The future of breast cancer screening in Australia: Insights from the transformation of the National Cervical Screening Program

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1 The future of breast cancer screening in Australia: Insights from the transformation of the National Cervical Screening Program BreastScreen Australia Conference, April 2018 Karen Canfell Director, Cancer Research Division, Cancer Council NSW Adjunct Professor, School of Public Health, University of Sydney Conjoint Professor, Prince of Wales Clinical School, UNSW Australia Disclosures: I am co-pi of an investigator-initiated trial of primary HPV screening in Australia ( Compass ) conducted by the Victorian Cytology Service, which has received a funding contribution from Roche Molecular Systems and Ventana Inc., USA. My modelling work is funded via grants from NHMRC)Australia, National Cancer Institute USA, government contracts in a number of countries, and funding from a number of other noncommercial agencies including Cancer Council NSW,. I receive salary support (Career Development Fellowship) from NHMRC.

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3 The renewed National Cervical Screening Program started on December 1 st 2017

4 Cytology 2-yearly Age to 69 years 26 tests in a lifetime HPV DNA testing 5-yearly Age years 10 tests in a lifetime

5 A decade ago Consistent observational findings on improved sensitivity of HPV screening HPV testing was substantially more sensitive in detecting CIN2+ than cytology (96.1% vs. 53.0%) Cuzick J et al., IJC, 2006

6 A decade ago HPV status as a risk prediction tool well established HPV 16 +ve at baseline Higher risk Else HPV 18 +ve Intermediate risk Else HPV other +ve Oncogenic HPV -ve Low risk Cumulative CIN3+ in 20,514 women (median age 34 years) Khan MJ, Castle PE, et al. JNCI 2005

7 These results support the use of HPV testing as the sole primary screening test, with cytology reserved for women who test HPV positive. Jack Cuzick, 2006 HPV screening that distinguishes HPV16 and HPV18 from other oncogenic HPV types may identify women at the greatest risk of CIN3+ and may permit less aggressive management of other women with oncogenic HPV infections. Khan, Castle & Schiffman, 2005

8 So, why did it take more than a decade - after this evidence was available - to transition to primary HPV screening in Australia?

9 Pathology quality standards New MBS items Pathology workforce Communications to women Provider training modules and resources Toolkit for underscreened populations Clinical management guidelines Colposcopy reporting Safety monitoring Reminder and recall systems National Cancer Screening Register

10 The Australian Population- Based Screening Framework Requires new evidence for program change Requires new evidence for program change

11 Key elements of transformation Evidence Catalyst Evaluation Sentinel experience Implementation

12 Key elements of transformation Evidence Catalyst Evaluation Sentinel experience Implementation

13 Natural history of cervical cancer (well understood, as per WHO screening criteria) Persistence & Progression Regression High grade precancer (CIN2/3) Invasion in small proportion of women Cervical cancer Secondary prevention via screening with cytology Secondary prevention via HPV screening Adapted from Schiffman and Castle, NEJM 2005

14 HPV 16 is a uniquely powerful human carcinogen HPV18,45,31,33,35,52,58 are the next most commonly identified in cancer, and a further 7 types have smaller and uncertain contributions to cancer Mark Schiffman

15 Impact of the National Cervical Screening Program Between and , falls in cervical cancer incidence of: 45% in women % in women % in women 70+ years Squamous cell cancer Adenocarcinoma But: No change in women aged years No change in adenocarcinoma Rates plateaued in all age groups in the early-mid 2000 s Smith M and Canfell K, MJA 2016 Squamous cell cancer Adenocarcinoma Squamous cell cancer Adenocarcinoma Smith M and Canfell K, MJA 2016

16 Cohort data: HPV vs. cytology screening Low risk Dillner, J. et al. BMJ 2008

17 Pooled data from RCTs: HPV vs. cytology screening Cytology HPV Cytology HPV Pooled data on invasive cervical cancer outcomes from four European trials - 176,000 women Ronco et al, Lancet 2014

18 Key elements of transformation Evidence Catalyst Evaluation Sentinel experience Implementation

19 Jian Zhou and Ian Frazer

20 Prophylactic HPV vaccination 98% vaccine efficacy against HPV 16/18-related CIN2+ in HPV-naïve women FUTURE II Study Group, NEJM 2007; Paavonen et al for the PATRICIA Study Group, Lancet 2009.

21 Australian National HPV Vaccination Program (NHVP) Quadrivalent HPV vaccine Routine vaccination of year girls from 2007 School and GP-based catch-up in females years to 2009 Boys included from 2013 National HPV Vaccination Register Sept 2011

22 11 years on all women aged 36 years or younger have been offered HPV vaccination

23 Prevalence of HPV infection fell 2005 to 2014 This slide edited for web version (pre-publication data) Adapted from Smith M et al, IJC 2008 Pre-vaccination prevalence from WHINURS (Garland et al. BMC Medicine 2011) Post-vaccination data from Compass trial (Canfell et al., in prep)

24 Prevalence of high grade precancerous abnormalities fell ~34% in year olds; 17% in year olds in Victoria to 2014 Brotherton et al., MJA % in year olds nationally to 2015 Australian Institute of Health and Welfare 2017,

25 Treatment rates fell Robertson & Robson, J Oncol 2016

26 What did this mean for cervical screening? A woman s lifetime risk of cervical cancer now depends on vaccination If vaccinated, what type of vaccine? Vaccinated after HPV exposure? How many doses? Unvaccinated but benefiting from herd immunity?.how should this be factored into cervical screening decisions?

27 Key elements of transformation Evidence Catalyst Evaluation Sentinel experience Implementation

28 Renewal of the National Cervical Screening Program Announced November 2011 Aim: To ensure that all Australian women, HPV vaccinated and unvaccinated, have access to a cervical screening program that is acceptable, effective, efficient and based on current evidence. The government's Medical Services Advisory Committee (MSAC) commissioned a systematic review of the international evidence & modelled evaluation of health outcomes and costs i.e. a linked evidence approach to guide decision- making Process guided by an expert reference group, the Renewal Steering Committee Evidence report released April 2014

29 MSAC evaluation: Decision Analytic Protocol Specified evaluation in both unvaccinated and cohorts offered vaccination Total of 132 detailed screening algorithms in main evaluation Supplementary analysis: screening end age 65 or 70 years LBC=Liquid-based cytology; LSIL= low grade cytology

30 Policy1-Cervix modelling platform Dynamic model of sexual behaviour, HPV transmission, HPV type-specific natural history and cervical screening 1-17 Extensively validated against screening and cancer outcomes. 6,11 Screening uptake informed by analysis of Victorian Cervical Cytology Service. Vaccine uptake informed by National HPV Vaccination Register data. 1. Canfell et al. Br J Cancer 2004; 2. Barnabas et al. PLoS Med 2006; 3. Smith et al. Int J Cancer 2008; 4. Creighton et al. BMC PH 2010; 5. Canfell et al. Vaccine 2010; 6. Smith et al. Vaccine 2011; 7. Shi et al. BMC Cancer 2011; 8. Walker et al. Stat Med 2012; 9. Lew et al, BMC HSR, 2012; 10. Legood et al, BMJ, 2012; 11. Simms and Lew et al., MSAC Australia 2013; 12. Kitchener et al, HTA UK 2014; 13. Smith and Canfell, BMC RN 2014; 14. Smith and Canfell, PLoSOne 2014; 15. Smith et al. BMC Health Services Research 2016; 16. Simms et al. PLoS ONE 2017; 17. Lew * & Simms * et al. Lancet Public Health 2017

31 Health impact and cost-effectiveness analysis of 132 potential screening strategies Lew/Simms et al., Lancet Public Health 2017

32 Recommendation: HPV screening with partial genotyping Negative HPV screening Other oncogenic HPV Reflex liquid-based cytology for colposcopy management HPV16/18 Routine screening in 5 years Cytology negative or low grade Cytology high grade Colposcopy (diagnostic referral) 12 month HPV FU Refer to colposcopy if any HPV +ve Otherwise return to routine screening Use the same strategy, whether or not a woman has been offered vaccination against HPV 16,18

33 The new program uses HPV-based risk stratification for management HPV 16 +ve at baseline Higher risk Else HPV 18 +ve Cumulative CIN3+ in 20,514 women (median age 34 years) Intermediate risk Else HPV other +ve Oncogenic HPV -ve Low risk Khan MJ, Castle PE, et al. JNCI 2005

34 Clinical management guidelines for the HPVbased screening program National Cervical Screening Program: Guidelines for the Management of Screen Detected Abnormalities, Screening in Specific Populations and Investigation of Abnormal Vaginal Bleeding. Released

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36 Long-term predicted impact on outcomes & costs Lew/Simms et al., Lancet Public Health 2017

37 Key elements of transformation Evidence Catalyst Evaluation Sentinel experience Implementation

38 Large scale RCT: Target recruitment 121,000 women 5-yearly HPV vs. 2.5 yearly liquid-based cytology (LBC) screening in women aged years Designed to provide evidence on: Test positivity and colposcopy referral rates in the first and subsequent rounds of screening Baseline CIN2+ detection in the first screening round Long term protection against CIN3+ (primary endpoint) Relative effectiveness of alternate triaging strategies for HPV positive women

39 Pilot Years Years 36,320 5,000 target reached 36,300 target reached 84,700 target Total Main Trial Recruitment as at 13/04/2018 = 72, Practitioners actively recruiting

40 In this study, primary HPV screening was associated with significantly increased detection of high-grade precancerous cervical lesions compared to cytology, in a population where high vaccine uptake was reported in women aged 33 years or younger who were offered vaccination. Canfell et al, PLoS MED 2017

41 It s inspirational that so many Victorian women and health professionals are actively involved in this research and are contributing to our understanding of cancer screening Todd Harper, CEO Cancer Council Victoria

42 Key elements of transformation Evidence Catalyst Evaluation Sentinel experience Implementation

43 Smith et al, BMC Health Services 2016 Transitional challenges Modelled impact of first rounds of HPV screening on colposcopy referrals in the Australian National Cervical Screening Program after transition in 2017 If no vaccination Up to 50% increase in first screening round With vaccination Long-term similar to pre-transition due to vaccine impact

44 Intermediate term (20 year) outcomes: Combined effect of HPV vaccination and HPV screening CIN2/3 Invasive cervical cancer Cervical cancer death Over the period , switching to primary HPV screening in Australia is expected to avert 2,006 cases of invasive cervical cancer and save 587 lives. Hall M et al., PLoSONE 2018

45 Joura EA et al, NEJM 2015

46 Will we need to screen cohorts offered HPV9 vaccine? Simms K et al., Int J Cancer 2016

47 Key elements of transformation Evidence Catalyst Evaluation Sentinel experience Implementation

48 Preliminary result. Not for distribution Timeline to elimination of cervical cancer in Australia This slide edited for web version (pre-publication data) Hall M et al., in prep.

49 We are on the threshold of a similar transformation at the global level

50 Global uptake of HPV vaccine 75 countries with national programs 47million females received full course 34% of females in target population vaccinated in more developed regions but only 2.7% vaccinated in less developed countries. Bruni L et al., Lancet Global Health 2016

51 Timeline to global elimination of cervical cancer This slide edited for web version (pre-publication data) Preliminary result. Not for distribution Simms K et al., submitted

52 This is a transformational moment for the health of women and girls across the world Seth Berkley, CEO GAVI Alliance Photo credit: Travel Stock / Shutterstock.com

53 Key elements of transformation Evidence Catalyst Evaluation Sentinel experience Implementation

54 A common theme that emerges is the ongoing challenge, as well as the opportunity, posed by the introduction of new screening technologies, and the need to ensure that the benefits, cost-effectiveness and harms associated with use of these technologies are comprehensively evaluated and communicated effectively to clinicians and consumers. Cancer Forum 2014

55 Acknowledgements and Funding Medical Services Advisory Committee MSAC Application No November Lew JB/Simms K, Smith M, Kang YK, Xu X, Caruana M, Walker R and Canfell K. National Cervical Screening Program Renewal: Effectiveness modelling and economic evaluation in the Australian setting (Assessment Report). 6FFC29E2CCA257CED007FB678/$File/Renewal%20Economic%20Evaluation.pdf National Cervical Screening Program: Guidelines for the management of screen-detected abnormalities, screening in specific populations and investigation of abnormal vaginal bleeding. Guidelines Working Party: Prof Ian Hammond (chair), A/Prof Marion Saville (Deputy Chair) Cancer Council Australia Guidelines Project Team: Ms Jutta von Dincklage, Ms Laura Wuellner. Cancer Council New South Wales Technical Team: Prof Karen Canfell, Jessica Darlington- Brown, Michaela Hall, Suzanne Hughes, Harriet Hui, Chloe Jennett, Jie Bin-Lew, Megan Smith, Dr Kate Simms, Dr Louiza Velentzis, Dr Susan Yuill. Cancer Council NSW in collaboration with VCS Ltd Co-Principal Investigators: Prof Karen Canfell, A/Prof Marion Saville Chief Investigators: Dr Philip Castle, Dr Michael Caruana, Prof Val Gebski, Jessica Darlington-Brown, Dr Stella Heley, A/Prof Julia Brotherton, Prof Dorota Gertig, A/Prof Marion Saville The VCS have received equipment and a funding contribution for the Compass trial from Roche Molecular Systems and Ventana Inc USA. Website Pilot Study Registration ACTRN Main Trial Registration: Clinicaltrials.gov NCT Associated grants: Project Grant APP Prof Karen Canfell, Prof You-Lin Qiao, Dr Philip Castle, Dr Kate Simms, Dr Ju-Fang Shi, Dr Jose Jeronimo Project Grant APP Prof Karen Canfell, Dr Michael Caruana, Dr Kate Simms, Jie-Bin Lew. Career Development Fellowship APP Prof Karen Canfell

56 IPVC nd International Papillomavirus Conference October 2-6 Sydney, Australia Towards Global Control of HPV Disease See you in Sydney!

57 Thank-you