Assessing and managing familial risk. Dr James Mackay Consultant Genetic Oncologist University College London

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1 Assessing and managing familial risk Dr James Mackay Consultant Genetic Oncologist University College London

2 Summary Clinical practice in offering BRCA gene testing Patient choice in mammographic screening The clinical introduction of a new blood test for early diagnosis of breast cancer

3 The Clinical Scene Relatives Breast/ Ovarian cancer patients Moderate risk High risk Direct gene testing feasible

4 A high risk family BrCa 51 DDD OvCa 55 DDD BrCa 38 DDD 37 BrCa 32

5 BRCA1 Structure 4 available bases: C G A or T Arranged in line 100,000 Mutation -CGATTCGGGTAAAA- -change of one base anywhere in the line

6 Genetic Testing A 2 step process: 1. identify mutation in affected family member then 2. offer direct gene test to other family members

7 Gene carriers have Increased lifetime risk of : 1. Breast cancer at a young age (below 50 years old 50% risk) and 2. Ovarian cancer (lifetime risk up to 40%)

8 BRCA mutation carriers Normal

9 BRCA mutation carriers Normal Tumour

10 Creating new drugs The repair pathway involving BRCA does not work in these cancer cells The alternative pathway uses an enzyme called poly ADP-ribose polymerase - PARP Drugs which stop this working are called PARP inhibitors They are now in early clinical trials in BRCA carriers Seem to have mild toxicity Have encouraging early results Only work in gene carriers

11 Current NHS practice Strict inclusion criteria before testing is offered Waiting list to see cancer genetics team Target for laboratory testing is 8 weeks

12 BRCA1/2 testing in the private sector in London No waiting list to see consultant Complete test looking at both genes takes 21 days maximum and 10 days at extra cost Testing is offered to all those who wish it after careful explanation of advantages and disadvantages of testing

13 Rush to test? Do cancer genetics team need to be involved? Testing must be speedy Reduce delay by oncologist testing cancer patient? If +ve result then prescribe PARP inhibitor If ve result then conventional chemotherapy If +ve; implications for family? If ve; implications for family? Who will discuss these implications with other family members? The NHS clinical service will have to respond to the introduction of this new drug class The private sector is ahead of the curve

14 Patient choice Breast screening with mammography for those concerned about their own risk of developing breast cancer

15 Current NHS practice Mammography available to all women in UK 3 yearly From age of 50, although some places offer from 47 Strict criteria for offering mammography from age 40 to those with a family history of breast cancer Family history services are patchy Screening MRI is available for high risk patients (gene carriers) in some centres

16 Current practice in the private sector in London Many women have legitimate concerns about their own risk of developing breast cancer because of their family history or other reasons Face to face consultation with consultant expert in breast disease Discussion of the advantages and disadvantages of regular screening with either mammography or MRI or both Patient makes their own decision based on the information presented

17 BCtect for early breast cancer diagnosis DiaGenic.com

18 The concept of peripheral gene expression profiling The primary diseased part of the body is not the only part responding to a disease subtle but systemic impact on gene expression The disease leaves a unique signature in other parts of the body, including the circulatory system response can be detected by measuring the amount of RNA for specific genes from peripheral blood These signatures can be identified using gene expression technologies

19 Promising new tools for early detection of cancers ColonSentry, 5-gene signature from GeneNews for early detection of colon cancer Clinical Cancer Research 2008 New 29-gene signature for early detection of NSCLS by Wistar Institute Cancer Research 2009 BCtect from DiaGenic for early detection of breast cancer Breast Cancer Research 2010

20 Multi-centre study BCtect CE-marking Performance characteristics Validation (N=109) Calibration (N= 223) Combined (N=332) Accuracy 72% 73% 72% Sensitivity 69% 73% 72% Specificity 74% 73% 73%

21 BCtect Is as accurate in pre-menopausal women as post menopausal women Identifies lobular and ductal cancers Identifies ER-ve and ER+ve cancers Smallest cancer identified is 3 mm Is unaffected by current medication Is positive in pregnant women

22 Published studies Sensitivity of various mammographic studies Kriege Chakraborti Kolb (All women) Kolb (High density) Malmo CNBSS-1 (40-49 yrs) Edinburgh CNBSS-2 (50-59 yrs) DMIST (Film) DMIST (Digital)

23 An innovative blood test

24 A rigorous quality check is carried out The result is reported either as a positive or negative

25 Initial clinical positioning Biopsy Clear abnormality Symptomatic and/or Anxious Mammography Diffuse abnormality/ Dense breasts Additional testing (MRI) Normal No further action Population estimates Negative: 75% of those referred for diagnostic mammography Positive: 16% of those referred for diagnostic mammography, 3 to 4 biopsies taken for 1 cancer Inconclusive: 10% of those referred for diagnostic mammography

26 Introducing BCtect into clinical care The UK experience Start with the private sector Keep the NHS informed Secure professional support Inform the public Manage the expectations created Conservative positioning initially adopted Will this apply in other health care settings

27 Introducing BCtect into clinical care The UK has been chosen as the primary point of entry into the global market Cautious strategy of scientific marketing pursued Exclusive distributor in UK and Ireland is Quest Diagnostics Ltd UK strategy group met; expertise from breast surgery, clinical pathology, screening radiology, breast care nursing; representation from Diagenic ASA, Quest Diagnostics UK Ltd and The London Breast Clinic An initial positioning of BCtect in the patient pathway agreed Presented to several professional audiences at meetings Launched through The London Breast Clinic Initially I will see everyone offered the test

28 Informing the public that BCtect is now available in the UK Conservative press release issued by The London Breast Clinic News picked up by the medical news services Article appeared in the Sunday Express; picked up by The Telegraph and The Daily Mail; by news agencies across the globe Enquiries are starting to come in from across the country: when will it be available outside central London? when will it be available in Scotland? Interest from other private breast units who also wish to offer BCtect to their patients We will enlarge the UK strategy group to be more representative

29 the Sunday Express of

30 the Daily Mail of

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32 Post test clinical data collection Pool clinical data on all tests done Quest Diagnostics Ltd are supportive Clinical information shared by treating clinicians The clinical experience from the UK may help inform other European clinicians

33 UK experience to date BCtect is not perfect It complements mammography Initial clinical positioning is conservative Establish a steering group Ensure that health professionals understand the test, including the limitations Inform the public

34 Summary Clinical practice in BRCA1/2 testing Patient choice in screening mammography Introducing a new blood test for early diagnosis

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36 The multi-disciplinary team of The London Breast Clinic provide high quality care across the entire spectrum of breast disease