%) in women aged 40 to 64 years. The prevalence of coinfections with Chlamydia trachomatis and Trichomonas vaginalis was low.

Uptake of co-testing with HPV and cytology for cervical screening: A population-based evaluation in the United States.

OBJECTIVES: Human papillomavirus (HPV) testing for cervical screening has been shown to increase the yield of precancerous disease and reduce the incidence of cervical cancer more than cytology alone. Here we document the state-wide uptake of co-testing with HPV and cytology in women aged 30-64 years as recommended by national and international bodies. METHODS: Registry-based study of all screening cytology and HPV tests in New Mexico from 2008 to 2019 among women aged 21-64 years, with a focus on cytology negative tests to distinguish co-testing from reflex HPV testing to triage equivocal or mildly abnormal cytology. RESULTS: A total of 1,704,055 cervical screening tests from 681,440 women aged 21-64 years in the state of New Mexico were identified. The proportion of screening tests which were co-tests rose from 5.6% in 2008 to 84.3% in 2019 among women aged 30-64 years with a marked change from the near exclusive use of the Hybrid Capture II HPV test, (a signal amplified test method) to the use of target amplified HPV tests. The largest increases were seen between 2013 and 2015, reflecting the introduction and adoption of new clinical guidelines. Increases in co-testing were also seen in younger women. CONCLUSIONS: Co-testing is now well established in women aged 30-64 years, but smaller increases have also been seen at younger ages, although this is not currently recommended. The impact of co-testing on cervical disease outcomes and number of colposcopies and biopsies in routine population settings remain important, especially in young women.

Clinical follow-up practices after cervical cancer screening by co-testing: A population-based study of adherence to U.S. guideline recommendations.

Failure to follow-up women after abnormal cervical screening could lead to cervical cancers, yet little is known about adherence to recommended follow-up after abnormal co-testing [cytology and high-risk human papillomavirus (hrHPV) testing]. We documented clinical management following cervical screening by co-testing in a diverse population-based setting. A statewide surveillance program for cervical screening, diagnosis, and treatment was used to investigate all cytology, hrHPV and biopsy reports in the state of New Mexico from January 2015 through August 2019. Guideline-adherent follow-up after co-testing required 1) biopsy within 6 months for low-grade cytology if positive for hrHPV, for high-grade cytology irrespective of hrHPV, and for HPV 16/18 positive results irrespective of cytology and; 2) repeat co-testing within 18 months if cytology was negative and hrHPV test was positive (excluding types 16/18). Screening co-tests (2015-2017) for 164,522 women were analyzed using descriptive statistics, Kaplan Meier curves, and pairwise comparisons between groups. Guideline adherence was highest when both cytology and hrHPV tests were abnormal, ranging from 61.7% to 80.3%. Guideline-adherent follow-up was lower for discordant results. Women with high-grade cytology were less likely to receive a timely biopsy when hrHPV-testing was negative (48.1%) versus positive (83.3%) (p < 0.001). Only 47.9% of women received biopsies following detection of HPV16/18 with normal cytology, and 30.8% received no follow-up within 18-months. Among women with hrHPV-positive normal cytology without evidence of HPV 16/18 infection, 51% received no follow-up within 18 months. Provider education and creation of robust recall systems may help ensure appropriate follow-up of abnormal screening results.

Impact of screening on cervical cancer incidence: A population-based case-control study in the United States.

Cervical cancer is widely preventable through screening, but little is known about the duration of protection offered by a negative screen in North America. A case-control study was conducted with records from population-based registries in New Mexico. Cases were women diagnosed with cervical cancer in 2006-2016, obtained from the Tumor Registry. Five controls per case from the New Mexico HPV Pap Registry were matched to cases by sex, age and place of residence. Dates and results of all cervical screening and diagnostic tests since 2006 were identified from the pap registry. We estimated the odds ratio of nonlocalized (Stage II+) and localized (Stage I) cervical cancer associated with attending screening in the 3 years prior to case-diagnosis compared to women not screened in 5 years. Of 876 cases, 527 were aged 25-64 years with ≥3 years of potential screening data. Only 38% of cases and 61% of controls attended screening in a 3-year period. Women screened in the 3 years prior to diagnosis had 83% lower risk of nonlocalized cancer (odds ratio [OR] = 0.17, 95% CI: 0.12-0.24) and 48% lower odds of localized cancer (OR = 0.52, 95% CI: 0.38-0.72), compared to women not screened in the 5 years prior to diagnosis. Women remained at low risk of nonlocalized cancer for 3.5-5 years after a negative screen compared to women with no negative screens in the 5 years prior to diagnosis. Routine cervical screening is effective at preventing localized and nonlocalized cervical cancers; 3 yearly screening prevents 83% of nonlocalized cancers, with no additional benefit of more frequent screening. Increasing screening coverage remains essential to further reduce cervical cancer incidence.

A state-wide population-based evaluation of cervical cancers arising during opportunistic screening in the United States.

OBJECTIVE: Despite widespread cervical screening, an estimated 13,800 women will be diagnosed with cervical cancer in the United States in 2020. To inform improvements, the screening histories of women diagnosed with cervical cancer in New Mexico were assessed. METHODS: Data were collected on all cervical screening, diagnostic tests and treatment procedures for all women diagnosed with cervical cancer aged 25-64 yrs. in New Mexico from 2006 to 2016. Women were categorized by their screening attendance in the 5-40 months (screening interval) and 1-4 months (peri-diagnostic interval) prior to cancer diagnosis. RESULTS: Of the 504 women diagnosed between May 2009-December 2016, 64% were not screened or had only inadequate screening tests in the 5-40 months prior to diagnosis, and 90 of 182 screened women (49%) had only negative screens in this period. Only 32% (N = 162) of cervical cancers were screen-detected. Women with adenocarcinomas were more likely to have had a recent negative screen (41/57 = 722%) than women with squamous cancers (50/112 = 45%). Both older women (aged 45-64 years) and women with more advanced cancers were less likely to have been screened, and if screened, were more likely to have a false-negative outcome. Only 9% of cancers were diagnosed in women who did not attend biopsy or treatment after positive tests requiring clinical management. Screening currently prevents 35% of cancers, whereas full screening coverage could prevent 61% of cervical cancers. CONCLUSION: Improved screening coverage has the largest potential for reducing cervical cancer incidence, though there is also a role for improved recall procedures and screening sensitivity.

Cervical cancer screening research in the PROSPR I consortium: Rationale, methods and baseline findings from a US cohort.

Little is known about the effect of evolving risk-based cervical cancer screening and management guidelines on United States (US) clinical practice and patient outcomes. We describe the National Cancer Institute's Population-based Research Optimizing Screening through Personalized Regimens (PROSPR I) consortium, methods and baseline findings from its cervical sites: Kaiser Permanente Washington, Kaiser Permanente Northern California, Kaiser Permanente Southern California, Parkland Health & Hospital System/University of Texas Southwestern (Parkland-UTSW) and New Mexico HPV Pap Registry housed by University of New Mexico (UNM-NMHPVPR). Across these diverse healthcare settings, we collected data on human papillomavirus (HPV) vaccinations, screening tests/results, diagnostic and treatment procedures/results and cancer diagnoses on nearly 4.7 million women aged 18-89 years from 2010 to 2014. We calculated baseline (2012 for UNM-NMHPVPR; 2010 for other sites) frequencies for sociodemographics, cervical cancer risk factors and key screening process measures for each site's cohort. Healthcare delivery settings, cervical cancer screening strategy, race/ethnicity and insurance status varied among sites. The proportion of women receiving a Pap test during the baseline year was similar across sites (26.1-36.1%). Most high-risk HPV tests were performed either reflexively or as cotests, and utilization pattern varied by site. Prevalence of colposcopy or biopsy was higher at Parkland-UTSW (3.6%) than other sites (1.3-1.4%). Incident cervical cancer was rare. HPV vaccination among age-eligible women not already immunized was modest across sites (0.1-7.2%). Cervical PROSPR I makes available high-quality, multilevel, longitudinal screening process data from a large and diverse cohort of women to evaluate and improve the effectiveness of US cervical cancer screening delivery.

Inefficiencies of over-screening and under-screening for cervical cancer prevention in the U.S.

There is limited information on the cost-inefficiencies of non-adherence to recommended cervical cancer screening or the potential value for improving non-adherence. We estimated the incremental value of adhering to recommended screening every three years with cytology, using a disease simulation model that integrated real-world screening practice data from New Mexico. The amount that can be spent to improve adherence was estimated by calculating the incremental net monetary benefit (INMB) under scenarios of Current Practice (assuming a population of mixed adherence) and Uniformly Non-Adherent populations with imperfect or perfect adherence to follow-up of screen-positive women. Getting unscreened women screened every three years by cytology was a better value than increasing screening in the under-screened or reducing screening in the over-screened. For example, INMBs were $3998 for screening previously unscreened women versus $136 for eliminating annual screening at a willingness-to-pay threshold of $100,000 per quality-adjusted life-year gained. Strategies to reach unscreened women are potentially high-value investments.

HPV16 Down-Regulates the Insulin-Like Growth Factor Binding Protein 2 to Promote Epithelial Invasion in Organotypic Cultures.

Cervical cancer is a multi-stage disease caused by human papillomaviruses (HPV) infection of cervical epithelial cells, but the mechanisms regulating disease progression are not clearly defined. Using 3-dimensional organotypic cultures, we demonstrate that HPV16 E6 and E7 proteins alter the secretome of primary human keratinocytes resulting in local epithelial invasion. Mechanistically, absence of the IGF-binding protein 2 (IGFBP2) caused increases in IGFI/II signalling and through crosstalk with KGF/FGFR2b/AKT, cell invasion. Repression of IGFBP2 is mediated by histone deacetylation at the IGFBP2 promoter and was reversed by treatment with histone deacetylase (HDAC) inhibitors. Our in vitro findings were confirmed in 50 invasive cancers and 79 cervical intra-epithelial neoplastic lesions caused by HPV16 infection, where IGFBP2 levels were reduced with increasing disease severity. In summary, the loss of IGFBP2 is associated with progression of premalignant disease, and sensitises cells to pro-invasive IGF signalling, and together with stromal derived factors promotes epithelial invasion.

Progression of HPV infection to detectable cervical lesions or clearance in adult women: Analysis of the control arm of the VIVIANE study.

The control arm of the phase III VIVIANE (Human PapillomaVIrus: Vaccine Immunogenicity ANd Efficacy; NCT00294047) study in women >25 years was studied to assess risk of progression from cervical HPV infection to detectable cervical intraepithelial neoplasia (CIN). The risk of detecting CIN associated with the same HPV type as the reference infection was analysed using Kaplan-Meier and multivariable Cox models. Infections were categorised depending upon persistence as 6-month persistent infection (6MPI) or infection of any duration. The 4-year interim analysis included 2,838 women, of whom 1,073 (37.8%) experienced 2,615 infections of any duration and 708 (24.9%) experienced 1,130 6MPIs. Infection with oncogenic HPV types significantly increased the risk of detecting CIN grade 2 or greater (CIN2+) versus non-oncogenic types. For 6MPI, the highest risk was associated with HPV-33 (hazard ratio [HR]: 31.9 [8.3-122.2, p < 0.0001]). The next highest risk was with HPV-16 (21.1 [6.3-70.0], p < 0.0001). Similar findings were seen for infections of any duration. Significant risk was also observed for HPV-18, HPV-31, and HPV-45. Concomitant HPV infection or CIN grade 1 or greater associated with a different oncogenic HPV type increased risk. Most women (79.3%) with an HPV infection at baseline cleared detectable infections of any duration, and 69.9% cleared a 6MPI. The risk of progression of HPV infection to CIN2+ in women >25 years in this study was similar to that in women 15-25 years in PATRICIA.

Variation in Screening Abnormality Rates and Follow-Up of Breast, Cervical and Colorectal Cancer Screening within the PROSPR Consortium.

BACKGROUND: Primary care providers and health systems have prominent roles in guiding effective cancer screening. OBJECTIVE: To characterize variation in screening abnormality rates and timely initial follow-up for common cancer screening tests. DESIGN: Population-based cohort undergoing screening in 2011, 2012, or 2013 at seven research centers comprising the National Cancer Institute-sponsored Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium. PARTICIPANTS: Adults undergoing mammography with or without digital breast tomosynthesis (n = 97,683 ages 40-75 years), fecal occult blood or fecal immunochemical tests (n = 759,553 ages 50-75 years), or Papanicolaou with or without human papillomavirus tests (n = 167,330 ages 21-65 years). INTERVENTION: Breast, colorectal, or cervical cancer screening. MAIN MEASURES: Abnormality rates per 1000 screens; percentage with timely initial follow-up (within 90 days, except 9-month window for BI-RADS 3). Primary care clinic-level variation in percentage with screening abnormality and percentage with timely initial follow-up. KEY RESULTS: There were 10,248/97,683 (104.9 per 1000) abnormal breast cancer screens, 35,847/759,553 (47.2 per 1000) FOBT/FIT-positive colorectal cancer screens, and 13,266/167,330 (79.3 per 1000) abnormal cervical cancer screens. The percentage with timely follow-up was 93.2 to 96.7 % for breast centers, 46.8 to 68.7  % for colorectal centers, and 46.6 % for the cervical cancer screening center (low-grade squamous intraepithelial lesions or higher). The primary care clinic variation (25th to 75th percentile) was smaller for the percentage with an abnormal screen (breast, 8.5-10.3 %; colorectal, 3.0-4.8 %; cervical, 6.3-9.9 %) than for the percentage with follow-up within 90 days (breast, 90.2-95.8 %; colorectal, 43.4-52.0 %; cervical, 29.6-61.4 %). CONCLUSIONS: Variation in both the rate of screening abnormalities and their initial follow-up was evident across organ sites and primary care clinics. This highlights an opportunity for improving the delivery of cancer screening through focused study of patient, provider, clinic, and health system characteristics associated with timely follow-up of screening abnormalities.