Management of inherited breast cancer:
implications for carriers and clinical
trials
Dr James Mackay
Consultant Clinical Genetic Oncologist
University College London
Summary
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BRCA1/2 testing in the UK
The Genetic Breast Cancer Trial
Chemocare database owned by Clinisys Ltd
The London Genetics Centre
High Risk
DDD
BrCa
51
OvCa
55
DDD
BrCa
38
DDD
37
BrCa
32
Setting the Scene
Relatives
Breast
cancer
patients
Moderate
risk
High risk
Direct gene
testing feasible
BRCA1 Structure
4 available bases:
C G A or T
Arranged in line – 100,000
-CGATTCGGGTAAAAMutation
-change of one base anywhere in the line
Genetic Testing
A 2 step process:
1. identify mutation in affected
family member
then…
2. offer direct gene test to other family
members
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
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
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
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”?
Once mutation identified in family
and unaffected individuals tested If mutation +ve; at risk of
• Breast cancer, particularly young breast cancer
• Ovarian cancer
BRCA2 mutation carriers
“Normal”
BRCA2 mutation carriers
Normal
Tumour
Steps to becoming a cancer cell
normal
cancer
metastasis
Increased relative sensitivity
cells without Brca2
(Tutt and Ashworth in collaboration with Lloyd Kelland, ICR Sutton)
Increased relative sensitivity
cells without Brca2
(Tutt and Ashworth in collaboration with Lloyd Kelland, ICR Sutton)
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
• 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
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?
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
Genetic Breast Cancer Trial Design
Docetaxel
100mg/m2 i.v. q3w
Carboplatin
AUC = 7, i.v. q4w
AUC = 5, i.v. q3w
End-points
BRCA1/2
carriers
1st metastatic
relapse
Toxicity
Response Rates
TTP
Carboplatin
AUC = 7, i.v. q4w
AUC = 5, i.v. q3w
End-points
Disease
progression
Toxicity
Response Rates
TTP
Docetaxel
100mg/m2 i.v. q3w
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
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
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
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
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
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
Conclusions
• BRCA testing in the UK
• The Genetic Breast Cancer Trial
• The Chemocare Database owned by Clinisys
Oncology Ltd
• The London Genetics Centre Ltd