Title: MRC SUPREMO Trial Launch
1MRC SUPREMO Trial Launch
- 17th June 2005
- The Queen Mother Conference Centre
- Royal College of Physicians of Edinburgh
2 SUPREMO Selective Use of Postoperative
Radiotherapy aftEr MastectOmy
- SUPREMO(BIG 2-04) Selective Use of
Postoperative Radiotherapy aftEr MastectOmy - Phase III randomised trial of chest wall RT in
intermediate- risk breast cancerKunkler I,
Canney P, Price A,Prescott R, Hophood P,Dixon J,
Sainsbury R,Aird E, Thomas G,Bowman A,Thomas J,
Bartlett J,Foster E, Denvir M,McDonagh T,Russell
N -
3BackgroundTrials of Postmastectomy RT
- Danish and Canadian trials 9-10 survival benefit
at 10 yrs from addition of RT to systemic therapy
(Overgaard 97,99Ragaz 97) - PMRT standard for T3 and /gt 4 N
- May be larger survival benefit in smaller tumours
with fewer involved nodes (Harris,1999) - Role of PMRT in 1-3 N research priority of NIH
(2000) - Weighting of risk factors (N, grade, LVI) in
selecting patients for PMRT unclear
42000 Overview of Trials of Postoperative RT
Trials (Peto et al)
5Trials of PMRT in premen1-3 N adjuvant
CMFchemo (Fowble,1999)
6Breast Cancer specific survival and metastasis
free survival, whole trial. Systemic therapy
therapy /- loco-regional irradiation (Ragaz,J
Natl Cancer Inst 97,116-26, 2005)
720 yr follow up of British Columbia Trial of
Systemic Therapy /- in premen N (Ragaz et al,
JNCI 200597116-26)
8Whelan Levine,JNCI Jan 2005
- Level I evidence needed to assess PMRT in 1-3 N
- Currently limited to subgroup analysis
- New RCTs needed to address the issue
9BCS or Mx /-RT in node negative pT1-2, NO
tumours (Voordeckers et al,2003Rad Oncol
68227-231)
- BCS (n343) or mastectomy (n388), axillary
lymph node dissection and post-operative RT - 1984 - 2000 731 pT1 (n427) or pT2 (n304) pN0
- compared with the SEER-data 1988-1997
10Mastectomy /- chest wall RT in pT1-pT2, pNO
compared tp SEER data (Voordeckers et al,2003
Radioth Oncol 200368227-231)
11Mastectomy /- chest wall RT in pT1-pT2, pNO
compared tp SEER data (Voordeckers et al,2003
Radioth Oncol 200368227-231)
12Eligibility Criteria
- 1. pT1, pN1, M0 or pT2, pN0-1 M0 histologically
confirmed invasive breast cancer. - 2. Unifocal invasive breast cancer or multifocal
breast cancer if at least a 2cm focus of invasive
breast cancer - 3. Fit for adjuvant chemotherapy (if indicated),
adjuvant endocrine therapy (if indicated) and
postoperative irradiation - 4. Undergone simple mastectomy (with minimum of
1mm clear margin) and an axillary staging
procedure - (i). If axillary node positive (1-3 positive
nodes including micrometastases gt0.2mm -lt2mm
then an axillary node clearance (minimum of 10
nodes removed) should have been performed. - (ii) Axillary node negative status can be
determined on the basis of either axillary node
clearance, or axillary node sampling or sentinel
node biopsy - T2NO tumours are eligible with grade III
histology and/or lymphovascular invasion - 5. Written informed consent
13Exclusion Criteria
- 1. Any pT0, pN0-1, or pT1, pN0 or pT3 or pT4
- 2. Patients who have undergone neoadjuvant
systemic therapy. - 3. Previous or concurrent malignant other than
non melanomatous skin - cancer and cancer in situ of the cervix
- 4. Male sex
- 5. Pregnancy
- 6. Bilateral breast cancer
- 7. Known BRCA1 and BRCA2 carriers
- 8. Not fit for surgery, radiotherapy or
adjuvant systemic therapy - 9. Internal mammary nodes positive on sentinel
node scintigraphy - 10. Unable or unwilling to give informed consent
14Randomisation in SUPREMO
- Chest wall irradiation
- Vs
- No chest wall irradiation
15Radiotherapy QA
- 40- 50 Gy standard fractionation
- 3D planning
- RT to supra/infraclav allowed in N
- Randomisation as close to start of RT as possible
16Endpoints for SUPREMO
- Primary overall survival
- Secondary
- Disease free survival
- Acute and late morbidity
- Quality of life
- Cost effectiveness (cost per life year)
- Molecular markers of local relapse and
- radiosensivity
17Powering of the Trial
- 3500 patients (1750 per arm) for 80 power to
detect a statistically significant difference at
the 5 level if the true rates of survival at 5
years are 75 and 79 - (i.e. 4 difference)
- Need 794 events (deaths)
18Biological,Cardiac, QL and Health Economic
Substudies
19TRANS-SUPREMO
- Archiving of tumour for future analysis for
molecular markers of radiation sensitivity
20From C. Hurkmans, NKI
21N- terminal Brain natriuretic peptide (NT-pro-BNP)
- Peptide hormone released primarily from cardiac
ventricles in response to myocyte stretch - Raised BNP may reflect increased left ventricular
wall stress and cardiac ischaemia
22Quality of Life Substudy
- Limited information on impact of PMRT on quality
of life - Small retrospective studies on impact of RT on
breast reconstruction and RT technique often
poorly described
23Cost Effectiveness of Postmastectomy Radiotherapy
24Feasibility Survey 350 UK Surgeons (Dixon,2003)
25BIG Collaboration in SUPREMO
- Anglo-Celtic Cooperative Oncology Group
- Australia and New Zealand Breast Cancer Trials
Group - Borstkanker Onderzoeksgroep Nederland
- European Organisation for Research and Treatment
of Cancer - GECO Peru
- Hellenic Breast Surgical Society
- Institute of Cancer Research Clinical trials
Statistics Unit
- International Breast Cancer Study Group
- Irish Clinical Oncology Research Group
- Japanese Breast Cancer Research Group
- National Cancer Institute of Canada Cancer
Trials Group - National Cancer Research Institute Breast Cancer
Studies Group - Swiss Group for Clinical Cancer Research
26MRC SUPREMO Trial Launch
- 17th June 2005
- The Queen Mother Conference Centre
- Royal College of Physicians of Edinburgh
27Professor PrescottStatistical Aspects
28SUPREMO Sample Size Considerations
- Primary Endpoint Overall survival
- Assumption 5 year survival 75 in controls
- Difference for power calculations increase to
79 - 80 power at 5 significance level ?
- N 1750 per group
29SUPREMO Sample Size Considerations
- 3500 evaluable patients required
- 3700 to be recruited to allow for
loss-to-follow-up
30SUPREMO Sample Size Considerations
- What if our assumed survival rate is wrong?
- 75 ? 79 ? Hazard ratio 1.22
- For 80 power we need 794 deaths at time of
analysis.
31SUPREMOStatistical Plan
- Based on intent-to-treat
- 2 tailed significance tests and confidence
intervals - Principally based on Cox proportional hazards
model - First report planned after 2.5 years of follow-up
- (subject to potential modification by the Trial
Steering Committee with advice from the Data
Monitoring and Ethics Committee)
32SUPREMOQoL Substudy
- 800 recruited for 400 to be evaluable at 5 years
- For binary variables (eg specified degree of
morbidity on a QoL domain), difference between
groups has - SE lt 5
- For continuous variables, standard error of
difference between groups 0.1 x S.D.
33SUPREMOCardiac Sub-study
- Assumptions
- Heart failure if not exposed to anthracyclines
0.5 p.a. - Percentage of patients receiving anthracyclines
70 - Attrition over 5 years 25
- If
- heart failure when exposed to anthracyclines
1.5 p.a. - and 1000 patients are recruited there will be 90
power to obtain a statistically significant
difference at 5 years.
34MRC SUPREMO Trial Launch
- 17th June 2005
- The Queen Mother Conference Centre
- Royal College of Physicians of Edinburgh
35QA for SUPREMORadiotherapy Trials QA centre
- Karen Venables
- Edwin Aird
36History
- CHART
- START
- RT01
- ProtecT
- Stanford V
- INCH
37Overview of Role of Trials QA Centre
- 1. Co-ordinate trials QA
- 2. Maintain a database of Radiotherapy Centres
equipment - 3. To liase with staff both in centres and in
trials QA teams - 4. Advise on Quality Assurance at protocol
writing and grant application stage
38Protocol Design
Initial Questionnaire
Ongoing Technical Advice
The QA process
Immobilisation Studies
Outlining or Planning Exercise
Visits
Individual Patient QA
39What is needed for SUPREMO?
- Initial Questionnaire
- Planning Exercise, including voluming of cardiac
structures - Visits
- Audit of Plans/In-vivo dosimetry
- Cardiac Study
40The Initial Questionnaire
- Establishing precise details of technique used
- patient position
- imaging
- planning system and algorithms used
- criteria applied for distribution(if different
from protocol) - Monitor unit check programs
- Make links with data already collected by QA
Centre for each trial centre (Particularly data
from START trial)
41Planning and Outlining Exercise
- Standard cross-section on which target is marked
for Centre to plan using protocol criteria - Simulator films/Ontreatment films to verify
inclusion/exclusion of cardiac tissue.
42Visits
Dosimetry audit using standards techniques and
anthropomorphic and semi-anthropomorphic
phantoms Centres using the same modality and
planning system as used in previous
interdepartmental and trial audits will not be
revisited.
43Audit of Plans
- Submission of first 5 plans to QA Centre together
with simulation and verification images in
electronic (DICOM) format. - All plans to be submitted to the trials office if
electronic transfer of data is possible for
future analysis. 1 in 10 of these plans will be
analysed as the trial is in progress to check for
continued protocol compliance. In exceptional
cases, if this is not possible 1 in 10 plans to
be submitted in hardcopy format. - All plans submitted to the QA team must be
anonymised by the centre submitting the data
44Individual Patient QA
In-Vivo dosimetry, using TLD for approximately 1
in 10 patients in each centre
45Cardiac Study
- For centres with electronic portal imagers
- On treatment images (minimum 3 images per
patient) for the first 20 left sided patients
from each centre will be collected and analysed
for lung depth and heart depth. Subsequently 1
in 10 patients (same patients as plans, left
sided only). - Patients treated with electrons, electronic
copies of simulator image, plus copy of outline
(preferably electronic) and electron energy - For centres with no electronic imaging
- Copies of films for first left sided chest wall
patient and any patient with greater than 0.5cm
heart in field
46Staff Liaison
- Advice for centres taking part in trials with
technical queries - Dedicated staff with technical knowledge
- Consistent information
47What else are we doing?
48- Rttrialsqa.dnsalias.org
- Linked from the NCRI radiotherapy group page
- Gm.e.wherts-tr.rttrialsqa_at_nhs.org
- Group e-mail linked to e-mail at MVH and RMH
49MRC SUPREMO Trial Launch
- 17th June 2005
- The Queen Mother Conference Centre
- Royal College of Physicians of Edinburgh
50Quality of Life Sub-studySUPREMO trial
- Dr Galina Velikova1
- Dr Penny Hopwood2
- 1 Cancer Research UK Clinical Centre, Leeds, St
Jamess University Hospital - 2 Christie Hospital, Manchester
51Background
- Multimodality breast cancer treatment improves
survival, but has adverse effects on QOL and
functioning (physical, psychological, sexuality) - Early effects - 1st year of treatment (Ganz 1998,
Hopwood 2002) - Late effects (Berglund 1991)
- Specific side-effects chest wall pain, arm
symptoms - Impact on general functioning physical,
emotional, fatigue, QOL
52Aim and hypothesis of QOL sub-study
- To compare the impact of different treatment arms
on QOL - To inform the balance between local tumour
control and adverse treatment effects - QOL is a secondary endpoint
- Hypothesis
- RT will have significant effects on chest wall
pain, appearance, fatigue, physical and emotional
functioning - Effects are likely to be small gt large sample
size
53Design of QOL sub-study
- Longitudinal design with repeated measurement
- Baseline, 3 months after RT or chemotherapy, 6
months, 1,2 and 5 years - Primary endpoints for QOL study
- Chest wall and arm symptoms
- Appearance and body image
- Fatigue
- Physical functioning
- Psychological functioning
- Descriptive analysis on
- Pain, Nausea, QOL
- Breast reconstruction (clinical forms)
54Choice of measures
- Rationale
- Both specific side effects and general impact
- Validated questionnaires
- Consistency across the field
- EORTC QLQ-C30 (Fatigue, Physical)
- EORTC Br-23 (arm symptoms)
- Body Image
- HADS (psychological distress)
55Choice of measures 2
- EORTC Br-23 (arm symptoms)
- Body image and appearance
56Choice of measures 3
- EORTC QLQ-C30
- Physical Function
- Fatigue
- HADS
57Eligibility
- All patients from selected centres
- Are entered into the SUPREMO Trial
- Consent to participate in QOL study
- Are willing and able to complete the
questionnaires
58Sample size
- N800
- With 200 evaluable patients per group
- Specific side effect can be estimated with a
standard error of 3.5 or less - Group differences can be estimated with a
standard error of 5 or less - Allow for attrition rate of 13 per year for 5
years - gt 400 patients per group
- Efforts to minimise missing data
- Statistical analysis repeated measures analysis
of covariance mixed effects models?
59Timing of assessments
- Baseline- For all patients in the clinic
- After consent
- Prior to randomisation
- Explanation by a member of staff
- Follow-up booklet sent by the Trials office
- 3 weeks after RT of chemotherapy
- 6 months
- 1,2 and 5 years
- Relapse
- Patients will be asked to continue to complete
the QOL
60Trial management and practical issues 1
- Multi-centre study
- Subset of centres
- Can opt out, but geographic / socio-economic
distribution monitored - All patients in these centres
- QOL will an integral part for all consenting
patients - If imbalances occur selected hospital may be
asked to take part
61Trial management and practical issues 2
- QOL sub-study will be run by the Trials office
- In the hospitals
- Identify person responsible for QOL sub-study
- Explain the questionnaires
- Check correct completion
- Informed consent prior to QOL completion
- Ethical issues
- Inform GP of patients with clinically significant
scores on HADS on two consecutive occasions
within 6 month - This is explained in PIS
62MRC SUPREMO Trial Launch
- 17th June 2005
- The Queen Mother Conference Centre
- Royal College of Physicians of Edinburgh
63SUPREMO
- Adjuvant Systemic Therapy
64SUPREMO endpoints of study
- Primary Overall Survival
- Secondary Disease-free survival
- Metastasis-free survival
- Cause of death
- Morbidity
- Quality of life
- Cost-effectiveness
65Overview 2000 effect of chemotherapy on
recurrence and death
66SUPREMO influence of changes in systemic therapy
- Anthracyclines
- Taxanes
- Monoclonal antibodies
- Aromatase inhibitors
67(No Transcript)
68(No Transcript)
69SUPREMO influence of changes in systemic therapy
- Anthracyclines
- Taxanes
- Monoclonal antibodies
- Aromatase inhibitors
70Effect of adjuvant docetaxel BCIRG001 study
-
- FAC TAC p-value
_______________________________________ - 5 year DFS 68 75
- HR for relapse 0.72 0.001
- 5 year OS 81 87
- HR for death 0.70 0.008
Martin NEJM 2005
71SUPREMO influence of changes in systemic therapy
- Anthracyclines
- Taxanes
- Monoclonal antibodies
- Aromatase inhibitors
72Herceptin Joint Analysis of NSABP B31 and NCCTG
9831
73Herceptin Joint Analysis of NSABP B31 and NCCTG
9831
74SUPREMO influence of changes in systemic therapy
- Anthracyclines
- Taxanes
- Monoclonal antibodies
- Aromatase inhibitors
75Overview 2000 effect of tamoxifen on recurrence
and death
76ATAC study DFS in HR tumours
HR 0.83 0.87
95 CI (0.730.94) (0.78-0.97)
p-value 0.005 0.01
A 424 575
T 497 651
25
HR
20
ITT
15
Patients ()
10
5
Absolute difference
1.6
2.6
2.5
3.3
0
0
1
2
3
4
5
6
Follow-up time (years)
At risk
A
2618
2540
2448
2355
2268
2014
830
T
2598
2516
2398
2304
2189
1932
774
DFS includes all deaths as a first event
77DFS in adjuvant AI studies
- HR p-value
- __________________________________________
- Immediate AI v tamoxifen
- Anastrozole (ATAC) 0.83 0.005
- Letrozole (BIG FEMTA) 0.81 0.003
- Switch to AI after 2 years
- Exemestane (IES) 0.73 0.0001
- Anastrozole (ABSCG8/ 0.60 0.0009
- ARNO95)
78Herceptin Cardiac toxicity in NSABP B31
79Can we predict the future of adjuvant therapy?
80SUPREMO choice of systemic therapies
Prescriptive clean study Recruitment slower
Permissive Generally applicable Faster
81SUPREMO
- Indications for adjuvant systemic therapy
- All patients should be considered for adjuvant
systemic therapy - Decision to treat is at investigator discretion
- Choice of regimen is at investigator discretion
- Treatment information will be collected
82SUPREMO
- Timing of adjuvant systemic therapy
- Chemotherapy should be completed before
radiotherapy - Radiotherapy to start within 6 weeks
- Neo-adjuvant systemic therapy not allowed
83SUPREMO
- Recommendations for adjuvant systemic therapy
- Anthracycline treatment is recommended
- Taxanes are allowed, ideally with an
anthracycline - Chemotherapy should last at least 3 months
- Adjuvant endocrine therapy should last for at
least 5 years
84MRC SUPREMO Trial Launch
- 17th June 2005
- The Queen Mother Conference Centre
- Royal College of Physicians of Edinburgh
85The Future of Molecular Predicting of Clinical
Outcomes in Breast Cancer
- Dimitry S.A. Nuyten, M.D.
- Department of Radiation Oncology
- The Netherlands Cancer Institute
- SUPREMO Trail Launch June 17th 2005 - Edinburgh
86Outline
- Different methods and techniques
- Focus on Micro-array analysis
- Principles, analysis methods
- Outcome prediction using different models
- Therapy response
- Incorporation in trials
- Conclusions
87Different methods for Molecular Prediction
88Different methods
- PCR-based test
- Investigate a (limited) number of genes
- Tissue micro array
- High throughput Immunohistochemistry
- Micro-array analysis
89PCR
- Extract tumor tissue from paraffin blocks
- Analyze a number of genes
- Quantify expression of those genes
- Weighted analysis
- Assign a score
- Predict Recurrence rate
90Example PCR
- Oncotype (Genomic Health)
- 16 Cancer genes (5 control genes)
- 668 Tamoxifen treated patients
- From NSABP-B14
- Lymph node negative
- Clinical Trail (NSABP) planned
Paik et al. NEJM 2004 Dec 351 27 2817 2826
91Results
- 10 year recurrence rates
- Low (51 of patients) 6.8
- Intermediate (22 of patients) 14.3
- High (27 of patients) 30.5
Paik et al. NEJM 2004 Dec 351 27 2817 2826
92Tissue Micro Arrays
- Small cores of tissue on microscopic slide
- Enables high throughput IHC
- Either standard set or validate genes that have
been identified with micro-array analysis
93Example TMA
94Micro-array analysis
95What is a micro-array?
- Collection of genes on a microscopic slide
96(No Transcript)
97Spots of micro-array
One spot PCR products of (part of) one gene
98Determining gene activity with micro-arrays
991 2 3 4 5 6 7 8 9 10
100Methods of Data Analysis
101Data Analysis- Unsupervised vs. Supervised
- Unsupervised
- Looking at gene expression differences only
- Distinguishing different clusters based on
similar gene expression - Appreciates biological differences
102Unsupervised Hierarchical Clustering
Chang Nuyten et al PNAS 2005
103Supervised
- Supervised
- Using outcome data to start with
- Labeling patients
- E.g. Metastasis versus non-metastasis
- Finding genes that predict these groups
- Prone to over fitting
104Micro array in prognosis outcome
105Micro array in prognosis outcome
- Biological subtypes
- Unsupervised
- Prognostic relevance
- Optimal prediction
- Metastasis free and overall survival
- Supervised Analysis
106Unsupervised Biological Subtypes
- Perou Sorlie (2000 2003)
- Multiple biological subtypes
- Basal, Luminal A B, ErBb2, Normal-like
- Prognostic value
- Poor outcome Basal and ErB2
- Good Outcome Luminal
Perou et al Nature 2000 Aug 406 747 -
52, Sorlie et al PNAS 2001 Sep 98 10869 - 74 and
2003 Jul 100 8418 - 23
107Recognizing different gene clusters
108Prognostic relevance of different subtypes
109Supervised
- 70-genes prognosis profile (van t Veer 2002)
- Supervised (distant metastasis)
- Validation (Vd Vijver 2002)
Van t Veer et al Nature 2002 Jan 415 530 -
36, Van de Vijver et al NEJM 2002 Dec 347
1999-2009.
110Supervised Classification for Prognosis
78 breast tumors patients lt 55 years Tumor size lt
5 cm Lymph node negative (LN0)
no distant metastasis gt 5 years (n44)
distant metastasis lt 5 years (n34)
111 Supervised Classification Prognosis
Leave-one-out cross-validation
70 significant prognosis genes
good signature
78 tumors
poor signature
112Metastasis-free probability and overall survival
for the whole cohort
113Unsupervised II
114Hypothesis Driven Gene Expression Profiling
- Hypothesis based on specific process in cancer
- Build in vitro model
- Example
- Wound Response Signature
115Wound Response Signature
- Similarities Tumor ? Wound
- Tumors wounds that do not heal
- Angiogenesis
- Proliferation
- Matrix remodeling
Dvorak N Engl J Med. 1986 Dec 25315(26)1650-9.
116Wound Response Signature
- In vitro Wound Model 516 genes
- Prognostic Significance in
- Breast
- Lung
- Gastric cancer
Iyer et al Science 1999 83-7 Chang et al
PLoS Biology 2004 Feb 2 2 1- 9
117Validate on Patients from Netherlands Cancer
Institute
- 295 Stage I and II Breast Carcinomas
- Age lt53
- 151 Lymph Node Negative
- 144 Lymph Node Positive
- 25k Oligonucleotide Micro-array
- Used to define and validate 70-gene prognosis
profile - Updated clinical data Median FU 12 yrs
118Unsupervised Hierarchical Clustering
Chang Nuyten et al PNAS 2005
119Unsupervised Hierarchical Clustering
120Wound Signature on Metastasis
- 15 year
- Quiescent 69
- Activated 47
- HR 2.8
- (95CI 1.8-2.3)
Quiescent
Activated
P0.0001
169 133 77
27 4 Quiescent
126 60 35
8 0 Activated
Chang Nuyten et al PNAS 2005, updated
121Wound Signature on Survival
- 15 year
- Quiescent 74
- Activated 47
- HR 3.6
- (95CI 2.3-5.6)
Quiescent
Activated
Plt110-7
169 154 105
35 7 Quiescent
126 85 51
11 0 Activated
Chang Nuyten et al PNAS 2005, updated
122Multi Variate Analysis
- Age lt40 yrs HR 1.8 (95CI 1.1-3.0)
- ER- HR 2.3 (95CI
1.4-3.8) - Angio-invasion HR 1.4 (95CI 1.1-1.8)
- Wound Signature HR 3.7 (95CI 1.5-9.2)
- Size, Chemotherapy, Age, Lymph Node Status,
Grade, Angio-invasion, ER and Wound Signature
have been analyzed.
123Wound Signature is Scalable
- Patients are assessed by a Wound Signature
score - Correlation to the in vitro model
- No need for clustering, reference patients
- Low correlation, good outcome
- Optimizing towards metastasis
124Wound Signature on MetastasisOriginal vs.
Optimized
Activated vs. Quiescent 228 vs. 67
Activated vs. Quiescent 126 vs. 169
125Hybrid Models
- Intergrading Biological Models and Supervised
Models
126Combination - Hybrid-model
- Hypothesis Driven
- Biological hypothesis driven
- High specificity, lower sensitivity
- Supervised
- Optimized Sensitivity, lower specificity
- New Hybrid model
- Integration of in vitro model and clinical data
127Updated 70 gene prognosis profile
- Overall Survival 15 yr
- Good 84
- Poor 51
- HR 5.3 (95CI 3-9.4)
Plt 110-9
Good 115 111 82
27 2 Poor 180
128 74 19
5
Nuyten et al ASCO 2005
128Wound Signature and 70 genes
Activated
129Wound Signature and 70 genes
Activated
Plt0.00001
Good 55 54 30
9 Poor Quiescent 32 26 14
5 Poor Activated 57 34
16 7
Chang Nuyten et al PNAS 2005
Note only pN
130Using Hybrid Model for Local Recurrence prediction
- After Breast Conservative Treatment
131Patients Breast Conserving Therapy
- Stage I and II Breast Carcinomas
- Age lt55
- Median FU 7.7 yr
- 161 patients
- 17 Local recurrence
132Prognosis Reporter Genes Wound Signature
133Prognosis Reporter Genes Wound Signature
134Wound-like Gene Signature in LR Local recurrence
free probability
Training
Validation
P0.0005
P0.00014
High 27 21 11
3 25
21 8 4 Low 54
50 27 8
55 47 22
4
135LR-Free rates at 10 years
- Learning
- All 83.9 LR-free
- WS Activated 63.5
- WS Quiescent 94.4
- P0.00014
- Validation
- All 85.8 LR-free
- WS Activated 69.5
- WS Quiescent 95.0
- P0.0005
136Therapy Response Prediction
137Therapy response prediction
- Response to neo-adjuvant Chemotherapy
- Docetaxel (Chang Lancet 2003)
- Paclitaxel FAC (Ayers JCO 2004)
- Tamoxifen
- Jansen JCO 2005
- Ma et al Cancer Res 2004
- Paik et al ASCO 2005
138Therapy response prediction 2
- Small series
- No independent validation yet
- Proof of principle
139Ongoing Trials
140The Young Boost Study
- Patients ? 50 years, T1-2N0-2a invasive breast ca
- Wide local excision with microscopically free
margins SN/ALND - (storage of blood and frozen tumor material)
-
-
- 16 Gy boost 26 Gy boost
R
25 x 2 Gy whole breast RT
141Adjuvant therapy trials
- MindAct
- Randomization for discordant patients
- 70-genes or St. Gallen for Adjuvant Setting
- Matador
- Monitoring response in adjuvant setting
142Study design MATADOR
A60C600 q 2wks Pegfilgrastim 6 mg sc
8 wks
randomize
S T R A T I F Y
? pT1-3 pN1-3 M0
12 wks
DT75A50C500 q 3wks Pegfilgrastim 6 mg sc
12 wks
18 wks
143Conclusions
- Outcome prediction seems powerful
- First Independent validation Finished
- 70-genes
- Both Biological and Supervised models
- Hybrid Models Better?
144Conclusions 2
- Local Recurrence and Therapy response
- Promising further validation needed
- Clinical Trials
- Started or planned
145Acknowledgements
- Harry Bartelink
- Laura van t Veer
- Sabine Linn
- Marc van de Vijver
146MRC SUPREMO Trial Launch
- 17th June 2005
- The Queen Mother Conference Centre
- Royal College of Physicians of Edinburgh