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Comparison of HPV Primary Screening Algorithms with Cytology- Based Strategies GISCI Workshop June 11, 2014 Catherine Behrens, MD, PhD, FACOG Director Clinical Research, Roche Molecular Systems

Comparison of HPV Primary Screening Algorithms with

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Page 1: Comparison of HPV Primary Screening Algorithms with

Comparison of HPV Primary Screening Algorithms with Cytology-Based Strategies

GISCI Workshop June 11, 2014 Catherine Behrens, MD, PhD, FACOG Director Clinical Research, Roche Molecular Systems

Page 2: Comparison of HPV Primary Screening Algorithms with

FDA approved Primary Screening Algorithm

The ATHENA Trial Design

Justification for Beginning Primary Screening at 25 years

ATHENA Longitudinal Data

3 year Performance of Strategies

Conclusions

Agenda

2

Page 3: Comparison of HPV Primary Screening Algorithms with

FDA approved Primary Screening Algorithm

The ATHENA Trial Design

Justification for Beginning Primary Screening at 25 years

ATHENA Longitudinal Data

3 year Performance of Strategies

Conclusions

Agenda

3

Page 4: Comparison of HPV Primary Screening Algorithms with

Indicazione Approvata per lo Screening con HPV test

4

Page 5: Comparison of HPV Primary Screening Algorithms with

Algoritmo di Screening HPV con genotipizzazione 16/18 e Citologia Reflex

hrHPV=high risk HPV

Routine screening HPV−

COLPOSCOPY

HPV16/18+

Follow-up in 12 months

NILM

≥ASC-US

COLPOSCOPY

Cytology 12 other hrHPV+

hrHPV

45

31 33

39

35

51

52 56 58

59 66 68

16 18

cobas® HPV Test

5

Page 6: Comparison of HPV Primary Screening Algorithms with

FDA approved Primary Screening Algorithm

The ATHENA Trial Design

Justification for Beginning Primary Screening at 25 years

ATHENA Longitudinal Data

3 year Performance of Strategies

Conclusions

Agenda

6

Page 7: Comparison of HPV Primary Screening Algorithms with

Colposcopy (n = 8,067)

NILM and hrHPV (-)

Women >25 yrs visiting for routine exam (n = 42,209)

>ASC-US or hrHPV (+)

Randomized (n = 895)

Exit study

<CIN2 ≥CIN2 Not Randomized

Year 3 Colposcopy

(n = 4,063)

Year 2 Visit

Year 1 Visit

ATHENA Study Design

7

Page 8: Comparison of HPV Primary Screening Algorithms with

cobas® HPV Test Technology Overview Approvato per ASC-US Triage, Cotesting e Screening primario

4 canali di lettura permettono di ottenere risultati per hrHPV, e contemporaneamente per HPV 16/18 nella stessa seduta

Wright TC Jr, et al. Am J ObstetGynecol2012; 206:46.e1-.e11

16 Detects HPV16 Channel 2

18 Detects HPV18 Channel 3

45 31 33 39 35 51 52 56 58 59 66 68

12 hrHPV genotypes as a pooled result Channel 1

Detects β-globin (internal control) Channel 4

8

Page 9: Comparison of HPV Primary Screening Algorithms with

FDA approved Primary Screening Algorithm

The ATHENA Trial Design

Justification for Beginning Primary Screening at 25 years

ATHENA Longitudinal Data

3 year Performance of Strategies

Conclusions

Agenda

9

Page 10: Comparison of HPV Primary Screening Algorithms with

Le attuali linee guida americane non raccomandano il cotesting per le donne di 25-29 anni

Le infezioni da HPV transienti sono comuni a questa età e gli autori delle linee guida non raccomandano esami di follow-up e colposcopie non necessarie

Esiste un’alta incidenza di lesioni CIN3 nelle donne 25-29 anni e la citologia è poco performante come mostrato negli audits dello screening UK

Nel 2013 Kaiser Permanente, N. California hanno rianalizzato I loro dati di registro ed hanno deciso di avviare il cotesting all’età di 25 anni

A quale età avviare lo screening?

10

Page 11: Comparison of HPV Primary Screening Algorithms with

Cervicocarcinoma invasivo negli U.S.A SEER Tumor Registry (1975-2010)

Cer

vica

l Can

cer I

ncid

ence

per

100

,000

Age Group

http://seer.cancer.gov/csr/1975_2010/

0

2

4

6

8

10

12

14

16

11

Page 12: Comparison of HPV Primary Screening Algorithms with

Percentage of ≥CIN3

ATHENA data on file

Più di 1/3 di lesioni ≥CIN3 è stato rilevato nelle donne di 25-29 anni

25%

N=6647 N=22,006

Age Group

40%

30%

20%

10%

0% 25-29 40-49 30-39 >50

34.3%

16.4

40.3

8.9

(N=6647) (N=22,006)

40.3%

12

ATHENA data

Page 13: Comparison of HPV Primary Screening Algorithms with

57,3 46,7 38,3

27,8

0%

20%

40%

60%

80%

100%

25-29 30-39 40-49 ≥50

42.7 53.3

61.7 72.2

ATHENA trial: Percentuale di donne con lesione ≥CIN3 e Citologia Negative (NILM)

Percentages shown are for hrHPV+ women with ≥CIN3, N=252 Huh W, et al. 27th International Papillomavirus Conference, Berlin, Germany, September 17–22, 2011, OP-229.

Prop

ortio

n of

≥C

IN3

(%)

Age

≥ASC-US NILM

13

ATHENA data

Page 14: Comparison of HPV Primary Screening Algorithms with

La genotipizzazione HPV 16/18 invia meno donne alla Colposcopia che Citologia ≥ASCUS ATHENA

0%

2%

4%

6%

8%

10%

12%

14%

21-24 25-29 30-39 40-49 >50

5.3

1.6

9.5

HPV 18 HPV 16 Abnormal Pap

Wright et al. Am J ObstGynecol, 2011.

Age Group

% H

avin

g H

PV b

y co

bas®

HPV

Ass

ay

14

Page 15: Comparison of HPV Primary Screening Algorithms with

FDA approved Primary Screening Algorithm

The ATHENA Trial Design

Justification for Beginning Primary Screening at 25 years

ATHENA Longitudinal Data

3 year Performance of Strategies

Conclusions

Agenda

15

Page 16: Comparison of HPV Primary Screening Algorithms with

Più del 90% delle donne ≥25 anni sono HPV(-)

0,34

0,78

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

Baseline Year 1 Year 2 Year 3

HPV Negative Pap Negative

CIR

≥C

IN3

(%)

Il minor rischio di lesione di una donna hrHPV negativa alla Baseline conferma la sicurezza di un risultato hrHPV negativo sui 3 anni

16

Page 17: Comparison of HPV Primary Screening Algorithms with

Il beneficio del cotesting rispetto ad HPV nel ridurre il rischio di ≥CIN3 su 3 anni è minimo

0,34

0.30*

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

Baseline Year 1 Year 2 Year 3

HPV Negative PAP and HPV Negative

CIR

≥C

IN3

(%)

un Pap test negativo insieme ad un hrHPV test negativo alla Baseline aggiunge pochi benefici ed aumenta le colposcopie da 4.6% a 5.4%

* Statistically significant difference 17

Page 18: Comparison of HPV Primary Screening Algorithms with

Rischio Cumulativo per ≥CIN3 a 3 anni Popolazione Screening (≥25 anni)

0

5

10

15

20

25

30

0 1 2 3

Years of Follow-up

CIR

≥C

IN3

(%)

HPV 16+

HPV 18+

Other 12 hrHPV+

HPV-

HPV+

VBA estimates 18

Page 19: Comparison of HPV Primary Screening Algorithms with

Rischio Cumulativo a 3 anni (corretto) per ≥CIN3 stratificato secondo il risultato citologico e HPV

N (% of 40,901) Screening Test CIR (95% CI)

38284 (93.6) Normal cytology 0.78 (0.53, 1.09) 2617 (6.4) Abnormal cytology 9.21 (7.91, 10.48)

35118 (85.9) Normal cytology & HPV– 0.30 (0.06, 0.64)

5783 (14.1) Abnormal cytology and/or HPV+ 9.68 (8.58, 10.73)

36626 (89.5) HPV– 0.34 (0.10, 0.65) 4275 (10.5) HPV+ 9.68 (8.58, 10.73)

3108 (7.6) HPV 12 other 5.37 (4.45, 6.35)

1167 (2.9) HPV 16/18 21.16 (18.39, 24.01)

3166 (7.7) Normal cytology & HPV+ 6.35 (5.30, 7.33) 1109 (2.7) Abnormal cytology & HPV+ 19.92 (17.06, 22.70)

2388 (5.8) Normal cytology & HPV 12 other 3.82 (2.88, 4.74)

778 (1.9) Normal cytology & HPV 16/18 14.12 (10.98, 17.21)

CIR ≥CIN3 19

Page 20: Comparison of HPV Primary Screening Algorithms with

0,1 1 10 100

N (% of 40,901) Screening Test CIR (95% CI)

38284 (93.6) Normal cytology 0.78 (0.53, 1.09) 2617 (6.4) Abnormal cytology 9.21 (7.91, 10.48)

35118 (85.9) Normal cytology & HPV– 0.30 (0.06, 0.64)

5783 (14.1) Abnormal cytology and/or HPV+ 9.68 (8.58, 10.73)

36626 (89.5) HPV– 0.34 (0.10, 0.65) 4275 (10.5) HPV+ 9.68 (8.58, 10.73)

3108 (7.6) HPV 12 other 5.37 (4.45, 6.35)

1167 (2.9) HPV 16/18 21.16 (18.39, 24.01)

3166 (7.7) Normal cytology & HPV+ 6.35 (5.30, 7.33) 1109 (2.7) Abnormal cytology & HPV+ 19.92 (17.06, 22.70)

2388 (5.8) Normal cytology & HPV12 other+ 3.82 (2.88, 4.74)

720 (1.8) Abnormal cytology & HPV12 other+ 11.1 (8.4, 13.9)

CIR ≥CIN3 20

Rischio Cumulativo a 3 anni (corretto) per ≥CIN3 stratificato secondo il risultato citologico e HPV

Page 21: Comparison of HPV Primary Screening Algorithms with

FDA approved Primary Screening Algorithm

The ATHENA Trial Design

Justification for Beginning Primary Screening at 25 years

The Comparator Strategies

ATHENA Longitudinal Data

3 year Performance of Strategies

Conclusions

Agenda

21

Page 22: Comparison of HPV Primary Screening Algorithms with

Secondo il disegno dello studio ATHENA, tutte le donne sono uscite se ≥CIN2. Pertanto, sono state fatte ipotesi sul modello:

– Tutte le ≥CIN2 presenti alla Baseline sono persistenti fino all’anno 1

– Lesioni HPV+ all’enrollment sarebbero rimaste HPV+ all’anno 1

– Tutte le <CIN2 sono state seguite per 12 mesi con cotesting

Persistenza HPV, resultati della ripetizione della citologia e perdita dei casi in follow-up sono stati considerati nel modello

Performance degli Algoritmi sui 3 anni: ipotesi per I modelli delle strategie

22

Page 23: Comparison of HPV Primary Screening Algorithms with

Citologia (ASC-US Triage)

Cervical Cytology

COLPOSCOPY

Positive

COLPOSCOPY

Negative

ASC-US HPV Testing

Negative or NILM

LSIL/HSIL

Routine screening

Rescreen in 3 years

23

Page 24: Comparison of HPV Primary Screening Algorithms with

Cotesting: Citologia (ASC-US Triage) nella fascia 25-29 e Cotesting per le donne ≥30 anni

Cervical Cytology

COLPOSCOPY

Positive

COLPOSCOPY

Negative

ASC-US HPV Testing

Negative or NILM

LSIL/HSIL

Routine screening

Rescreen in 3 years

Women 25-29 years: ASC-US Triage

24

Page 25: Comparison of HPV Primary Screening Algorithms with

Women ≥30 years: Cotesting

Cytology

45

31 33

39

35

51

52 56 58

59 66 68

16 18

HPV Test

NILM / HPV+

Routine screening

COLPOSCOPY

Cotesting 12 months

NILM / HPV- ASC-US / HPV-

ASC-US / HPV+ >ASC-US

cobas® HPV Test, high risk HPV DNA test 25

Cotesting: Citologia (ASC-US Triage) nella fascia 25-29 e Cotesting per le donne ≥30 anni

Page 26: Comparison of HPV Primary Screening Algorithms with

Screening con HPV test HPV con genotipizzazione 16/18 inclusa

hrHPV=high risk HPV

Routine screening HPV−

COLPOSCOPY

HPV16/18+

Follow-up in 12 months 12 other hrHPV+

hrHPV

45

31 33

39

35

51

52 56 58

59 66 68

16 18

cobas® HPV Test

26

Page 27: Comparison of HPV Primary Screening Algorithms with

Screening con HPV test HPV con Citologia Reflex

hrHPV=high risk HPV

Routine screening HPV−

HPV+

Follow-up in 12 months

NILM

≥ASC-US

COLPOSCOPY

Cytology hrHPV

45

31 33

39

35

51

52 56 58

59 66 68

16 18

cobas® HPV Test

27

Page 28: Comparison of HPV Primary Screening Algorithms with

Algoritmo di Screening HPV con genotipizzazione 16/18 e Citologia Reflex

hrHPV=high risk HPV

Routine screening HPV−

COLPOSCOPY

HPV16/18+

Follow-up in 12 months

NILM

≥ASC-US

COLPOSCOPY

Cytology 12 other hrHPV+

hrHPV

45

31 33

39

35

51

52 56 58

59 66 68

16 18

cobas® HPV Test

28

Page 29: Comparison of HPV Primary Screening Algorithms with

Performance sui 3 anni delle diverse Strategie: popolazione ≥25

Number of Detected Cases

Outcome Strategy Total Detected

at Baseline

Detected Years 1-3

Total Missed Cases

No. of Screening

Tests

No. of Colposcopies

Colposcopies to Detect 1

Case

CIN3+ Cytology 179 143 36 168 45,152 1,927 10.8

29

Page 30: Comparison of HPV Primary Screening Algorithms with

Number of Detected Cases

Outcome Strategy Total Detected

at Baseline

Detected Years 1-3

Total Missed Cases

No. of Screening

Tests

No. of Colposcopies

Colposcopies to Detect 1

Case

CIN3+ Cytology 179 143 36 168 45,152 1,927 10.8

Hybrid strategy 240 143 97 107 82,989 3,096 12.9

30

Performance sui 3 anni delle diverse Strategie: popolazione ≥25

Page 31: Comparison of HPV Primary Screening Algorithms with

Number of Detected Cases

Outcome Strategy Total Detected

at Baseline

Detected Years 1-3

Total Missed Cases

No. of Screening

Tests

No. of Colposcopies

Colposcopies to Detect 1

Case

CIN3+ Cytology 179 143 36 168 45,152 1,927 10.8

Hybrid strategy 240 143 97 107 82,989 3,096 12.9 HPV with 16/18

genotyping 276 150 126 71 49,830 3,218 11.7

31

Performance sui 3 anni delle diverse Strategie: popolazione ≥25

Page 32: Comparison of HPV Primary Screening Algorithms with

Number of Detected Cases

Outcome Strategy Total Detected

at Baseline

Detected Years 1-3

Total Missed Cases

No. of Screening

Tests

No. of Colposcopies

Colposcopies to Detect 1

Case

CIN3+ Cytology 179 143 36 168 45,152 1,927 10.8

Hybrid strategy 240 143 97 107 82,989 3,096 12.9 HPV with 16/18

genotyping 276 150 126 71 49,830 3,218 11.7

HPV with reflex cytology

271 133 138 76 54,098 3,191 11.8

32

Performance sui 3 anni delle diverse Strategie: popolazione ≥25

Page 33: Comparison of HPV Primary Screening Algorithms with

Number of Detected Cases

Outcome Strategy Total Detected

at Baseline

Detected Years 1-3

Total Missed Cases

No. of Screening

Tests

No. of Colposcopies

Colposcopies to Detect 1

Case

CIN3+ Cytology 179 143 36 168 45,152 1,927 10.8

Hybrid strategy 240 143 97 107 82,989 3,096 12.9 HPV with 16/18

genotyping 276 150 126 71 49,830 3,218 11.7

HPV with reflex cytology

271 133 138 76 54,098 3,191 11.8

HPV with 16/18 genotyping and reflex cytology

294 197 97 53 52,651 3,767 12.8

33

Performance sui 3 anni delle diverse Strategie: popolazione ≥25

Page 34: Comparison of HPV Primary Screening Algorithms with

Number of Detected Cases

Outcome Strategy Total Detected

at Baseline

Detected Years 1-3

Total Missed Cases

No. of Screening

Tests

No. of Colposcopies

Colposcopies to Detect 1

Case

CIN2+ Cytology 270 215 55 317 45,152 1,927 7.1

Hybrid strategy 384 215 169 203 82,989 3,096 8.1

HPV with 16/18 genotyping

441 197 244 146 49,830 3,218 7.3

HPV with reflex cytology

443 200 243 144 54,098 3,191 7.2

HPV with 16/18 genotyping and reflex cytology

471

283

188

116

52,651

3,767

8.0

34

Performance sui 3 anni delle diverse Strategie: popolazione ≥25

Page 35: Comparison of HPV Primary Screening Algorithms with

Conclusioni:

• Lo screening con HPV test con genotipizzazione16/18 e citologia in reflex, solo o in combinazione, è più sensibile della citologia nelle donne ≥25

• L’algoritmo che comprende cobas® HPV Test con genotipizzazione 16/18 e citologia reflex

– individua più lesioni alla baseline ed evita le perdite in follow-up

– offre almeno una sensibilità equivalente al cotesting e richiede ~1/2 diel numero di tests

– nella fascia 25-29 anni: individua più lesioni rispetto alla citologia e invia alla colposcopia solo le donne a più alto rischio

• La sicurezza del test cobas HPV come test primario è confermata dalla dimostrazione che un test negativo alla Baseline predice un rischio minore di lesioni ≥CIN3 a 3 anni rispetto ad un Pap test negativo alla Baseline

35

Page 36: Comparison of HPV Primary Screening Algorithms with

Doing now what patients need next

Page 37: Comparison of HPV Primary Screening Algorithms with

Backup slides

Page 38: Comparison of HPV Primary Screening Algorithms with

3 Year Performance of Various Strategies: Women 25-29 years

Number of Detected Cases

Outcome Strategy Total Detected

at Baseline

Detected Years 1-3

Total Missed Cases

No. of Screening

Tests

No. of Colposcopies

Colposcopies to Detect 1

Case CIN3+ Cytology 51 37 14 68 7,846 634 12.4

Hybrid strategy 51 37 14 68 7,846 634 12.4

HPV with 16/18 genotyping

97 49 48 22 9,413 1,081 11.1

HPV with reflex cytology

92 35 57 27 10,829 1,037 11.3

HPV with 16/18 genotyping and reflex cytology

102 61 41 17 10,227 1,246 12.2

Page 39: Comparison of HPV Primary Screening Algorithms with

3 Year Performance of Various Strategies: Women 25-29 years

Number of Detected Cases

Outcome Strategy Total Detected

at Baseline

Detected Years 1-3

Total Missed Cases

No. of Screening

Tests

No. of Colposcopies

Colposcopies to Detect 1

Case CIN2+ Cytology 85 71 14 125 7,846 634 7.5

Hybrid strategy 85 71 14 125 7,846 634 7.5

HPV with 16/18 genotyping

160 75 85 50 9,413 1,081 6.8

HPV with reflex cytology

158 67 91 52 10,829 1,037 6.6

HPV with 16/18 genotyping and reflex cytology

172 105 67 38 10,227 1,246 7.2

Page 40: Comparison of HPV Primary Screening Algorithms with

3 Year Performance of Various Strategies: Women ≥30 years

Number of Detected Cases

Outcome Strategy Total Detected

at Baseline

Detected Years 1-3

Total Missed Cases

No. of Screening

Tests

No. of Colposcopies

Colposcopies to Detect 1 Case

CIN2+ Cytology 185 144 41 192 37,306 1,293 7.0

Hybrid strategy 299 144 155 78 75,148 2,462 8.2

HPV with 16/18 genotyping

281 122 159 96 40,417 2,137 7.6

HPV with reflex cytology

285 133 152 92 43,269 2,154 7.6

HPV with 16/18 genotyping and reflex cytology

299 178 121 78 42,424 2521 8.4

CIN3+ Cytology 128 106 22 100 37,306 1293 10.1

Hybrid strategy 189 106 83 39 75,148 2,462 13.0

HPV with 16/18 genotyping

179 101 78 49 40,417 2,137 11.9

HPV with reflex cytology

179 98 81 49 43,269 2,154 12

HPV with 16/18 genotyping and reflex cytology

192 136 56 36 42,424 2,521 13.1