Prevention and prognosis of cervical cancer : the interplay of human papillomavirus, vaccination and screening

Human papillomavirus (HPV) is the major cause of cervical cancer. The well-established natural history from HPV infection to the occurrence of invasive cervical cancer serves as the basis for prevention of cervical cancer through prophylactic HPV vaccination (primary prevention) and cervical screening (secondary prevention). Cervical cancer detected through screening also has better chances of being cured than cancers not detected through screening. This thesis addresses research questions on prevention and prognosis of cervical cancer within the framework of the interplay of HPV, vaccination, and cervical screening, and it also provides insights for evidence-based decision-making. In Paper I, we examined the association between cervical screening with cytology and risk of adenosquamous cell carcinoma (ASC) and rare histological types of invasive cervical carcinoma (RICC). Based on a nationwide cervical cancer Audit, we conducted a nested casecontrol study including 338 cases of ASC and RICC diagnosed during 2002-2011 in Sweden with their year-of-birth-matched controls. We found that screening with cytology was associated with decreased risk of ASC and RICC, but the magnitude of risk reduction in relation to cervical screening was less for RICC than for ASC. The majority of ASC and RICC cases were positive for high-risk HPV in tumor tissues. In Paper II, we evaluated whether the tumor high-risk human papillomavirus (hrHPV) status was associated with the prognosis of cervical cancer. In a nationwide population-based study, we included 2845 primary invasive cervical cancer cases diagnosed in Sweden during 2002– 2011, and comprehensively tested diagnostic blocks for 13 hrHPV types and 24 HPV types which were not established as oncogenic. Women with hrHPV-positive cervical tumors had a substantially better prognosis (39% lower excess mortality) than women with hrHPV-negative tumors. The difference of prognosis by tumor hrHPV status remained statistically significant, irrespective of age, cancer stage, and histological type. In Paper III, we investigated screening performance in terms of positive predictive value (PPV) of cytology for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) among HPVvaccinated birth cohorts. Using a population-based cohort design, we included women born 1989-1993 who were resident in Sweden since the introduction of HPV vaccination and attended cervical screening at age 23, based on records from Swedish National Cervical Screening Registry (NKCx). We found that vaccinated women had lower PPV of cytology for CIN2+ compared to unvaccinated women. The decrease in PPV was greater among women vaccinated before age 17 than those vaccinated at age 17-22. In Paper IV, we assessed the association between HPV vaccination and the risk of invasive cervical cancer in a population-based cohort study. An open cohort of women aged 15-30 (including age 30) living in Sweden were included and followed during 2006-2017 for HPV vaccination and first occurrence of invasive cervical cancer. The findings showed that HPV vaccination was related to a 52% lower risk of invasive cervical cancer for vaccinated women compared to unvaccinated women. Younger age at vaccination initiation was associated with a more pronounced risk reduction (83% risk reduction when vaccinated before age 17). In conclusion, this thesis shows that cervical screening can effectively reduce the risk of ASC and RICC, which is beyond the established evidence on preventing squamous cell carcinoma and adenocarcinoma. HPV vaccination can effectively reduce the risk of cervical cancer; the ultimate goal of cervical cancer prevention. With the implementation of HPV vaccination, the PPV of cytology for CIN2+ has decreased in vaccinated women compared to unvaccinated women, especially among those vaccinated at younger age. Tumor hrHPV status is associated with the prognosis of cervical cancer, which could add value to the clinically established prognostic factors. Taken together, these studies add knowledge to the current understanding of cervical cancer prevention strategies and prognosis of cervical cancer, and serve as a basis for evidence-based decision-making and policy changes in the future. LIST OF SCIENTIFIC PAPERS I. Lei J, Andrae B, Ploner A, Lagheden C, Eklund C, Nordqvist Kleppe S, Wang J, Fang F, Dillner J, Elfström KM, Sparén P. Cervical screening and risk of adenosquamous and rare histological types of invasive cervical carcinoma: population based nested case-control study. BMJ. 2019 Apr 3;365:l1207 II. Lei J, Ploner A, Lagheden C, Eklund C, Nordqvist Kleppe S, Andrae B, Elfström KM, Dillner J, Sparén P, Sundström K. High-risk human papillomavirus status and prognosis in invasive cervical cancer: A nationwide cohort study. PLoS medicine 2018 15;10 e1002666 III. Lei J, Ploner A, Lehtinen M, Sparén P, Dillner J, Elfström KM. Impact of HPV vaccination on cervical screening performance: A population-based cohort study. (Submitted) IV. Lei J, Ploner A, Elfström KM, Wang J, Roth A, Fang F, Sundström K, Dillner J, Sparén P. Effectiveness of HPV vaccination against invasive cervical cancer: A population-based cohort study. (Submitted) RELATED PUBLICATIONS (Not included in the thesis)  Lagheden C, Eklund C, Lamin H, Kleppe SN, Lei J, Elfström KM, et al. Nationwide comprehensive human papillomavirus (HPV) genotyping of invasive cervical cancer. Br J Cancer. 2018;118(10):1377-81.  Wang J, Elfström KM, Andrae B, Nordqvist Kleppe S, Ploner A, Lei J, et al. Cervical cancer case-control audit: Results from routine evaluation of a nationwide cervical screening program. Int J Cancer. 2019.  Arroyo Muhr LS, Lagheden C, Eklund C, Lei J, Nordqvist Kleppe S, Sparén P, et al. Sequencing detects human papillomavirus in some apparently HPV-negative invasive cervical cancers. J Gen Virol. 2019. CONTENTS