Management of inherited breast cancer: implications for carriers and clinical trials

1. Management of inherited breast cancer: implications for carriers and clinical trials Dr James Mackay Consultant Clinical Genetic Oncologist University College London

2. Summary • BRCA1/2 testing in the UK • The Genetic Breast Cancer Trial • Chemocare database owned by Clinisys Ltd • The London Genetics Centre

3. DDD DDD DDD BrCa 51 OvCa 55 BrCa 38 BrCa 32 37 High Risk

4. Relatives Breast cancer patients Moderate risk High risk Direct gene testing feasible Setting the Scene

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

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

7. The current situation in the UK; 2005 • In London about 3,000 families offered a 60% stage 1 test by the NHS • Testing takes between 6 and 12 months • Testing offered by genetics services over last 10 years • In North East Thames all were consented for further testing if funds became available

8. Myriad Genetics Inc. • Based in Salt Lake City, Utah • Offers complete sequence of both BRCA1 and BRCA2 in 3 weeks • Costs $2,900 • Possible to get faster service at higher price • Blood sample has to be taken by a Doctor • Doctor responsible for interpreting the result for the patient • There are patient information materials available from Myriad • Myriad has set up a partner, Lab21 in the UK

9. The UK white paper promises • 2nd stage testing – 2 weeks • 1st stage testing – 8 weeks • Significant investment into clinical laboratories • Machines have been purchased • About to start offering 100% testing in London

10. But there are some concerns • What do people understand by the test that was done a few years ago? • What were they told about the result? • What did they understand about the result? • Did they appreciate that it was only a partial test? • Did they think they have been given the “all clear”?

11. Once mutation identified in family and unaffected individuals tested - If mutation +ve; at risk of • Breast cancer, particularly young breast cancer • Ovarian cancer

12. BRCA2 mutation carriers “Normal”

13. BRCA2 mutation carriers Tumour Normal

14. Steps to becoming a cancer cell normal cancer metastasis

15. Increased relative sensitivity cells without Brca2 (Tutt and Ashworth in collaboration with Lloyd Kelland, ICR Sutton)

16. Increased relative sensitivity cells without Brca2 (Tutt and Ashworth in collaboration with Lloyd Kelland, ICR Sutton)

17. Alan Ashworth and the Breakthrough Breast Cancer Centre • Protein encoded by BRCA2 in repair of DNA breaks • Double strand DNA breaks repaired by two different mechanisms • One path is error free but needs an intact BRCA2 pathway • Second path works without BRCA2 but allows far more errors

18. The chemotherapy drug platinum causes double strand DNA breaks • Cells without BRCA2 repair this damage by the error prone mechanisms • These cells are therefore much more sensitive to platinum

19. Clinical Hypothesis to test • Are tumours in BRCA2 carriers more sensitive to platinum than other drugs? • Is the normal tissue in BRCA2 carriers more sensitive to platinum than other drugs?

20. Optimal study design • A randomised study in known BRCA carriers with breast cancer at relapse of a platinum versus a taxane • Strong international support • May be difficult to recruit enough volunteers • First trial of chemotherapy based on inherited genetic make-up in the world

21. Docetaxel 100mg/m2 i.v. q3w Carboplatin AUC = 7, i.v. q4w AUC = 5, i.v. q3w End-points Toxicity Response Rates TTP BRCA1/2 carriers 1st metastatic relapse Disease progression Carboplatin AUC = 7, i.v. q4w AUC = 5, i.v. q3w Docetaxel 100mg/m2 i.v. q3w Genetic Breast Cancer Trial Design End-points Toxicity Response Rates TTP

22. Genetic Breast Cancer Trial • Fully funded by Breakthrough and Cancer Research UK • MREC approved January 2005 • Recruitment in UK started • Awaiting finalisation of international sponsorship arrangements

23. The Chemocare Database Improving the collection of routine clinical data Using a chemotherapy prescription database Has very accurate information on drug dose, prescription and delivery Has accurate information on over 150 chemotherapy protocols, including detailed information on common and rare side effects Has accurate information on all laboratory tests performed since chemotherapy was started

24. The research potential • Data on over 2.4 million prescriptions • The market leader for electronic chemotherapy prescription in the UK • Being marketed across Europe • Can identify individual and institutional deviations from protocol • Could identify all those who had mild or severe reactions to a particular drug regime • With informed consent take a single blood sample from each individual • Examine inherited genetic variation in the important metabolising enzymes for the drugs involved

25. Improving clinical care • Use the database to electronically trap clinical outcome; side effects and efficacy • Examine inherited genetic variation and markers of tumour biology • Look for associations between these markers and outcome • Predict who is going to develop severe side effects and who is going to respond well • Combining developments in IT and old fashioned epidemiological principles of research • Working towards individualised cancer care

26. The London Genetics Centre Ltd A collaboration of seven academic medical institutions in London Imperial, King’s, St George’s, Queen Mary’s, The London School of Hygiene and Tropical Medicine, Institute of Cancer Research and University College London

27. The London Genetics Centre • Aims to provide genetic services to clinical trial activity within a commercial framework • Start up funding of £2 million from the Department of Trade and Industry and the London Development Agency • Make London the European centre for genetic medicine • Start with oncology, and then rapidly spread into other important disease areas • A unique initiative for London medicine • Formalities currently being finalised

28. Conclusions • BRCA testing in the UK • The Genetic Breast Cancer Trial • The Chemocare Database owned by Clinisys Oncology Ltd • The London Genetics Centre Ltd