Nancy Poitras

Impact of repeatedly screening negative on cervical cancer risk

Abstract Background We demonstrated that cervical cancer risk following any screening result is lower if there is a known prior negative screening history vs an unknown screening history. We extended these findings to look at how screening performs following repeatedly negative screening results. Methods Approximately 1.7 million women aged 30-64 years underwent triennial human papillomavirus (HPV) and cytology co-testing from 2003 to 2021. We modeled 5-year risks of cervical intraepithelial neoplasia grade 3 or more severe diagnoses (CIN3+) and invasive cervical cancer for the initial co-test, and then successive rounds following negative co-testing. A logistic-Weibull prevalence-incidence model was used to model risks. Results HPV test positivity was greater than cytology positivity for only the first co-test, and both positivity rates decreased with each screening round. Diagnostic yields of CIN3+ and cancer declined with each round of screening so the first screen yielded 8-fold more CIN3+ and invasive cancer than the fifth screen following 4 consecutive negative co-tests. Five-year risks of CIN3+ for positive and negative HPV and cytology results, individually or combined, decreased considerably after the first screen, with smaller decreases in each subsequent round. For cancer, we noticed a considerable decrease with the first screen only. Five-year CIN3+ risks were greater for positive HPV or cytology results, with a longer antecedent screening interval and younger age at screening (Ptrend < .001). Conclusions Triennial screening that includes HPV testing becomes inefficient after a single and more so after multiple negative screens. These data support the use of longer screening intervals, especially following negative screen(s).

The Improving Risk Informed HPV Screening (IRIS) Study: Design and Baseline Characteristics

Abstract Background: Cervical cancer screening with high-risk human papillomavirus (HrHPV) testing is being introduced. Most HrHPV infections are transient, requiring triage tests to identify individuals at highest risk for progression to cervical cancer. Head-to-head comparisons of available strategies for screening and triage are needed. Endometrial and ovarian cancers could be amenable to similar testing. Methods: Between 2016 and 2020, discarded cervical cancer screening specimens from women ages 25 to 65 undergoing screening at Kaiser Permanente Northern California were collected. Specimens were aliquoted, stabilized, and stored frozen. Human papillomavirus (HPV), cytology, and histopathology results as well as demographic and cofactor information were obtained from electronic medical records (EMR). Follow-up collection of specimens was conducted for 2 years, and EMR-based data collection was planned for 5 years. Results: Collection of enrollment and follow-up specimens is complete, and EMR-based follow-up data collection is ongoing. At baseline, specimens were collected from 54,957 HPV-positive, 10,215 HPV-negative/Pap-positive, and 12,748 HPV-negative/Pap-negative women. Clinical history prior to baseline was available for 72.6% of individuals, of which 53.9% were undergoing routine screening, 8.6% recently had an abnormal screen, 30.3% had previous colposcopy, and 7.2% had previous treatment. As of February 2021, 55.7% had one or more colposcopies, yielding 5,563 cervical intraepithelial neoplasia grade 2 (CIN2), 2,756 cervical intraepithelial neoplasia grade 3 (CIN3), and 146 cancer histopathology diagnoses. Conclusions: This robust population-based cohort study represents all stages of cervical cancer screening, management, and posttreatment follow-up. Impact: The IRIS study is a unique and highly relevant resource allowing for natural history studies and rigorous evaluation of candidate HrHPV screening and triage markers, while permitting studies of biomarkers associated with other gynecologic cancers.

Long-Term Prospective Cohort Study of Cervical Cancer Screening Using Triage of Women Who Are Human Papillomavirus–Positive With Dual Stain and Human Papillomavirus Genotyping

PURPOSE Primary human papillomavirus (HPV) testing has the best tradeoff of benefits and harms for cervical screening but requires triage to determine management among HPV positives. We conducted a prospective observational study to evaluate triage of women who are HPV-positive using dual stain (DS) and HPV genotyping. MATERIALS AND METHODS We included 9,645 consecutive women who are HPV-positive undergoing cervical screening in two periods between 2015 and 2017 in the organized cervical screening program at Kaiser Permanente Northern California. Absolute risk and clinical performance of DS and cytology for detection of cervical intraepithelial neoplasia grade 3 and greater (CIN3+) were estimated overall and by HPV genotype and by age. Cumulative absolute risk of CIN3+ was modeled over 5 years using a prevalence-incidence mixture model, which allows estimating risk accounting for differences in disease ascertainment, surveillance intervals, and compliance. RESULTS The baseline risk of CIN3+ was 9.4% and 0.8% for women testing positive and negative for DS, respectively, and 6.9% and 2.0% for women testing positive and negative for cytology, respectively. Sensitivity, specificity, and predictive values for CIN3+ detection were better for DS compared with cytology over 5 years ( P < .001 for all comparisons). Risk in women with HPV16-positive/negative for intraepithelial lesion or malignancy was substantially higher than the risk in women with HPV16-positive/DS-negative (7.5% v 2.9%, P < .001). DS had better triage performance compared with cytology in all age groups and in women positive for HPV types other than HPV16 or HPV18. CONCLUSION Long-term reassurance of low risk among DS negatives suggests that DS detects molecular changes earlier in the carcinogenic pathway than cytology. DS has better risk stratification than cytology overall, within HPV risk strata, and across all screening age groups and is a better option for triage of vaccinated populations.