Transcript Document

Genomics in the Treatment of
Early Stage Breast Cancer
Oncotype DX™
Breast Cancer Assay
ROSEMARY LEEMING, MD, FACS
April 11, 2008
Agenda
•
•
•
Introduction
Development of Oncotype DX
Clinical Studies
–
–
–
•
ASCO Data (6/07)
–
•
RS and local recurrence (SABCS 12-06)
Node Positive Data (ASCO 6/07)
Other Gene Profiles
–
–
•
•
Clinical Utility Studies
Exploratory Studies
–
–
•
Validation studies
Hormonal therapy benefit study (B-14)
Chemotherapy benefit study (B-20)
MammaPrint
“Invasiveness” gene signature
TAILORx
Clinical Summary
2
Breast Cancer Treatment Planning:
History
• Treatment planning for N–, ER+ disease
is based on:
– Traditional prognostic factors with limited
predictive power (tumor size, patient age) or
poor reproducibility (tumor grade)
– IHC markers (eg, Ki-67) lacking
standardization and validation
– Limited insight into relative benefits of
chemotherapy for different individuals
Bundred. Cancer Treat Rev. 2001;27:137-142.
3
Breast Cancer Treatment Planning:
Not Optimized
• Chemotherapy treatment for N–, ER+
disease
– Many women are offered chemotherapy,
knowing that few benefit
– Guidelines assume all patients benefit equally
– Some patients are under-treated, many others
are over-treated
4
Oncotype DX™:
Unmet Clinical Need for Better Markers
Optimize
High risk/
Large chemo benefit chemotherapy +
local therapy +
hormonal therapy
Biopsy
or
Resection
Robust
markers
Low risk/
Little chemo benefit
Optimize local
therapy and
hormonal
therapy
5
Development and Validation of a 21-Gene Assay
for N–, ER+, Tam+ Patients
YEAR
Develop real-time RT-PCR method for paraffin block
2001
Select candidate genes (250 genes)
2002
Model building studies
(N = 447, including 233 from NSABP B-20)
2002
Commit to a single 21-gene assay
2003
Validation studies in NSABP B-14 and
Kaiser Permanente
2003
Paik et al. N Engl J Med. 2004;351:2817-2826.
6
Oncotype DX™ Technology:
Final Gene Set Selection
Objective
Gene expression and relapse-free survival correlations across three
independent studies – testing 250 genes in 447 patients
N
Node
Status
ER
Status
Treatment
NSABP B-20,
Pittsburgh, PA
233
N–
ER+
Tamoxifen (100%)
Rush
University,
Chicago, IL
78
>10
positive
nodes
ER+/–
Tamoxifen (54%)
Chemotherapy
(80%)
Providence
St. Joseph’s
Hospital,
Burbank, CA
136
N+/–
ER+/–
Tamoxifen (41%)
Chemotherapy
(39%)
Study Site
21 genes and
Recurrence
Score (RS)
algorithm
Paik et al. SABCS 2003. Abstract #16.
Cobleigh et al. Clin Cancer Res. 2005;11(24 Pt 1):8623-8631.
Esteban et al. Proc ASCO 2003. Abstract #3416.
7
Oncotype DX™ 21-Gene
Recurrence Score (RS) Assay
16 Cancer and 5 Reference Genes From 3 Studies
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
ESTROGEN RS =
ER
PR
Bcl2
SCUBE2
GSTM1
INVASION
Stromelysin 3
Cathepsin L2
HER2
GRB7
HER2
BAG1
CD68
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
+ 0.47 x HER2 Group Score
- 0.34 x ER Group Score
+ 1.04 x Proliferation Group Score
+ 0.10 x Invasion Group Score
+ 0.05 x CD68
- 0.08 x GSTM1
- 0.07 x BAG1
Category
RS (0-100)
Low risk
RS <18
Int risk
RS ≥18 and <31
High risk
RS ≥31
Paik et al. N Engl J Med. 2004;351:2817-2826.
8
Oncotype DX™
Clinical Validation:
The NSABP B-14 Study*
*Paik et al. N Engl J Med. 2004;351:2817-2826.
Oncotype DX™ Clinical Validation:
Genomic Health – NSABP B-14
• Objective: Prospectively validate RS as predictor of
distant recurrence in N–, ER+ patients
• Design
Placebo—not eligible
Randomized
Tamoxifen—eligible
Registered
Tamoxifen—eligible
– Multicenter study with prespecified 21-gene assay,
algorithm, endpoints, analysis plan
Paik et al. N Engl J Med. 2004;351:2817-2826.
10
Oncotype DX™ Clinical Validation:
B-14 Results – Distant Recurrence-Free
Survival (DRFS)
DRFS Over Time – All 668 Patients
100%
90%
80%
DRFS
70%
60%
10-year DRFS = 85%
50%
40%
30%
20%
10%
0%
0
2
4
6
8
Years
10
12
14
16
Paik et al. N Engl J Med. 2004;351:2817-2826.
11
Oncotype DX™ Clinical Validation:
B-14 Study Objectives
• First primary objective
– Validate that 10-year DRFS in the
low-risk group (RS <18) is larger than 10-year
DRFS in the high-risk group (RS ≥31)
• Second primary objective
– Determine whether Recurrence Score as a
predictor of DRFS is more significant than age
and tumor size
Paik et al. N Engl J Med. 2004;351:2817-2826.
12
Oncotype DX™ Clinical Validation:
B-14 Results – DRFS
DRFS for the three distinct cohorts identified
100%
90%
80%
DRFS
70%
60%
P <0.00001
50%
40%
30%
Low Risk (RS <18) n = 338
20%
Intermediate Risk (RS 18-30) n = 149
10%
High Risk (RS 31) n = 181
0%
0
2
4
6
8
Years
10
12
14
16
Paik et al. N Engl J Med. 2004;351:2817-2826.
13
Oncotype DX™ Clinical Validation:
B-14 Results – DRFS (cont.)
Risk Group
% of
10-yr Rate of
Patients Recurrence
95% CI
Low (RS <18)
51%
6.8%
4.0%, 9.6%
Intermediate (RS 18-30)
22%
14.3%
8.3%, 20.3%
High (RS ≥31)
27%
30.5%
23.6%, 37.4%
Test for the 10-year DRFS comparison between the
low-and high-risk groups: P <0.00001
Paik et al. N Engl J Med. 2004;351:2817-2826.
14
Oncotype DX™ Clinical Validation: B-14 Results
Multivariate Analysis Confirms Power of RS
Multivariate Cox Models: Age, Size Alone vs Age, Size + RS
Variable
Hazard Ratio
95% CI
P value
Age ≥50
0.57
(0.39, 0.83)
0.004
Size >2.0 cm
1.44
(0.99, 2.11)
0.058
Age ≥50
0.71
(0.48, 1.05)
0.084
Size >2.0 cm
1.26
(0.86, 1.85)
0.231
Recurrence
Score
3.21
(2.23, 4.61) <0.00001
P <0.00001
Age at surgery used as a binary factor: 0 = <50 yr, 1 = ≥50 yr.
Clinical tumor size (CTS) used as a binary factor: 0 = ≤2 cm, 1 = >2 cm.
Recurrence Score used as a continuous variable, with HR relative to an increment of 50 RS units.
Paik et al. N Engl J Med. 2004;351:2817-2826.
15
Oncotype DX™ Clinical Validation:
Conclusions – NSABP B-14
• RS validated as predictor of recurrence in N–,
ER+ patients
• RS performance exceeds standard measures
(age, size)
• 50% of patients are reclassified by RS when
compared to NCCN criteria
• RS (based on tumor gene expression) more
accurately quantifies the risk of distant
recurrence than do the NCCN guidelines (based
on age, tumor size, and tumor grade)
16
Oncotype DX™
Clinical Validation:
The Kaiser Permanente Study
Habel et al. Breast Cancer Res. 2006;May 31;8(3):R25.
The Kaiser Permanente Study:
Methods
Study Design
Case-control
Study Population
Kaiser Permanente patients <75 yr in 14 Northern
California hospitals diagnosed with node-negative
BC 1985-94, no chemotherapy (N = 4964)
Cases: Deaths from BC (n = 220)
Controls: Randomly selected, matched on age,
race, diagnosis year, KP facility, tamoxifen (n = 570)
Data Sources
Cancer registry, medical records, archived
diagnostic slides, and tumor blocks
Habel et al. Breast Cancer Res. May 2006.
18
The Kaiser Permanente Study:
Risk of BC Death at 10 Years: ER+, Tam+ Patients
Risk Classifier
Recurrence Score
Low (<18)
Intermediate (18-30)
High (>31)
1Based
% of
Cases
(n = 55)
% of
Controls
(n = 150)
10-yr
Absolute
Risk1
29%
40%
31%
63%
23%
13%
2.8%2
10.7%
15.5%
on methods by Langholz and Borgan, Biometrics 1997;53:767-774.
2Consistent
with 3.0% absolute risk of breast cancer death in similar population of
tamoxifen-treated patients in NSABP B-14.
Habel et al. Breast Cancer Res. May 2006.
19
The Kaiser Permanente Study:
Conclusions
• “The RS has now been shown to be strongly
associated with risk of breast cancer-specific
mortality among LN–, ER+, tam-treated patients
participating in a clinical trial and among similar
patients from the community setting.”
• “Combining Recurrence Score, tumor grade,
and tumor size provides better risk classification
than any one of these factors alone.”
Habel et al. Breast Cancer Res. May 2006.
20
Oncotype DX™
Prediction of Tam Benefit:
NSABP B-14 Placebo and
Tamoxifen Arms*
*Paik et al. ASCO 2004. Abstract #510.
Tamoxifen Benefit and Oncotype DX™
NSABP B-14 Tam Benefit Study in N–, ER+ Patients
Design
Placebo-Eligible
Randomized
Tam-Eligible
Objective: Determine whether the 21-gene RS assay
provides information on:
1) Prognosis (likelihood of recurrence)
2) Response to tamoxifen (change in likelihood of
recurrence with tamoxifen)
3) Both
Paik et al. ASCO 2004. Abstract #510.
22
B-14 Overall Benefit of Tamoxifen
All Patients (N = 645)
1.0
0.9
0.8
DRFS
0.7
0.6
0.5
0.4
0.3
0.2
Placebo
Tamoxifen
0.1
0.0
0
2
4
6
8
10
12
14
16
Years
Paik et al. ASCO 2004. Abstract #510.
23
1.0
0.8
0.8
DRFS
1.0
0.6
0.4
0.6
0.4
Low Risk (RS<18)
N
171
Placebo
Tamoxifen 142
0.2
Int Risk (RS 18-30)
N
85
Placebo
Tamoxifen 69
0.2
0.0
0.0
0
2
4
6
8
10
12
14
16
0
2
4
Years
6
8
10
12
14
16
Years
1.0
0.8
DRFS
DRFS
B-14 Benefit of Tamoxifen
By Recurrence Score Risk Category
0.6
Interaction P = 0.06
0.4
High Risk (RS≥31)
0.2
Placebo
Tamoxifen
N
99
79
0.0
0
2
4
6
8
Years
10
12
14
16
Paik et al. ASCO 2004. Abstract #510.
24
Analysis of Placebo and Tam-Treated
Patients in NSABP B-14
• Conclusions
– RS combines prognostic and predictive
factors into one assay report
– RS performance is derived from
measurement of expression of each of the 21
genes on a continuous scale with high
precision and reproducibility
Paik et al. ASCO 2004. Abstract #510.
25
Oncotype DX™
Prediction of Chemo Benefit:
NSABP B-20 Study*
*Paik et al. J Clin Oncol. 2006;24:3726-3734
Chemotherapy Benefit and Oncotype DX™
NSABP B-20 Chemo Benefit Study in N–, ER+ Pts
Design
Tam + MF
Randomized
Tam + CMF
Tam
Objective:
Determine the magnitude of the chemo
benefit as a function of the 21-gene RS assay
Paik et al. J Clin Oncol. 2006;24:3726-3734.
27
B-20 Results
Tam vs Tam + Chemo – All 651 Patients
1.0
0.9
4.4% absolute
benefit from
tam + chemo
0.8
DRFS
0.7
0.6
0.5
0.4
0.3
0.2
All Patients
N
424
227
Tam + Chemo
Tam
0.1
Events
33
31
P = 0.02
0.0
0
2
4
6
Years
8
10
12
Paik et al. J Clin Oncol. 2006.
28
B-20 Results: Tam vs Tam + Chemo
1.0
1.0
0.9
0.9
0.8
0.8
0.7
0.7
Low RS
DRFS
0.6
0.5
N
218
135
0.4
0.3
0.2
Low Risk Patients (RS < 18)
Tam + Chemo
Tam
0.1
Events
11
5
Int RS
0.5
0.4
0.3
0.2
Int Risk (RS 18 - 30)
Tam + Chemo
Tam
0.1
N
89
45
Events
9
8
0.0
0.0
0
2
4
6
8
10
0
12
2
p = 0.61
Years
4
6
8
Years
10
12
p = 0.39
1.0
0.9
28% absolute
benefit from
tam + chemo
0.8
0.7
0.6
DRFS
DRFS
0.6
High RS
0.5
0.4
N
117
47
0.3
0.2
High Risk Patients (RS  31)
Tam + Chemo
Tam
0.1
Events
13
18
0.0
0
2
4
6
Years
8
10
12
p < 0.0001
Paik et al. J Clin Oncol. 2006.
29
B-20 Results:
Absolute % Increase in DRFS at 10 Years
n = 353
Low
RS <18
n = 134
Int
RS 18-30
n = 164
High
RS ≥31
0
10%
20%
30%
40%
% Increase in DRFS at 10 Yrs (mean ± SE)
Paik et al. J Clin Oncol. 2006. 30
RS and Breast Cancer Death in
NSABP B-14 and B-20
• Benefits of adjuvant treatment differ by
Recurrence Score risk category
– Benefits of tamoxifen are greater in patients with
low-risk or intermediate-risk tumors
– Benefits of chemotherapy are greater in patients
with high-risk tumors
31
ASCO ABSTRACTS JUNE 2007
• CLINICAL UTILITY OF ONCOTYPE DX
– ABSTRACT #577: LOYOLA UNIVERSITY
– ABSTRACT #576: MAYO CLINIC
32
Prospective multi-center study of the impact of the 21-gene
Recurrence Score (RS) assay on medical oncologist (MO) and patient
(pt) adjuvant breast cancer (BC) treatment selection.
Shelly S. Lo1, John Norton1, Patricia B. Mumby1, Jeffrey
Smerage2, Joseph Kash3, Helen K. Chew4, Daniel Hayes2,
Andrew Epstein5, Kathy S. Albain1
1Loyola
University, Maywood IL, 2University of Michigan,
AnnArbor MI, 3Edward Hospital, Naperville IL, 4UC Davis,
Sacramento CA, 5Mount Sinai Medical Center, New York NY
Background
• The 21-gene Recurrence Score (RS) assay (Oncotype
DXTM) has been validated to quantify the risk of distant
recurrence in tamoxifen treated patients in lymph node
negative, estrogen receptor (ER) positive breast cancer.
The RS also predicts benefit from adjuvant
chemotherapy.
• There is little data regarding the impact of the RS on
medical oncologist (MO) and patient (pt) decision
making. A multi-center study was designed to
prospectively examine whether the RS affects MO and
pt adjuvant treatment selection.
ASCO 2007, Abstract #577
34
Methods
• 17 MOs at 1 community and 3 academic practices participated in
this study. Each participating MO consecutively offered enrollment
to eligible women with node negative, ER positive breast cancer.
• Each participating MO and consenting patient completed pre- and
post-RS assay questionnaires specifically developed for the study.
• MOs stated their adjuvant treatment recommendation and
confidence in it pre and post RS assay.
• Pts indicated treatment choice pre and post RS assay. In addition,
patients completed measures for quality of life, anxiety, and
decisional conflict pre and post assay.
• RS assay results were returned to MO and shared with pt for
routine clinical care.
• Frequency distributions and co-frequency tables are used to
display categorical distributions of nominal variables; means and
standard deviations are used to summarize continuous variables.
35
Medical Oncologist Characteristics
• 17 medical oncologists from 4 institutions
– University of Michigan: 6
– LUMC: 6
– Edward: 3
– UC Davis: 2
• Length of time in practice <5 yrs: 29%
• Length of time in practice>5 yrs: 71%
ASCO 2007, Abstract #577
36
Change in Treatment Recommendation by RS
Treatment
Recomm.
CHT
HT alone
Equipoise
Pre-RS
Post- RS
Number (%)
Mean RS
Number
(%)
Mean
RS
42 (47.2%)
46 (51.7%)
1 (1.1%)
21
18
19
23 (25.8%)
60 (67.4%)
6 (6.7%)
29
16
19
ASCO 2007, Abstract #577
37
MO Treatment Recommendations Changed
31.5% of the Time
MO Pre to Post-RS Assay
Treatment Recommendation
Number of Cases(%)
CHT to HT
20 (22.5)
HT to CHT
3 (3.4)
CHT or HT to Equipoise
5 (5.6)
Treatment plan did not change
61 (68.5)
Total
89 (100)
Treatment recommendation changed in 28 (31.5%) after results
of RS Assay known. The largest change was from a
recommendation of CHT to HT in 22.5% of cases.
38
Conclusions
• RS Assay changed physician adjuvant treatment
recommendations in 31.5% of the cases
• RS Assay is used by patients in their adjuvant
treatment decisions
• Results from the RS assay was associated with
less adjuvant chemotherapy administration
– The largest treatment recommendation change for
MO was changing recommendation from CHT to HT
39
How Well Do Standard Prognostic Criteria
Predict Oncotype DX Scores?
Kamal AH, Loprinzi CL, Reynolds C,
Dueck AC, Geiger XJ, Ingle JN,
Carlson RW, Hobday TJ, Winer EP,
Perez EA, Goetz MP
Mayo Clinic, Rochester, MN; Mayo Clinic,
Jacksonville, FL; Stanford Comprehensive
Cancer Center, Palo Alto, CA; Dana-Farber
Cancer Institute, Boston, MA
40
Mayo Clinic Study
Methods:
31 patients with Oncotype DX scores available
Slides reviewed for path, receptors and her-2
Cases presented to 6 “academic” oncologists,
blinded to RS
asked to predict RS and to recommend
chemo
given RS and asked chemo question again
42
Mayo Clinic Study
Results:
RS: low – 18, int – 10, high – 3
Concordance between predicted and
actual RS low/int vs. high >87%
Easier to pick out high risk
More important to identify low risk than
low/int
43
Mayo Clinic Study
Results:
Most frequent discrepancies:
actual low RS predicted as intermed
(31/80 discordant 39%)
actual intermed RS predicted as low
(29/80 discordant 36%)
Treatment recommendations following
Oncotype DX changed about 18.2%
most frequent change from CHT to HT
44
Mayo Clinic Study
Conclusions:
“Proper evaluation and interpretation of
traditional prognostic criteria will identify most
node negative, ER+ patients at high risk of
recurrence (as predicted by RS), but poorly
discriminate low vs. intermediate risk.”
Recommendation for treatment was changed in
about 20% of cases
This study used expert pathologists and
nationally known breast oncologists.
45
Conclusions of clinical utility studies
• Oncotype DXTM directly changes treatment
recommendations approx. 20 – 30+% of the time
• Physicians and patients alike find the RS useful
• Even when treatment decisions are not altered, the RS
can increase confidence in the decision
46
ONCOTYPE DX
EXPLORATORY STUDIES:
ONCOTYPE DX AND LOCAL
RECURRENCE
ONCOTYPE DX AND NODE POSITIVE
PATIENTS
ONCOTYPE DX AND NEO-ADJUVANT
CHEMOTHERAPY
47
Association Between Recurrence Score
and Risk of Local-regional Failure
in N─, ER+ Breast Cancer:
Results from NSABP B-14 and NSABP B-20
E. Mamounas, G. Tang, J. Bryant, S Paik, S Shak,
J Costantino, D Watson, D. L Wickerham, and N Wolmark
48
48
Study Objectives
• To examine the relationship between RS
and Risk of Loco-Regional Failure (LRF)
in Node-Negative, ER-Positive, Patients
from NSABP B-14 and NSABP B-20:
–Placebo treated patients from B-14
–Tamoxifen treated patients from B-14, B-20
–Chemo-TAM treated patients from B-20
49
Study Population
• Patients with RS Assay from NSABP nodenegative, ER-positive adjuvant trials:
– B-14 Placebo: 355 pts
– B-14/B-20 Tamoxifen: 895 pts
• B-14: 668
• B-20: 227
– B-20 Chemo + Tamoxifen: 424 pts
50
Patient Characteristics
Surgery Type
Surgery
Type
Lumpectomy
Mastectomy
B-14
B-14
B-20
B-20
Placebo
TAM
TAM
TAM+Chem
(n=355) (n=668) (n=227)
32%
68%
42%
58%
48%
52%
(n=424)
39%
61%
• All lumpectomy patients received breast XRT
• Post-mastectomy chest wall XRT was not allowed
• Regional nodal XRT was not allowed irrespective of surgical
procedure
51
P=0.022
P<0.0001
20
30
RS < 18
RS 18-30
RS >31
20
18.4
10
15.8
P=0.028
10.8
7.2
4.3
0
%
40
10 Year LR Failure Rates According to
Treatment and RS Category
Placebo
n=355
TAM n=895
7.8
1.6 2.7
Chemo + TAM
n=424
52
Multivariate Cox Proportional Hazard Models
TAM-Treated Pts (n=895)
P-value
Variable
HR
Recurrence Score
0.005
Age (> 50 vs. < 50) 0.0002
Mastectomy vs.
Lumpectomy +
0.047
XRT
CTS ( >2 cm vs. <
0.933
2 cm)
Grade (Mod vs.
0.966
Well)
Grade (Poor vs.
0.105
HR
95% CI for
2.16
0.40
(1.26, 3.68)
(0.25, 0.65)
0.62
(0.39, 0.99)
0.98
(0.61, 1.59)
1.10
(0.54, 1.92)
1.76
(0.89, 3.48)
53
10-Year Loco-Regional Failure Rates
TAM-Treated Pts with Mastectomy (n=505)
LRF
Age
RS
95% CI
Rate
<50 < 18
1.5% (0, 4.5%)
18 - 30 7.6% (0, 17.6%)
(9.4%,
≥ 31 23.8%
38.1%)
≥ 50 < 18
2.6% (0.1%, 5%)
18 - 30 3.8% (0, 8.1%)
(4.3%,
≥ 31 12.8%
21.3%)
PEvents
value
0.001 2/73
2/31
9/49
0.005 6/189
3/82
9/81
54
Exploratory Analysis
10-Year Loco-Regional Failure Rates
TAM-Treated Pts with Mastectomy (n=505)
• RS correlated with 10-year LRF rates in patients
< 50 and > 50
– High (23.8%) LRF rate in pts <50 with a high RS
– However, small sample size of pts <50 who had
high RS and mastectomy (49 pts)
• Subset analysis - hypothesis-generating ONLY
55
55
10-Year Loco-Regional Failure Rates
TAM-Treated Pts with Lumpectomy/XRT (n=390)
Age
RS
LRF Rate
<50
< 18
12.5%
(4.4%, 20.7%) 0.057
10/72
18 - 30
27.7%
(8.8%, 46.6%)
7/23
≥ 31
26.5%
(12.2%,
40.8%)
12/45
< 18
18 - 30
≥ 31
3.6%
3.7%
4.8%
(0.1%, 7.1%)
(0, 8.7%)
(0, 11.2%)
≥ 50
95% CI
PEvents
value
0.663
6/139
4/58
3/53
56
Exploratory Analysis Summary
10-Year Loco-Regional Failure Rates
TAM-Treated Pts with Lumpectomy/XRT (n=390)
• Women < 50: RS associated with LRF (p = 0.057)
– LRF is high with intermediate/high RS
• Women > 50: RS NOT associated with LRF (p = 0.663)
• However, as a subset analysis these findings should be
hypothesis-generating ONLY
57
57
Summary
• The 21-Gene Recurrence Score was found to predict risk of
LRF in node-negative, ER-positive, pts treated with
tamoxifen.
• In this group of pts, RS was an independent predictor of
LRF along with age and surgery type.
• RS also predicted risk of LRF in node-negative, ER-positive
pts treated with chemotherapy + tamoxifen and to a lesser
extent in those treated without adjuvant therapy
58
Conclusions
• The present study demonstrates a similar association between
RS and risk for LRF as the one previously shown for RS and
risk of distant failure.
• This information has biologic implications and may have
clinical implications relative to loco-regional therapy decisions
in patients with node-negative, ER-positive breast cancer.
59
Can Oncotype DX be used for
node positive patients?
60
60
Prognostic Utility of the 21-Gene Assay in Hormone Receptor (HR) Positive
Operable Breast Cancer and 0-3 Positive Axillary Nodes Treated with
Adjuvant Chemohormonal Therapy (CHT):
An Analysis of Intergroup Trial E2197
Goldstein LJ1, Gray R1, Childs B2, Watson D3,
Yoshizawa C3, Rowley S2, Shak S3, Badve S1,
Davidson NE1, Sledge GW1, Sparano JA1
From the Eastern Cooperative Oncology Group1,
sanofi aventis2, & Genomic Health, Inc.3
62
ASCO 2007 - Abstract #52662
Objectives
Specific:
1. To evaluate the prognostic utility of Oncotype DX
Recurrence Score (RS) in patients with HR-Pos treated
with adjuvant chemotherapy
2. To perform an exploratory analysis for individual genes
associated with prognosis in patients with HR-Pos and HRNeg disease treated with adjuvant chemotherapy (analysis
ongoing)
3. To perform an exploratory analysis to identify individual
genes associated with differential sensitivity to AC versus
AT (analysis ongoing)
63
Outcomes by Nodal Status
64
Outcomes by Recurrence Score
65
5-Year Event Rates by Nodal Status & RS
Recurrence Rates Are Very Low (< 5%) if the RS < 18 Irrespective of
Axillary Lymph Node Status
RS
Low <18
Int 18-30
High ≥ 31
Nodes
RFI (%) DFS (%)
OS (%)
Neg
96
93
95
Pos
95
91
97
Neg
86
87
97
Pos
87
77
86
Neg
87
80
92
Pos
75
61
7266
ASCO - Abstract #526
66
Conclusions
For HR-Pos Disease with 0-3 Pos Axillary Lymph Nodes
• Low RS (< 18) predictive of excellent
outcomes at 5 yrs
• including patients with 1-3 positive axillary lymph nodes
• when adjusted for centrally determined tumor grade
• Low RS (< 18) common
• ~ 46% of patients with HR-positive disease in this study,
of whom 49% had 1-3 positive axillary lymph nodes
67
ASCO - Abstract #526
67
Prognostic and Predictive Value of the
21-Gene Recurrence Score Assay in
Postmenopausal, Node-Positive (N+), ERPositive (ER+) Breast Cancer
SWOG 8814, TBCI 0100
Oral Presentation #10
K. Albain, W. Barlow, S. Shak, G. Hortobagyi, R.
Livingston, I. Yeh, P. Ravdin, C. Yoshizawa, F.
Baehner, N. Davidson, G. Sledge, E. Winer, C.
Hudis, J. Ingle, E. Perez, K. Pritchard, L.
Shepherd, C. Allred, K. Osborne, and D.
Hayes for The Breast Cancer Intergroup of
North America
68
SWOG 8814/TBCI 0100 Correlative Science
Rationale
• The 21-gene Recurrence Score assay (RS) is
prognostic for women with node(-), ER+ breast
cancer on 5 years of tamoxifen*
• A high RS predicts large benefit from
chemotherapy in node(-) disease, but no
improvement if the RS is low**
• There are no RS data in a N+ population with a
tamoxifen-alone control
• SWOG 8814 is an ideal trial to explore this
question
Albain, SABCS 2007, Abstract #10
*Paik, et al. NEJM, 2004
**Paik, et al. J Clin Oncol, 2006
69
Phase III SWOG 8814 (TBCI 0100)
Postmenopausal, N+, ER+
RANDOMIZEn = 1477
tamoxifen x 5 yrs
(n = 361)
CAF x 6, with
concurrent tam
CAF x 6, then
tamoxifen
(n = 550)
(n = 566)
Superior Disease-Free Survival
(DFS) and Overall Survival (OS)
Albain, SABCS 2007, Abstract #10
over 10 Years
Albain, et al. Breast Cancer Res Treat 2005
70
SWOG 8814/TBCI 0100 Correlative Science
Study
Two co-primary objectives
were
to determine if the RS:
1) Provides prognostic information for women
with N+ disease treated only with tamoxifen,
and
2) Allows prediction of a N+ group that does not
derive benefit from chemotherapy
Albain, SABCS 2007, Abstract #10
71
Outcomes in RS Subset Mirror Those
Reported in Main Trial: Superiority of CAF-T
0.75
0.50
0.25
Stratified log-rank p-value = 0.054 at 10 years
(adjusted for nodal status)
Tamoxifen (n=148, 63 events)
CAF-T
(n=219, 74 events)
0.00
Disease-free survival
1.00
Disease-Free Survival
0
2
4
6
8
10
Years since registration
Albain, SABCS 2007, Abstract #10
72
SWOG 8814/TBCI 0100
21-Gene Recurrence Score is Prognostic for DFS
and OS in Tamoxifen Arm
Overall Survival by Risk Group
Disease-Free Survival by Risk Group
2
4
6
1.00
8
0.25
Stratified log-rank p = 0.003 at 10 years
Low RS <18 (n=55)
Intermediate RS 18-30 (n=46)
High RS ≥31 (n=47)
0.00
Low RS <18 (n=55)
Intermediate RS 18-30 (n=46)
High RS ≥31 (n=47)
0
(tamoxifen alone)
Overall Survival
0.50
0.75
0.75
0.50
0.25
Stratified log-rank p = 0.017 at 10 years
0.00
Disease-free survival
1.00
(tamoxifen alone)
10
Years since registration
10-yr: 60%, 49%, 43%
0
2
4
6
8
10
Years since registration
10-yr: 77%, 68%, 51%
Albain, SABCS 2007, Abstract #10
73
Disease-Free Survival by Treatment
0.75
0.50
Stratified log-rank p = 0.97 at 10 years
Tamoxifen (n=55, 15 events)
CAF-T
(n=91, 26 events)
0.00
Strong benefit
if high RS
Low risk (RS < 18)
0.25
Disease-free survival
1.00
No benefit to
CAF over time
if low RS
0
2
4
6
8
10
Disease-Free Survival by Treatment
Disease-Free Survival by Treatment
1.00
1.00
0.25
Stratified log-rank p = 0.033 at 10 years
0
2
4
6
Years since registration
8
0.75
0.50
Stratified log-rank p = 0.48 at 10 years
Tamoxifen
CAF-T
0.00
Tamoxifen (n=47, 26 events)
CAF-T
(n=71, 28 events)
Intermediate risk (RS 18-30)
0.25
0.50
0.75
Disease-free survival
High risk (RS ≥31)
0.00
Disease-free survival
Years since registration
10
0
2
Albain, SABCS 2007, Abstract #10
4
(n=46, 22 events)
(n=57, 20 events)
6
Years since registration
8
10
74
CAF Benefit Greatest in Higher RS
for Both Nodal Subsets,
with No Benefit in Lower RS
Five-Year Probability of Death or Disease Recurrence
Five Year Probability of an Event
.2
.4
.6
1
.8
Linear model for Recurrence Score and interactions with treatment
Tam, 4+ nodes (n=54)
CAF-T, 4+ nodes (n=86)
Tam, 1-3 nodes (n=94)
CAF-T, 1-3 nodes (n=133)
Chemo benefit 4+ nodes
0
Chemo benefit 1-3 nodes
0
20
40
60
Recurrence Score
80
100
Albain, SABCS 2007, Abstract #10
75
NEOADJUVANT DATA
Milan and Baylor Studies
76
Chemotherapy Response: Exploratory Studies
in Stage 3 neoadjuvant setting confirm the
findings from NSABP B20 Study
Milan Study
Neoadjuvant anthracyline-taxane treatment
Baylor Study
Neoadjuvant docetaxel therapy
– Independent & Exploratory Studies in Stage 3 patients
– Nearly identical trends with neoadjuvant & CR rates
– Consistent with B20
77
Gene Expression Profiles in Paraffin-Embedded
Core Biopsy Tissue Predict Response to
Chemotherapy in Women With Locally Advanced
Breast Cancer
L. Gianni, M. Zambetti, K. Clark, J. Baker,
M. Cronin, J. Wu, G. Mariani, J. Rodriguez, M. Carcangiu,
D. Watson, P. Valagussa, R. Rouzier, W. Symmans, J. Ross,
G. Hortobagyi, L. Pusztai, and S. Shak
Gianni et al. J Clin Oncol. 2005;23(29):7265-7277.
Study Design
Istituto Nazionale Tumori – Milan
for RT-PCR
analysis
Core biopsy
Primary chemotherapy
DOX/TAX  3  w TAX  12
for pathology
determination
of pCR
Surgery
Adjuvant chemotherapy
IV CMF q 4 wks  4
Nonrandomized in women with LABC
RT  TAM
89 evaluable patients
Gianni et al. J Clin Oncol. 2005;23(29):7265-7277.
79
Results – Chemotherapy Response
• 89 evaluable patients
– 11 patients with pathologic complete response (pCR)
• 4 pts ER+ by IHC
– pCR rate in ER+ pts = 8% (95% CI 1%-15%)
• 7 pts ER– by IHC
– pCR rate in ER– pts = 23% (95% CI 8%-37%)
– Overall pCR rate = 12%
Gianni et al. J Clin Oncol. 2005;23(29):7265-7277.
80
Higher Recurrence Score Associated With Higher
Likelihood of pCR (P = 0.005) to neoadjuvant
anthracyline-taxane treatment
Milan Study
P=0.005
N=89
Gianni et al. J Clin Oncol. 2005;23(29):7265-7277.
81
Gene expression profiles in
paraffin-embedded core biopsies
predict docetaxel chemosensitivity
J. Chang, A. Makris, SG. Hilsenbeck, J.
Hackett, J Jeong, M Liu, J Baker, K Sexton,
K Osborne, S Shak
Methods
Patients identified from 3 phase II clinical trials who
received neoadjuvant docetaxel (100 mg/m2 q3wks)
for 4 cycles before surgery
Diagnostic biopsies: 10-micron sections x 3
98 clinically eligible patients
81 (83%) of 98 with adequate tumor tissue (≥5% tumor)
80 (99%) of 81 with adequate RNA and expression signal
72 (90%) of 80 with response data (RECIST)
Chang, ASCO 2006, Abstract #538
83
Correlation between RS and
clinical complete response
Recurrence Category
Complete Response
Yes
Low Risk
No
0 (0%)
8 (100%)
Intermediate Risk
3 (13.6%)
19 (86.4%)
High Risk
9 (21.4%)
33 (78.6%)
Likelihood of correlation between RS and clinical complete response (CR) is not
significant among all 3 categories (P = 0.3792)
Chang, ASCO 2006, Abstract #538 84
≥1.7-fold increase in the odds of CR to
neoadjuvant docetaxel therapy for
high vs. low RS
Baylor Study
N=72
Chang, ASCO 2006, Abstract #538
85
Exploratory Studies Summary
• RS is associated with LRF
• Associated with response to modern
Neoadjuvant Chemotherapy
• Prognostic in Node Positive Disease
86
86
Other Gene Profiles
• MammaPrint
– 70-gene signature
– Netherlands–based Agendia
• “Invasiveness” Gene Signature
– 186-gene signature
– University of Michigan, Ann Arbor
• Wound Response Signature
87
MammaPrint and Oncotype DX Distinctions
MammaPrint
Oncotype DX
• Fresh Tissue by Microarray
• 81% Microarray success rate
for RNA extraction
• Binary result (low risk vs. high
risk)
• Patients all <61 years old
• FPET by RT-PCR
• 99% FPET success rate for
RNA extraction
• Continuous Predictor Curve
(Individual Recurrence Score)
• 302 untreated patients (LN-,
ER+, ER-)
• Clinical Utility Not Yet
Established
–Patients not representative of
those diagnosed and treated
today
• Insurance Coverage TBD
• Multiple, reproducible studies in
>2,600 treated patients with
ER+, LN- disease
• Provides Clinical Utility for
adjuvant treatment decisions
–>20,000 patients, 4,500
physicians
• Over 100 million lives insured
• No age barriers
88
TAILORx
(PACCT-1 Trial)
Sponsored by NCI
Administered by ECOG
Participating cooperative groups include
ECOG, SWOG, NCCTG, CALGB, NCIC,
ACOSOG, and NSABP
Trial Assigning IndividuaLized Options for
Treatment (Rx) (TAILORx)
• Premise
– Integration of a molecular profiling test (Oncotype DX™)
into the clinical decision-making process
• Implications
– Reduce chemotherapy overtreatment in those likely to
be optimally treated with hormonal therapy alone
– Reduce inadequate treatment by identifying individuals
who derive great benefit from chemotherapy
– Evaluate benefit of chemotherapy where uncertainty
still exists about its utility
90
Schema: TAILORx
Node-Neg, ER-Pos Breast Cancer
Register
Specimen
banking
Oncotype DX™
Assay
RS 11-25
RS <10
Hormone
Therapy
Registry
Randomize
Hormone Rx
vs
Chemotherapy
+ Hormone Rx
RS >25
Chemotherapy
+
Hormone Rx
Primary study group
91
Study Design: Primary Objectives
• To determine whether adjuvant hormonal therapy
(ie, experimental arm) is not inferior to adjuvant
chemohormonal (standard arm) for patients in the
“primary study group” (Oncotype DX™ RS 11-25)
• To create a tissue and specimen bank for patients
enrolled in this trial to learn more about breast
cancer
92
Study Design: Secondary Objectives
• Low RS group (<11)
– To determine risk of recurrence with hormonal therapy prospectively
• Comparison with clinical models (Adjuvant! Online)
• Refine estimates of Oncotype DX™ RS in contemporary
practice
• Evaluate individual gene groups
–
–
–
–
–
Proliferation gene group
HER2 gene group
ER gene group
Invasion gene group
Other genes
93
40%
Intermediate
Risk Group
Distant Recurrence at 10 Years
Low Risk Group
35%
High Risk Group
30%
25%
20%
15%
10%
5%
0%
0
5
10
15
20
25
30
Recurrence Score
35
40
45
50
94