Download Normal - Cancer de Mama

Current and future role of genetics in
breast cancer management
Dr James Mackay
Consultant Clinical Genetic Oncologist
University College London
Medical Director, Opaldia Ltd
Breast Cancer Management
• Importance of understanding the host
response
• Importance of understanding tumour biology
• Concentrating on genetics
• Inherited genetic variation
• Somatic genetic changes
Summary
• Brief look back at history of BRCA1/BRCA2
identification
• Does BRCA1/2 status affect treatment?
• The BRCA trial
• Genetic expression signatures: Mammaprint
• Controversy in the introduction of Mammaprint into
clinical practice: personal thoughts
The recent past
• International effort to identify breast cancer
genes
• Consortium collected families with high
incidence of young breast cancer
• BRCA1 identified in 1994
• BRCA2 identified in 1995
• Very positive press reports of these
laboratory discoveries
The Clinical Scene
Relatives
Breast
cancer
patients
Moderate
risk
High risk
Direct gene
testing feasible
High Risk
DDD
BrCa
51
OvCa
55
DDD
BrCa
38
DDD
37
BrCa
32
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 second step
If mutation +ve; at risk of
• Breast cancer, particularly young breast cancer
• Ovarian cancer
Founder mutations
• In some populations there are a small
number of mutations which are relatively
frequent
• Called founder mutations
• In Ashkenazi population
• 3 mutations; 2.2% of population
• Different founder in Iceland
• Founders in Poland
• Unique mutations in Cyprus
BRCA mutation carriers
“Normal”
BRCA 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)
Clinical Hypothesis to test
• Are tumours in BRCA carriers more sensitive
to platinum than other drugs?
• Is the normal tissue in BRCA carriers more
sensitive to platinum than other drugs?
Genetic Breast Cancer Trial
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
The BRCA Trial
• First prospective randomised trial of
chemotherapy based on inherited genotype in
the world
• Fully funded by academic funders
• Problems caused by European directive
• Recruitment slow
• Poor collaboration between oncology and
clinical genetics
• International support is essential
Genetic variation and drug response
• Examining inherited genetic variation gives
information about likely response
• Response involves toxicity and efficacy
• Accepted that inherited genetic variation may affect
toxicity seen
• Inherited variation also affects measured drug levels
and therefore may influence efficacy
• We will see many tests being developed to predict
toxicity
• Should the company selling the drug also offer the
genotype test predicting toxicity?
Steps to becoming a cancer cell
normal
cancer
metastasis
A new company
Genetic medicine:
Opaldia offers:
Opaldia is the first private UK
healthcare company providing a
comprehensive service to the
public and healthcare providers
High quality clinical services to
patients, their families and
friends
Information, screening, testing
and ongoing support
Healthcare systems will face some tough questions in the
coming years!
– Increasing number of pts.
– Innovation in technology
– New more effective drugs
– Higher pts. expectations
And it will be no surprise that
this all will come at a price!
Prognosis classifier for breast cancer based on genomic profiling
Tumor samples
70 significant prognosis genes
(van´t Veer et al., Nature 415, p. 530-536, 2002).
The genes analysed in MammaPrint are
(please note that all genes are in the public domain)
By studying the activity of all human genes in over 300 “clean” breast cancer
tumour samples. NKI and Agendia’s scientists identified a group of 70 genes
that have a different expression pattern in correlation to the aggressiveness of
the tumour.
The 70 genes selected for their prognostic value are found in:
• Cell cycle
• Invasion
• Metastasis
• Angiogenesis.
BRCA1 signature
100 genes optimal for classification
38 patients
Top BRCA-1 signature
Bottom ‘sporadic’ signature
36/38
correctly
classified
95% accuracy.
Work in progress
Conclusions
• The last decade has seen genetic testing entering the
cancer clinic
• Inherited genetic variation can affect response to
treatment
• Complex analysis of tumour biology is now possible
• Advanced diagnostic tests should improve patient
care
• How will these advances affect your working life over
the next decade?