Evoluzione dello screening cervicale e ruolo del GISCI. Silvia Franceschi, CRO, Aviano NO CONFLICTS OF INTEREST

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1 Evoluzione dello screening cervicale e ruolo del GISCI Silvia Franceschi, CRO, Aviano NO CONFLICTS OF INTEREST

2 Lancet Oct 6;2(8406): "Pap" smear and the risk of cervical neoplasia: quantitative estimates from a case-control study.la Vecchia C, Franceschi S, Decarli A, Fasoli M, Gentile A, Tognoni G Compared with no previous screening smear, the RR for invasive cancer was 0.44 (with 95% CI = ) for those who had had one smear and 0.20 (95% CI = ) for those who had had two or more smears. The RR for intervals of more than 5, 3-5, and less than 3 years were 0.36, 0.18, and 0.10 for invasive cancer. RRs were not materially modified by adjustment for the major risk factors for cervical cancer, such as indicators of socioeconomic status and sexual habits. 64% of invasive cervical cancers could be prevented by screening at intervals of more than 5 years, an additional 18% by reducing the interval to 3-5 years

3 Trends in cervical cancer in Italy: BADATE: Senza interventi sarebbe probabilmente Effetto screening

4 Carrozzi et al, Epidemiologia&Prevenzione, % di copertura: la difficoltà dell ultimo miglio

5 GISCI: 20 yearactivity and > 20 key publications Tumori Nov- Dec;84(6): A first survey of organized cervical cancer screening programs in Italy. GISCi working group on organization and evaluation. Gruppo Italiano Screening Citolo gico. Ronco G 1, Iossa A, Naldoni C, Pilutti S, Anghinoni E, Zappa M, Dalla Palma P, Ciatto S, Segnan N 2017

6 A quando tutta l Italia? 2012

7 GISCI website

8 Eur J Can, 2016 The % of HPV+ women directly referred to colposcopy varied across programmes (20-57%; average 37%) and so did CIN2+ detection (49e94%; average 77%). Overall, 63% (range 41-75%) of HPV+ were referred to colposcopy either immediately or at HPV repeat. An absolute 10% increase in immediate colposcopy referral resulted in only 4.2% (95% CI: %) increase in overall referral. An absolute 10% increase in cytology s sensitivity resulted in a 1.1% (95% CI: %) increase in overall CIN2+ detection. Repeat HPV testing limits the effect of subjectivity of cytology or different sensitivity of any triage test

9 Tailored screening protocols based on vaccination status could be replaced by one size fits all protocols only when a herd immunity effect has been reached. Vaccinated women should start screening at age 30, instead of 25, with HPV test. >5-yrs intervals for re-screening HPV-neg women are predictable, but research is needed on optimal screening time points. For non-vaccinated women and for women vaccinated in their fifteenth year or later, the current protocol should be kept.

10 New Technologies for Cervical Cancer Screening (NTCC): il gioiello della corona

11 2007 > 20 Key publications from NTCC 2018

12 Randomised controlled trial 1:1 Nested in organised screening programmes Nine programmes in 6 Regions Recruitment phase Phase Torino Trento Padova Verona Imola Bologna Ravenna Firenze Viterbo

13 CONVENTIONAL ARM women Conventional cytology Routine protocol CONVENTIONAL ARM women Conventional cytology Routine protocol PHASE I (2002-3) women PHASE 2 (2002-3) women EXPERIMENTAL ARM women Thin layer cytology + hrhpv DNA test Referral to colposcopy with cytology ASCUS or more severe With normal cytology but HPV positive(1 pg/ml): - if age 35 years or more. referral to colposcopy - If age < 35 years retesting for HPV and cytology and referral if still HPV positive or cytology became ASCUS+ EXPERIMENTAL ARM women hrhpv DNA test Referal to colposcopy if positive at 1 pg/ml cutoff. If HPV+ and no CIN2+ detected post-colposcopy follow-up until HPV negative At 2 + screening round cytology in both arms SUPER-SMART DESIGN

14 Baseline accuracy

15 NTCC STUDY PHASE 1 YRS YRS Detection rate, positive predictive value (PPV), relative sensitivity and relative PPV for histology-confirmed CIN2+ vs conventional cytology ASCUS HPV 1pg/mL HPV 2pg/mL Liquid-based cytology ASCUS or HPV 1pg/mL Conventional cytology ASCUS Detectio n Rate per 1000 Relative sensitivity (95% CI) Endpoint CIN2+ % Experimental arm (1.00 to 2.04) (0.98 to 2.01) (1.03 to 2.09) Conventional arm PPV Relative PPV (95% CI) (0.33 to 0.98) (0.45 to 1.27) (0.23 to 0.66) (referent) (referent) Ronco et al. J. Natl.Cancer. Inst. 2006; 98: modified

16 NTCC STUDY PHASE 1 - WOMEN yrs Rel. sensitivity and relative PPV vs. conventional cyto ASCUS Similar sensitivity gain but detection rate nearly double than older women. Some regressive HPV. Criteria for referral (retrospectively applied) HPV 1pg/ml; triage HPV+ by cytology; if cytology <ASCUS repeat both tests and refer if either is positive Endpoint CIN2+ Detection Relative PPV % Rate sensitivity per 1000 (95%CI) EXPERIMENTAL ARM ( ) Relative PPV (95%CI) ( ) HPV 2pg/ml; if cytology <ASCUS repeat both tests and refer if both are positive ( ) ( ) Experimental procedure ( ) ( ) CONVENTIONAL ARM Conventional Cytology ASCUS Ronco et al. Lancet Oncol 2006; 7: modif

17 Longitudinal rounds 1 and 2

18 NTCC STUDY WOMEN AGE Lead time gain DETECTION OF CIN 2 or 3 or AIS BY STUDY PERIOD Phase 1 Women enrolled (invited to round 2) screening round1 N (%) screening round2 N (%) Total over both rounds N (%) HPV group (16332) 107 (0.64%) 11 (0.07%) 118 (0.71%) Cytology group (16561) 55 (0.33%) 15 (0.09%) 70 (0.42%) RR (95%CI) 1.94 ( ) Phase ( ) 1.68 ( ) HPV group (17401) 98 (0.55%) 5 (0.03%) 103 (0.58%) Cytology group (17658) 46 (0.26%) 17 (0.10%) 63 (0.35%) RR (95%CI) 2.13 ( ) P heterogeneity between phases Ronco et al. Lancet Oncol 2010 modif 0.30 ( ) 1.64 ( )

19 NTCC INSPIRED the pooled analysis of EU trials for cervical Ca incidence All RCTs with 2 screening rounds SWEDESCREEN triage POBASCAM triage ARTISTIC triage NTCC no triage 176,464 women enrolled Median follow-up 6.5 years 1,214,415 person-years of observation 107 invasive carcinomas identified

20 Risk of invasive carcinoma per 100,000 women after a negative entry test (HPV- in HPV arm and cytology- in cytology arm) Solid lines: HPV group. Dotted lines: cytology group Pooled RR 0.30 ( ) 3.5 years 5.5 years cytology 15.4 (CI ) 36.0 ( ) HPV 4.6 ( ) 8.7 ( ) observations censored 2.5 yrs after CIN2 or CIN3 detection, if any Ronco et al. Lancet 2013 modif.

21 Big contributions on many other aspects of HPV epidemiology and cancer prevention Reproducibility HPV test (Carozzi et al. Am.J.Clin.Pathol. 2005) LBC (Confortini et al. Diagnostic Cytopathol 2007) Histology (Dalla Palma et al. Am.J.Clin.Pathol. 2008, Dalla Palma et al. Am.J.Clin.Pathol. 2009) Analytical false positives HC2 (Gillio-Tos et al. J Clin Microbiol 2013) Baseline cost per detected hgcin (Giorgi-Rossi et al Int J Cancer 2007) HPV testing for management of unsatisfactory LBC (Giorgi-Rossi et al. Am.J.Clin.Pathol. 2012) Prevalence by genotype/age/centre Baussano et al. BMC Infect Dis 2013; Carozzi et al. J Clin Virol. 2014

22 Mimmo Ronco: da Biometria (1983) all HPV

23 Infections and Cancer, Fond. Merieux, Annecy, 2000

24 Cervical cancer screening,

25 Qualche verso per Mimmo e gli altri della mia generazione (o circa) C è un tempo per le sere sotto le stelle Ed uno per le sere con gli album di foto* Ad una certa età si dovrebbe essere esploratori Calmi eppure in movimento Verso un altra intensità East Coker, from Four Quartets T: S: Eliot *Sarebbe ora di fare qualche foto...

26 HPV and cancer: another intensity Genomic Microenvironment Immunity landscape

27 HPV16 E7 was devoid of variants in precancers/cancers compared to higher levels in the controls Strict conservation of the 98 amino acids of E7, which disrupts Rb function, is critical for HPV16 carcinogenesis, presenting a highly specific target for etiologic and therapeutic research. 2017

28 2015 Decrease in estrogen receptor alpha (ERα) in CxC progression ERα expression shuts off in tumor epithelium, but stromal fibroblasts in microenvironment retain ERα Role of stromal estrogen signaling in CxCa development and may have implications for CxC management and control

29 C2 (IFN-γ dominant) comprises of cervical tumors, highly mutated breast, gastric, ovarian, HNSC, and shows the highest M1/M2 macrophage polarization, a strong CD8 signal and greatest T-cell receptor diversity. C2 also showed a high proliferation rate, which may override an evolving type I immune response C2 tumors show an unfavorable survival despite having a robust anti-tumor immune response 6 Immune sub-types The immune response may Not be enough to control the rapid growth of C2 tumors Another hypothesis is that C2 tumors in are those that have already been remodeled by the lymphocyte infiltrate and have escaped immune recognition

30 Conclusioni Il GISCI ha rappresentato in Italia un esempio unico di lavoro multidisciplinare e indipendente. Si tratta di un modello da seguire anche nel campo della prevenzione e del trattamento dei tumori

31 Criterion NTCC STUDY PHASE 1 WOMEN YRS Sensitivity and specificity of liquid-based cytology and human papillomavirus (HPV) in the experimental arm* Not corrected for verification bias Sensitivity (95% CI) Specificity (95% CI) CIN2+ CIN3+ CIN2+ CIN3+ Liquid-based cytology ASCUS 54/73=74.0% (62.4 to 83.6) 31/38=81.6% (65.7 to 92.3) 15,593/16,443= 94.8% (94.5 to 95.2) 15,605/16,478= 94.7% (94.4 to 95.0) HPV 1pg/mL HPV 2pg/mL 73/75=97.3% (90.7 to 99.7) 72/75=96.0% (88.8 to 99.2) 38/39=97.4% (86.5 to 99.9) 37/39=94.9% (82.7 to 99.4) 15,223/16,335= 93.2% (92.8 to 93.6) 15,499/16,335= 94.9% (94.5 to 95.2) 15,224/16,371= 93.0% (92.6 to 93.4) 15,500/16,371= 94.7% (94.3 to 95.0) *Women (including 1 CIN2 and 1 CIN3+) without valid cytology (n=190) were excluded from computations for liquidbased cytology =ASCUS. Women (no CIN2+) were excluded from computations for HPV (n=296). Women (including 1 CIN2 and 1 CIN3+) without either valid test were excluded from computations of P values comparing tests (n=451). ASCUS = atypical squamous cells of undetermined significance. P<.001 versus Liquid-based cytology =ASCUS (McNemar test) P=0.034 versus Liquid-based cytology =ASCUS (McNemar test) Ronco et al. J. Natl.Cancer. Inst. 2006; 98: