MRC SUPREMO Trial Launch

1
MRC 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
•  

3
BackgroundTrials 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

4
2000 Overview of Trials of Postoperative RT
Trials (Peto et al)
5
Trials of PMRT in premen1-3 N adjuvant
CMFchemo (Fowble,1999)
6
Breast Cancer specific survival and metastasis
free survival, whole trial. Systemic therapy
therapy /- loco-regional irradiation (Ragaz,J
Natl Cancer Inst 97,116-26, 2005)
7
20 yr follow up of British Columbia Trial of
Systemic Therapy /- in premen N (Ragaz et al,
JNCI 200597116-26)
8
Whelan 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

9
BCS 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

10
Mastectomy /- chest wall RT in pT1-pT2, pNO
compared tp SEER data (Voordeckers et al,2003
Radioth Oncol 200368227-231)
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Mastectomy /- chest wall RT in pT1-pT2, pNO
compared tp SEER data (Voordeckers et al,2003
Radioth Oncol 200368227-231)
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Eligibility 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

13
Exclusion 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 

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Randomisation in SUPREMO

• Chest wall irradiation
• Vs
• No chest wall irradiation

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Radiotherapy QA

• 40- 50 Gy standard fractionation
• 3D planning
• RT to supra/infraclav allowed in N
• Randomisation as close to start of RT as possible

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Endpoints 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

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Powering 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)

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Biological,Cardiac, QL and Health Economic
Substudies
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TRANS-SUPREMO

• Archiving of tumour for future analysis for
  molecular markers of radiation sensitivity

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From C. Hurkmans, NKI
21
N- 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

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Quality 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

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Cost Effectiveness of Postmastectomy Radiotherapy
24
Feasibility Survey 350 UK Surgeons (Dixon,2003)
25
BIG 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

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MRC SUPREMO Trial Launch

• 17th June 2005
• The Queen Mother Conference Centre
• Royal College of Physicians of Edinburgh

27
Professor PrescottStatistical Aspects
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SUPREMO 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

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SUPREMO Sample Size Considerations

• 3500 evaluable patients required
• 3700 to be recruited to allow for
  loss-to-follow-up

30
SUPREMO 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.

31
SUPREMOStatistical 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)

32
SUPREMOQoL 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.

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SUPREMOCardiac 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.

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MRC SUPREMO Trial Launch

• 17th June 2005
• The Queen Mother Conference Centre
• Royal College of Physicians of Edinburgh

35
QA for SUPREMORadiotherapy Trials QA centre

• Karen Venables
• Edwin Aird

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History

• CHART
• START
• RT01
• ProtecT
• Stanford V
• INCH

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Overview 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

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Protocol Design
Initial Questionnaire
Ongoing Technical Advice
The QA process
Immobilisation Studies
Outlining or Planning Exercise
Visits
Individual Patient QA
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What is needed for SUPREMO?

• Initial Questionnaire
• Planning Exercise, including voluming of cardiac
  structures
• Visits
• Audit of Plans/In-vivo dosimetry
• Cardiac Study

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The 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)

41
Planning 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.

42
Visits

• Insert photos

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.
43
Audit 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

44
Individual Patient QA
In-Vivo dosimetry, using TLD for approximately 1
in 10 patients in each centre
45
Cardiac 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

46
Staff Liaison

• Advice for centres taking part in trials with
  technical queries
• Dedicated staff with technical knowledge
• Consistent information

47
What else are we doing?

• Website
• E-mail

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

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MRC SUPREMO Trial Launch

• 17th June 2005
• The Queen Mother Conference Centre
• Royal College of Physicians of Edinburgh

50
Quality 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

51
Background

• 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

52
Aim 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

53
Design 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)

54
Choice 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)

55
Choice of measures 2

• EORTC Br-23 (arm symptoms)
• Body image and appearance

56
Choice of measures 3

• EORTC QLQ-C30
• Physical Function
• Fatigue
• HADS

57
Eligibility

• 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

58
Sample 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?

59
Timing 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

60
Trial 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

61
Trial 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

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MRC SUPREMO Trial Launch

• 17th June 2005
• The Queen Mother Conference Centre
• Royal College of Physicians of Edinburgh

63
SUPREMO

• Adjuvant Systemic Therapy

64
SUPREMO endpoints of study

• Primary Overall Survival
• Secondary Disease-free survival
• Metastasis-free survival
• Cause of death
• Morbidity
• Quality of life
• Cost-effectiveness

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Overview 2000 effect of chemotherapy on
recurrence and death
66
SUPREMO influence of changes in systemic therapy

• Anthracyclines
• Taxanes
• Monoclonal antibodies
• Aromatase inhibitors

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(No Transcript)
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(No Transcript)
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SUPREMO influence of changes in systemic therapy

• Anthracyclines
• Taxanes
• Monoclonal antibodies
• Aromatase inhibitors

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Effect 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
71
SUPREMO influence of changes in systemic therapy

• Anthracyclines
• Taxanes
• Monoclonal antibodies
• Aromatase inhibitors

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Herceptin Joint Analysis of NSABP B31 and NCCTG
9831
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Herceptin Joint Analysis of NSABP B31 and NCCTG
9831
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SUPREMO influence of changes in systemic therapy

• Anthracyclines
• Taxanes
• Monoclonal antibodies
• Aromatase inhibitors

75
Overview 2000 effect of tamoxifen on recurrence
and death
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ATAC 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
77
DFS 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)

78
Herceptin Cardiac toxicity in NSABP B31
79
Can we predict the future of adjuvant therapy?
80
SUPREMO choice of systemic therapies

Prescriptive clean study Recruitment slower
Permissive Generally applicable Faster
81
SUPREMO

• 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

82
SUPREMO

• Timing of adjuvant systemic therapy
• Chemotherapy should be completed before
  radiotherapy
• Radiotherapy to start within 6 weeks
• Neo-adjuvant systemic therapy not allowed

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SUPREMO

• 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

84
MRC SUPREMO Trial Launch

• 17th June 2005
• The Queen Mother Conference Centre
• Royal College of Physicians of Edinburgh

85
The 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

86
Outline

• Different methods and techniques
• Focus on Micro-array analysis
• Principles, analysis methods
• Outcome prediction using different models
• Therapy response
• Incorporation in trials
• Conclusions

87
Different methods for Molecular Prediction
88
Different methods

• PCR-based test
• Investigate a (limited) number of genes
• Tissue micro array
• High throughput Immunohistochemistry
• Micro-array analysis

89
PCR

• Extract tumor tissue from paraffin blocks
• Analyze a number of genes
• Quantify expression of those genes
• Weighted analysis
• Assign a score
• Predict Recurrence rate

90
Example 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
91
Results

• 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
92
Tissue 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

93
Example TMA
94
Micro-array analysis
95
What is a micro-array?

• Collection of genes on a microscopic slide

96
(No Transcript)
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Spots of micro-array
One spot PCR products of (part of) one gene

98
Determining gene activity with micro-arrays
99
1 2 3 4 5 6 7 8 9 10
100
Methods of Data Analysis
101
Data Analysis- Unsupervised vs. Supervised

• Unsupervised
• Looking at gene expression differences only
• Distinguishing different clusters based on
  similar gene expression
• Appreciates biological differences

102
Unsupervised Hierarchical Clustering
Chang Nuyten et al PNAS 2005
103
Supervised

• 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

104
Micro array in prognosis outcome
105
Micro array in prognosis outcome

• Biological subtypes
• Unsupervised
• Prognostic relevance
• Optimal prediction
• Metastasis free and overall survival
• Supervised Analysis

106
Unsupervised 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
107
Recognizing different gene clusters
108
Prognostic relevance of different subtypes
109
Supervised

• 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.
110
Supervised 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
112
Metastasis-free probability and overall survival
for the whole cohort
113
Unsupervised II

• Hypothesis Driven

114
Hypothesis Driven Gene Expression Profiling

• Hypothesis based on specific process in cancer
• Build in vitro model
• Example
• Wound Response Signature

115
Wound 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.
116
Wound 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
117
Validate 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

118
Unsupervised Hierarchical Clustering
Chang Nuyten et al PNAS 2005
119
Unsupervised Hierarchical Clustering
120
Wound 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
121
Wound 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
122
Multi 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.

123
Wound 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

124
Wound Signature on MetastasisOriginal vs.
Optimized
Activated vs. Quiescent 228 vs. 67
Activated vs. Quiescent 126 vs. 169
125
Hybrid Models

• Intergrading Biological Models and Supervised
  Models

126
Combination - 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

127
Updated 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
128
Wound Signature and 70 genes
Activated
129
Wound 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
130
Using Hybrid Model for Local Recurrence prediction

• After Breast Conservative Treatment

131
Patients Breast Conserving Therapy

• Stage I and II Breast Carcinomas
• Age lt55
• Median FU 7.7 yr
• 161 patients
• 17 Local recurrence

132
Prognosis Reporter Genes Wound Signature
133
Prognosis Reporter Genes Wound Signature
134
Wound-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
135
LR-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

136
Therapy Response Prediction
137
Therapy 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

138
Therapy response prediction 2

• Small series
• No independent validation yet
• Proof of principle

139
Ongoing Trials
140
The 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
141
Adjuvant therapy trials

• MindAct
• Randomization for discordant patients
• 70-genes or St. Gallen for Adjuvant Setting
• Matador
• Monitoring response in adjuvant setting

142
Study 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
143
Conclusions

• Outcome prediction seems powerful
• First Independent validation Finished
• 70-genes
• Both Biological and Supervised models
• Hybrid Models Better?

144
Conclusions 2

• Local Recurrence and Therapy response
• Promising further validation needed
• Clinical Trials
• Started or planned

145
Acknowledgements

• Harry Bartelink
• Laura van t Veer
• Sabine Linn
• Marc van de Vijver

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MRC SUPREMO Trial Launch

• 17th June 2005
• The Queen Mother Conference Centre
• Royal College of Physicians of Edinburgh