Long-term cervical cancer risk following negative hrHPV-based versus negative cytology-based screening: A population-based study

BACKGROUND: Randomized trials have shown that hrHPV-testing provides better protection against cervical cancer than cytology. However, long-term assessment of programme sensitivity remains essential. In the Netherlands, hrHPV-screening replaced cytology in 2017. We estimated the long-term cervical cancer risk following negative results in hrHPV- versus cytology-based screening. METHODS: Screening and histology data from the nationwide Dutch pathology databank (Palga) were used to identify 469,116 women without referral in 2014 (cytology-based) and 362,128 in 2017 (hrHPV-based), representing 4,071,690 person-years. Cervical cancer risk following non-referral, including interval cancers (IC) and those detected in the next screening round were analysed. FINDINGS: The incidence rate per 100,000 person-years was 3.3 IC following non-referral in cytology-based versus 2.7 following non-referral in hrHPV-based screening. Including next-round cancers, these numbers increase to 5.7 and 4.5. HrHPV-test negative women had a 50 % lower IC risk compared to those with normal cytology (HR 0.5; 95 % CI: 0.3-0.8), and 60 % lower when including next-round cancers (HR 0.4; 95 % CI: 0.3-0.5). HrHPV-positive women without referral had the highest cancer risk: 24 IC per 100,000 person-years, rising to 45 when including next-round cancers. Their risk was 3.4 times higher than for women with positive primary cytology without referral (HR: 3.4; 95 % CI: 1.1-8.1 for IC and HR: 3.4; 95 % CI: 1.4-8.1 including next-round cancers). INTERPRETATION: A negative hrHPV test was linked to lower long-term risk of cervical cancer than normal cytology, supporting longer screening intervals for hrHPV-negative women. However, hrHPV-positivity with negative cytology was associated with increased risk, suggesting the possible need for alternative triage guidelines.