Optimization Study Of Cervical Cancer Screening

ObjectivesFocusing on HPV DNA testing,firstly,this article was aimed to evaluate the long-term performance,predictive ability and appropriate screening interval of self-collected HPV DNA testing and the to explore the feasibility;then to evaluate the clinical performance and predictive value of host gene(ASTNl et al)methylation panel as the triage method for HPV positive women;and finally to analyze the clinical performance of HPV DNA testing among post-menopausal women and to explore the optimal screening method for post-menopausal women.Ultimately to promote and advance cervical cancer screening program in China from the perspective of the way of cervical cancer screening,triage method for HPV positive women and optimal screening method for post-menopausal women.Materials and methods1.Long-term screening performance of self－collected HPV testing:The cervical cancer screening cohort was established in 1999 in Xiangyuan County,Shanxi province(SPOCCS-I)with 1997 women aged 35 to 45 years.All women were screened by self-collected HPV testing,physician-collected HPV testing,liquid based cytology(LBC)and visual inspection of acetic acid(VIA)at baseline,and were followed up in 2005,2010,2014,respectively.The long-term clinical performance of screening methods at different follow-up time were analyzed with the study endpoint of incident CIN2+and cumulative CIN2+,respectively.The CIN2+cumulative incidence rate(CIR)of women with different baseline screening result was evaluated by Kaplan-Meier.The screening interval of self-collected HPV testing was explored based on the CIN2+CIR of women with negative screening result.2.Host gene(SOX17 et al)methylation triage for HPV positive women:The self-collected HPV cervical cancer screening cohort was conducted in 2017 in Shanxi and Inner Mongolia with 9526 women aged 30 to 64 years old.2112 women with HPV positivity at baseline were followed up after one year.The targetd host gene(SOX17,DLX1,ITGA4.RXFP3,ASTNI and ZNF671)methylation testing based on PCR was performed on the residual cytology sample.The optimal panel of the targeted host gene methylation for CIN2+was explored.Then the triage clinical performance,predictive value and triage efficiency of the host gene methylation panel was compared to cytology,HPV16/18 genotyping with cytology,respectively.The feasibility of host gene as a triage method for HPV positive women was evaluated comprehensively.3.Screening method for post-menopausal women:Pool the 17 cross-sectional cervical cancer screening studies conducted during 1991 to 2008.The HPV,cervical precancer and cervical cancer prevalence of pre-menopausal women were compared to that of post-menopausal women.The optimal screening method for post-menopausal women was explored by comparing the clinical performance and screening efficiency of HPV DNA testing,LBC,VIA and several screening strategies based on the above primary screening methods.Results1.Self-collected HPV testing prospectively detected 83.3%(95%CI:74.9%,89.3%)?70.3%(95%CI:62.5%,77.2%)and 63.3%(95%CI:55.7%,70.2%)of cumulative CIN2+at 6-year,11-year and 15-year follow-up,respectively.The cumulative sensitivity of self-collected HPV testing was 16%lower than that of physician-collected HPV testing over 15 years,but comparable to cytology and significantly higher than VIA by at least 20%.Among women positive by self-collected HPV testing at baseline,26.2%(95%CI:21.5%,30.9%)developed CIN2+during 6-year follow-up and no difference was observed with physician-collected HPV testing even15 years after baseline(P>0.05).Negative self-collected HPV results provided great protection against CIN2+and ascertained CIN2+cumulative incident rates as low as 1.1%(95%CI:0.5%,1.7%)at the 6-year follow-up.2.Host gene(SOX17 et al)methylation panel remarkably decreased the colposcopy referral rate to 21.6%,which was much lower than that of cytology(44.3%,P<0.001)and HPV16/18 with combination of cytology(53.1%,p<0.001).Compared to the above two triage strategies,host gene methylation panel maintained the high sensitivity of 96.9%(95%CI:84.3%5 99.5%)for CIN3+,and with the higher specificity of 79.9%(95%CI:77.9%,81.8%)compared to cytology(56.7%,P<0.001)and HPV 16/18 genotyping with combination of cytology(47.8%,p<0.001).To detect one CIIN3+case,host gene methylation panel just needed to refer about 11 women,correspondingly,the number for cytology,HPV 16/18 genotyping with combination of cytology were about 24 and 27.The CIR of CIN3+for women with positive methylation result at baseline reached 11.9%(95%CI:8.4%,15.4%),which was highest compared to cytoIogy(5.9%,p=0.001),HPV16/18 genotyping with combination of cytology(5.4%,p<0.001).3.Premenopausal and postmenopausal women had equal HPV infection and cervical neoplasia prevalence(p>0.05).With CIN3+as study endpoint,the sensitivity of VIA decreased from 56.0%(95%CI:51.3%,60.6%)among premenopausal women to 41.7%(95%CI:28.4%,55.9%)among postmenopausal women,which was the lowest compared to HPV DNA testing(97.5%,P<0.001)and cytology(95.4%,P<0.001).Only HPV DNA testing remained similar satisfactory clinical performance among premenopausal and postmenopausal women,with sensitivity of about 95%and specificity of 85%.Compared to HPV DNA testing,among 7 screening strategies,only cotest(HPV DNA testing with cytology,HPV DNA testing with VIA)had higher sensitivity with no significant difterence(both 100%,both P>0.05),but with lower specificity(75.6%,79.5%,both P<0.001).The specificities of HPV DNA viral load triage,HPV DNA testing with cytology triage,cytology with HPV tiage for ASCUS were higher(all P<0.001)but the sensitivities were lower(p=0.016,0.001,0.006,respectively)than that of HPV DNA testing.Conclusions1.From the prospective perspective,self－collected HPV testing demonstrated lower sensitivity than physician-collected HPV testing but performed comparably to cytology and provided satisfactory assurance against CIN2+.2.The host gene(SOX17 et al)methylation panel significantly decreased the colposcopy referral rate,and improved the clinical performance and triage efficiency compared to cytology,HPV16/18 genotyping with cytology.3.Only HPV DNA testing still maintained satisfactory clinical performance among post-menopausal women.Compared to other triage strategies,HPV DNA testing alone showed satisfactory clinical efficiency and comparable clinical performance among post-menopausal women.HPV DNA testing was applicable to post-menopausal women as cervical cancer primary screening method.Based on the screening interval promoted by guideline,we can adopt self-collected HPV testing with five-year interval as an alternative screening method in cervical cancer prevention to improve screening coverage.And the host gene(ASTN1/DLX1/ITGA4/RXFP3/SOX17/ZNF671)methylation panel could be a promising option for triage HPV positive women.HPV DNA testing is suitable for post-menopausal women to respond to the challenges posed by population aging.