Breast Cancer Genetics and Clinical
Trials
Dr James Mackay
Consultant Clinical Genetic Oncologist
Inherited genetic variation and
treatment outcome
Clinical Pharmaco-genetics
Summary
• Current practice in BRCA testing
• Genetic Breast Cancer Trial
• Acquiring new knowledge from
routinely collecte...
High Risk
DDD
DDD
DDD
DDD DDDDDD
BrCa 51 OvCa 55
BrCa 38 37 BrCa 32
Genetic Testing
A 2 step process:
1. identify mutation in affected
family member
then
2. offer direct gene test
The Genetic Breast Cancer Trial
Breakthrough Breast Cancer
Cancer Research UK
BRCA2 mutation carriers
“Normal”
BRCA2 mutation carriers
Normal Tumour
Steps to becoming a cancer cell
normal cancer metastasis
Drug Sensitivity of Brca2/P53 Null MEFs
Compared to Wild-Type
(Tutt and Ashworth in collaboration with Lloyd Kelland, ICR ...
Drug Sensitivity of Brca2/P53 Null MEFs
Compared to Wild-type
(Tutt and Ashworth in collaboration with Lloyd Kelland, ICR ...
Alan Ashworth and the Breakthrough Breast
Cancer Centre
• Protein encoded by BRCA2 in repair of DNA
breaks
• Double strand...
• The chemotherapy drug platinum causes double
strand DNA breaks
• Cells without BRCA2 repair this damage by the
error pro...
BRCA2 mutation carriers
Normal Tumour
Clinical Hypothesis to test
• Are tumours in BRCA2 carriers more sensitive to
platinum than other drugs?
• Is the normal t...
Optimal study design
• A randomised study in known BRCA carriers
with breast cancer at relapse of a platinum versus
a taxa...
Deriving new knowledge from
routinely collected clinical data
The Clinisys clinical database
Originally designed as a best practice clinical treatment system
The database currently has...
An example from metastatic breast
cancer
• Vinorelbine (a new chemotherapy drug) is only given in
metastatic breast cancer...
Hypothetical example of differential toxicity
Time to progression after Vinorelbine
treatment of breast cancer
0
5
10
15
1...
Developing a national structure to
pursue cancer pharmaco-genetic
research
• Association between inherited genetic variati...
Pharmaco-genetics in an adjuvant
breast trial
• TACT 2 is a trial of accelerated chemotherapy in the
adjuvant treatment of...
London Genetics
• A collaboration between several London medical schools
and academic institutes
• Start up funding from t...
Further developments
• Deputy director of the National Translational Cancer
Research Network (NTRAC) has agreed to come an...
Why should we do this work in the
UK
• The NHS is gradually developing national standards for
cancer care
• Many trusts ar...
Conclusions
• Genetic Breast Cancer Trial
• The Clinisys system for collection of routine clinical data
• Examining inheri...
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Breast Cancer Genetics and Clinical Trials

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Breast Cancer Genetics and Clinical Trials

  1. 1. Breast Cancer Genetics and Clinical Trials Dr James Mackay Consultant Clinical Genetic Oncologist
  2. 2. Inherited genetic variation and treatment outcome Clinical Pharmaco-genetics
  3. 3. Summary • Current practice in BRCA testing • Genetic Breast Cancer Trial • Acquiring new knowledge from routinely collected clinical oncology data • A national structure for investigating pharmaco-genetics
  4. 4. High Risk DDD DDD DDD DDD DDDDDD BrCa 51 OvCa 55 BrCa 38 37 BrCa 32
  5. 5. Genetic Testing A 2 step process: 1. identify mutation in affected family member then 2. offer direct gene test
  6. 6. The Genetic Breast Cancer Trial Breakthrough Breast Cancer Cancer Research UK
  7. 7. BRCA2 mutation carriers “Normal”
  8. 8. BRCA2 mutation carriers Normal Tumour
  9. 9. Steps to becoming a cancer cell normal cancer metastasis
  10. 10. Drug Sensitivity of Brca2/P53 Null MEFs Compared to Wild-Type (Tutt and Ashworth in collaboration with Lloyd Kelland, ICR Sutton) Increasedrelativesensitivity cellswithoutBrca2
  11. 11. Drug Sensitivity of Brca2/P53 Null MEFs Compared to Wild-type (Tutt and Ashworth in collaboration with Lloyd Kelland, ICR Sutton) Increasedrelativesensitivity cellswithoutBrca2
  12. 12. 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
  13. 13. • 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
  14. 14. BRCA2 mutation carriers Normal Tumour
  15. 15. 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?
  16. 16. 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
  17. 17. Deriving new knowledge from routinely collected clinical data
  18. 18. The Clinisys clinical database Originally designed as a best practice clinical treatment system The database currently has data from • 60 NHS trusts • 2.4m patients • Over 50 distinct disease categories • 250 treatment protocols • Patient data includes diagnostic information, histo-pathological information, routine laboratory measurements, tumour markers Objective is to refine inputs to the database to incorporate • Improved outcomes measurements • More specific questions relating to reason for changes in prescriptions/dosage
  19. 19. An example from metastatic breast cancer • Vinorelbine (a new chemotherapy drug) is only given in metastatic breast cancer as second or third line • Look at all the patients who have had vinorelbine • Examine all the previous drug regimes they have had • Compare the side-effect profile for the first two courses of vinorelbine (low platelets, low white blood count, severe vomitting) across patients who have had different preceeding drug regimes; or even across patients who have had different numbers of drug regimes
  20. 20. Hypothetical example of differential toxicity Time to progression after Vinorelbine treatment of breast cancer 0 5 10 15 1 3 5 7 9 11 13 15 17 19 Time to progression patients('000) Taxane CMF White Blood Cell Count after 1 month on Vinorelbine 0 5 10 15 1 3 5 7 9 11 13 15 17 19 White Blood Cell Count patients('000) CMF Taxane Vinorelbine is more effective as second line therapy after CMF then after Taxane Toxicity of Vinorelbine is worse after CMF then after Taxane
  21. 21. Developing a national structure to pursue cancer pharmaco-genetic research • Association between inherited genetic variation and clinical outcome – response to treatment • Treatment response is the sum of toxicity profile and efficacy • Toxicity profile is the response of normal cells • Efficacy is the response of the tumour cells
  22. 22. Pharmaco-genetics in an adjuvant breast trial • TACT 2 is a trial of accelerated chemotherapy in the adjuvant treatment of breast cancer • We have secured funding to collect a single blood sample for analysis of constitutional DNA from all 4,000 patients • Patient information sheet and consent form has been approved by MREC • Awaiting some minor modifications relating to information on other trials
  23. 23. London Genetics • A collaboration between several London medical schools and academic institutes • Start up funding from the Department of Trade and Industry and the London Development Agency of £2 million • To offer genetic services within clinical trial activity in a commercial environment • Once established will align itself with national initiatives such as the National Cancer Tissue Resource • Will start with oncology and then move into other disease areas, in parallel with the UK Clinical Research Collaboration,led by Leeds and UCL
  24. 24. Further developments • Deputy director of the National Translational Cancer Research Network (NTRAC) has agreed to come and lead the crucial patient engagement work • Aim to collect a blood sample from everyone in a NCRI sponsored clinical trial • Improve Clinisys to record useful, accurate clinical outcome data • Develop a pilot study in UCLH, collecting a blood sample from everyone with cancer treated in UCLH • Roll this initiative into all the hospitals using Clinisys for data capture
  25. 25. Why should we do this work in the UK • The NHS is gradually developing national standards for cancer care • Many trusts are now willing to use the same system for recording of clinical data • MRC funded large project on bringing IT into clinical trial activity • The National Programme for IT in the NHS is the largest IT project the world has seen • The NCRI Informatics Initiative will act as a catalyst for this type of activity
  26. 26. Conclusions • Genetic Breast Cancer Trial • The Clinisys system for collection of routine clinical data • Examining inherited genetic variation and treatment response in clinical trials • Pilot study within UCLH of cancer pharmaco-genetics in non-trial patients • Build a national structure for pharmaco-genetic investigation in oncology, and then in other disease areas

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