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

Abstract

Background: High-risk human papillomavirus (hrHPV) testing has higher sensitivity but lower specificity than cytology for cervical (pre)-cancerous lesions. Therefore, triage of hrHPV-positive women is needed in cervical cancer screening.Methods: A cohort of 1,100 hrHPV-positive women, from a population-based screening trial (POBASCAM: n ¼ 44,938; 29-61 years), was used to evaluate 10 triage strategies, involving testing at baseline and six months with combinations of cytology, HPV16/18 genotyping, and/or repeat hrHPV testing. Clinical endpoint was cervical intraepithelial neoplasia grade 3 or worse (CIN3

Cervical cancer risk in HPV‐positive women after a negative FAM19A4/mir124‐2 methylation test: A post hoc analysis in the POBASCAM trial with 14 year follow‐up

“…Various studies have evaluated triage strategies for HPV‐positive women in screening cohorts, including virus‐ and host cell‐based strategies, such as HPV16/18 genotyping,4, 5 HPV E7 mRNA analysis,6, 7 cytology,8, 9 p16/ki67 dual staining,10, 11 epigenetic changes in the host and/or viral genome,12, 13 and combinations thereof 8, 9. At present, reflex cytology testing, which has been adopted in the Dutch HPV‐based screening program, is considered an appropriate triage test,1, 4, 8, 9, 14 although a short‐term repeat cytology is needed to assure a sufficiently low risk of cervical cancer for triage test‐negative women. Furthermore, cytology is subjective and prior knowledge of HPV presence, as is the case in the setting of primary HPV screening, will likely increase the false‐positivity rate 15.…”

Management of high-risk HPV-positive women for detection of cervical (pre)cancer

“…Currently, Pap cytology is the most advocated triage strategy for hrHPV-positive women [39,40,45,46]. Due to experience with Pap cytology as a primary cervical screening test for decades, Pap cytology is a well-studied strategy embedded in the healthcare infrastructure of many developed countries.…”

“…The main limitation of Pap cytology is its subjective nature, which results in a suboptimal sensitivity for ≥CIN3. In large population-based screening studies (ATHENA n = 4275; VUSA-screen n = 1303, POBASCAM n = 1100), triage of hrHPV-positive women by a single Pap cytology test had a sensitivity for ≥CIN3 varying between 52.8% and 75.4%, with a corresponding specificity of 78.0-85.6% [39,40,47]. Of note, these estimates were obtained in study settings where cytologists were blinded to hrHPV-test results.…”

“…Ideally, the negative predictive value (NPV) for ≥CIN3 should be determined longitudinally to assess the screening interval that can be maintained after a negative triage test [38]. In previous studies evaluating the clinical applicability of different triage strategies, a cross-sectional NPV threshold of 98% for ≥CIN3 has been suggested, indicating that the ≥CIN3 risk after a negative triage test result should be less than 2% [38][39][40]. This threshold is similar to the ≥CIN3 risk of women with borderline or mild dyskaryosis cytology followed by a negative cytology result at 6 and 18 months follow-up (1.2%) [41], which is presently accepted in the Netherlands.…”

“…In addition, the positive predictive value (PPV) has been suggested as a criterion for implementation, as it indicates the ability of a test to prevent unnecessary colposcopy referrals. Of note, this is a more subjective criterion dependent of the available resources and the screening interval used in different countries: in US settings, using a 3-year interval, a PPV threshold of 10% is considered acceptable [38], whereas in the Netherlands, where 5-year intervals are used, this threshold is 20% [39,40].…”