Evoluzione dello screening cervicale e ruolo del GISCI

Silvia Franceschi, CRO, Aviano

NO CONFLICTS OF INTEREST

Lancet. 1984 Oct 6;2(8406):779-82."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 = 0.24-0.80) for those who had had one smear and 0.20 (95% CI = 0.13-0.32) 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

https://www.ncbi.nlm.nih.gov/pubmed/6148523https://www.ncbi.nlm.nih.gov/pubmed/?term=La%20Vecchia%20C%5BAuthor%5D&cauthor=true&cauthor_uid=6148523https://www.ncbi.nlm.nih.gov/pubmed/?term=Franceschi%20S%5BAuthor%5D&cauthor=true&cauthor_uid=6148523https://www.ncbi.nlm.nih.gov/pubmed/?term=Decarli%20A%5BAuthor%5D&cauthor=true&cauthor_uid=6148523https://www.ncbi.nlm.nih.gov/pubmed/?term=Fasoli%20M%5BAuthor%5D&cauthor=true&cauthor_uid=6148523https://www.ncbi.nlm.nih.gov/pubmed/?term=Gentile%20A%5BAuthor%5D&cauthor=true&cauthor_uid=6148523https://www.ncbi.nlm.nih.gov/pubmed/?term=Tognoni%20G%5BAuthor%5D&cauthor=true&cauthor_uid=6148523

Trends in cervical cancer in Italy: BADATE: Senza interventi sarebbe probabilmente

Effetto screening

Carrozzi et al, Epidemiologia&Prevenzione, 201580% di copertura: la difficolt dellultimo miglio

Tumori. 1998 Nov-Dec;84(6):624-30.A first survey of organizedcervical cancerscreening programs in Italy. GISCi working group on organization and evaluation. Gruppo Italiano Screening Citologico.Ronco G1, Iossa A, Naldoni C, Pilutti S, Anghinoni E, Zappa M, Dalla Palma P, Ciatto S, Segnan N

2017

GISCI: 20 year-activity and > 20 key publications

https://www.ncbi.nlm.nih.gov/pubmed/10080665https://www.ncbi.nlm.nih.gov/pubmed/?term=Ronco%20G%5BAuthor%5D&cauthor=true&cauthor_uid=10080665https://www.ncbi.nlm.nih.gov/pubmed/?term=Iossa%20A%5BAuthor%5D&cauthor=true&cauthor_uid=10080665https://www.ncbi.nlm.nih.gov/pubmed/?term=Naldoni%20C%5BAuthor%5D&cauthor=true&cauthor_uid=10080665https://www.ncbi.nlm.nih.gov/pubmed/?term=Pilutti%20S%5BAuthor%5D&cauthor=true&cauthor_uid=10080665https://www.ncbi.nlm.nih.gov/pubmed/?term=Anghinoni%20E%5BAuthor%5D&cauthor=true&cauthor_uid=10080665https://www.ncbi.nlm.nih.gov/pubmed/?term=Zappa%20M%5BAuthor%5D&cauthor=true&cauthor_uid=10080665https://www.ncbi.nlm.nih.gov/pubmed/?term=Dalla%20Palma%20P%5BAuthor%5D&cauthor=true&cauthor_uid=10080665https://www.ncbi.nlm.nih.gov/pubmed/?term=Ciatto%20S%5BAuthor%5D&cauthor=true&cauthor_uid=10080665https://www.ncbi.nlm.nih.gov/pubmed/?term=Segnan%20N%5BAuthor%5D&cauthor=true&cauthor_uid=10080665

2012

A quando tutta lItalia?

GISCI website

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: 3.3-5.1%) increase in overall referral. An absolute 10% increase in cytologys sensitivity resulted in a 1.1% (95% CI: 0.1-2.0%) increase in overall CIN2+ detection.Repeat HPV testing limits the effect of subjectivity of cytology or different sensitivity of any triage test

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.

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

2007

2018

> 20 Key publications from NTCC

Randomised controlled trial 1:1

Nested in organised screening programmes

Nine programmes in 6 Regions

Recruitment phase 1 2002-3 Phase 2 2003-4

Torino Bologna

Trento Ravenna

Padova Firenze

Verona Viterbo

Imola

PHASE I (2002-3)45174 women

PHASE 2 (2002-3)49196 women

CONVENTIONAL ARM22466 women

EXPERIMENTAL ARM22708 women

Routine protocol

Conventional cytology

Thin layer cytology + hrHPV DNA testReferral 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+

Referal to colposcopy if positive at 1 pg/mL cutoff.

Routine protocol

Conventional cytology

hrHPV DNA test

CONVENTIONAL ARM24535 women

EXPERIMENTAL ARM24661 women

If HPV+ and no CIN2+ detected post-colposcopy follow-up until HPV negative

At 2+ screening round cytology in both arms

SUPER-SMART DESIGN

Baseline accuracy

Endpoint CIN2+ Detection Rate

per 1000

Relative sensitivity (95% CI)

PPV %

Relative PPV (95% CI)

Experimental arm HPV 1pg/mL

4.37 1.43 (1.00 to 2.04)

6.6 0.58 (0.33 to 0.98)

HPV 2pg/mL

4.25 1.41 (0.98 to 2.01)

8.5 0.75 (0.45 to 1.27)

Liquid-based cytology ASCUS or HPV 1pg/mL

4.49

1.47

(1.03 to 2.09)

4.5

0.40

(0.23 to 0.66) Conventional arm

Conventional cytology ASCUS

3.06 1.00 (referent) 11.4 1.00 (referent)

Ronco et al. J. Natl.Cancer. Inst. 2006; 98: 765-74 modified

NTCC STUDY PHASE 1 YRS 35-60 YRSDetection rate, positive predictive value (PPV), relative sensitivity and relative PPV for histology-confirmed CIN2+ vs conventional cytology

ASCUS

Endpoint CIN2+

Detection Rate

per 1000

Relative sensitivity

(95% CI)

PPV %

Relative PPV

(95% CI)

Experimental arm

HPV ( 1pg/mL

4.37

1.43

(1.00 to 2.04)

6.6

0.58

(0.33 to 0.98)

HPV ( 2pg/mL

4.25

1.41

(0.98 to 2.01)

8.5

0.75

(0.45 to 1.27)

Liquid-based cytology ( ASCUS

or HPV (1pg/mL

4.49

1.47

(1.03 to 2.09)

4.5

0.40

(0.23 to 0.66)

Conventional arm

Conventional cytology ( ASCUS

3.06

1.00 (referent)

11.4

1.00 (referent)

NTCC STUDY PHASE 1 - WOMEN 25-34 yrsRel. sensitivity and relative PPV vs. conventional cyto ASCUS

Similar sensitivity gain but detection rate nearly double than older women. Some regressive HPV.

Endpoint CIN2+ Criteria for referral (retrospectively applied) Detection

Rate per 1000

Relative sensitivity (95%CI)

PPV % Relative PPV

(95%CI) EXPERIMENTAL ARM

HPV 1pg/ml; triage HPV+ by cytology; if cytology

Longitudinal rounds 1 and 2

NTCC STUDY WOMEN AGE 35-60

DETECTION OF CIN 2 or 3 or AIS BY STUDY PERIODWomen enrolled (invited to round 2)

screening round1 N (%)

screening round2 N (%)

Total over both rounds N (%)

Phase 1HPV group 16706 (16332) 107 (0.64%) 11 (0.07%) 118 (0.71%)

Cytology group

16658 (16561) 55 (0.33%) 15 (0.09%) 70 (0.42%)

RR (95%CI) 1.94(1.40-2.68)

0.74(0.34-1.62)

1.68(1.25-2.26)

Phase 2HPV group 17724 (17401) 98 (0.55%) 5 (0.03%) 103 (0.58%)

Cytology group

17747 (17658) 46 (0.26%) 17 (0.10%) 63 (0.35%)

RR (95%CI) 2.13(1.50-3.03)

0.30(0.11-0.81)

1.64(1.18-2.24)

P heterogeneity between phases

0.70 0.15 0.90

Ronco et al. Lancet Oncol 2010 modif

Lead time gain

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

Risk of invasive carcinoma per 100,000 women after a negative entry test

(HPV- in HPV arm and cytology- in cytology arm)

3.5 years 5.5 yearscytology 15.4 (CI 7.9-27.0) 36.0 (23.2-53.5) HPV 4.6 (1.1-12.1) 8.7 (3.3-18.6)

observations censored 2.5 yrs after CIN2 or CIN3 detection, if any

Solid lines: HPV group.

Dotted lines: cytology group

Pooled RR

0.30 (0.15-0.60)

Ronco et al. Lancet 2013 modif.

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

Mimmo Ronco: da Biometria (1983) allHPV

Infections and Cancer, Fond. Merieux, Annecy, 2000

Cervical cancer screening, 2004- 2044

Qualche verso per Mimmo e gli altri della mia generazione (o circa)

C un tempo per le sere sotto le stelleEd uno per le sere con gli album di foto*Ad una certa et si dovrebbe essere esploratoriCalmi eppure in movimentoVerso unaltra intensit

East Coker, from Four QuartetsT: S: Eliot

*Sarebbe ora di fare qualche foto...

HPV and cancer: another intensity

Genomic

Microenvironment

Immunity landscape

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

Decrease in estrogen receptor alpha (ER) in CxCprogression ER expression shuts off in tumor epithelium, but stromal fibroblasts in micro-environment retain ER Role of stromal estrogensignaling in CxCa develop-ment and may have implic-ations for CxC management and control

2015

C2 (IFN- 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 responseC2 tumors show an unfavorable survival despite having a robust anti-tumorimmune response

The immune response mayNot 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

6 Immune sub-types

ConclusioniIl 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

NTCC STUDY PHASE 1 WOMEN 35-60 YRSSensitivity and specificity of liquid-based cytology and human

papillomavirus (HPV) in the experimental arm*Not corrected for verification bias

*Women (including 1 CIN2 and 1 CIN3+) without valid cytology (n=190) were excluded from computations for liquid-based cytology =ASCUS. Women (no CIN2+) were excluded from computations for HPV (n=296). Women (including 1CIN2 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