Transcript No Slide Title

ASCO 2005
Adjuvant Breast Cancer
Update
Lori J. Goldstein, MD
Director, Breast Evaluation Center
Leader, Breast Cancer Research Program
Fox Chase Cancer Center
Philadelphia, PA
ASCO 2005
Breast Cancer Update
Abstract #/ Session
512
513
MoAB Ed
MoAB Ed
MoAB Ed
Title/ Subject
E2197: Adjuvant AT vs. AC
ECTO: A->CMF vs AT->CMF
N9831/ NSABP B31 Joint
Analysis – Adjuvant Trastuzumab
N9831 – Adjuvant Trastuzumab
HERA: Adjuvant Trastuzumab
MoAB Ed
E2100: T +/- bevacizumab MBC
E2197: Phase III AT vs. AC in the
Adjuvant Treatment of Node
Positive and High Risk Node
Negative Breast Cancer
Goldstein LJ, O’Neill A, Sparano JA,
Perez EA, Shulman LN, Martino S,
Davidson NE.
E2197 Rationale
Phase II Studies Anthracyline + Taxane
Study
A/Por D mg/m2
RR %
CHF %
Gianni/
60/P200
80-90
20
50/P150
60/P200
47
57
9.8
6
60/D60
60/D60
50/D75
57
63
81
6
10
0
Dombernowsky
Sledge E1193
Sparano E4195
Sparano E1196
Cresta
Misset
E2197 Rationale
Phase III Studies:Anthracyline + Docetaxel
Phase III Studies:
MBC
AT (50/75)
RR%
60
TTPwk
37.1
CHF %
2
FN%
33
No difference OS
AC (60/600)
47
p=.012
31.9 p=.015
4
10
Nabholtz JCO 2003
TAC vs. FAC MBC
Mackey ASCO 2002
Increase RR with TAC; no difference in TTP or OS
TAC vs. FAC Adjuvant: Nabholtz ASCO 2002
TAC increase DFS/ OS
E2197: Schema
T1-3 N0-1 M0
No then
T> 1.0cm
R
A
N
D
O
M
I
Z
E
Adriamycin 60mg/m2
Docetaxel (T) 60mg/m2
IV q 3wk x 4
Cipro 500mg
po. bid D8 x 10d
Adriamycin 60mg/m2
IV q 3wk x 4
2
Cyclophosphamide 600mg/m
Tamoxifen 20mg daily x 5 years
post chemotherapy for ER and/or
PR positive tumor
*G-CSF per ASCO guidelines
Stratified:
•Nodal Status
•HR Status (ER+PR+,ER+PR-,
ER-PR+,ER- PR-,ER/PR unknown)
•Menopausal Status
E2197: Objectives
• To determine whether AT will
improve DFS and OS
• To compare toxicity of AT vs. AC
No difference in LVEF between AT
and AC reported ASCO 2003.
E2197: Study Design
• Primary endpoint: DFS-recurrences, new breast
primaries, or death without recurrence whichever
comes first.
• Design: 83% power to detect a 25% reduction of
the DFS failure hazard rate
(5% absolute improvement in 5 yr DFS from 78%
to 83% by using AT)
• Sample size: 2778 including an estimated 10%
ineligible
• Primary Analysis: Intent-to-treat analysis on
eligible patients.
E2197:Results
• Opened 7/30/98; closed 1/21/00
• 2952 entered through the
collaborative effort of ECOG, CALGB,
NCCTG, SWOG and EPP.
• 3% Ineligibility rate
• 2885 eligible and analyzable
E2197: Patient Characteristics
• Balanced for age, HR, menopause,
nodes, surgery, grade and size
• Age range 24-85 yo, Median age 51
• 64% ER +
• 65% LN• Grade: 10% low, 38% int., 46% high
• Size: 0.1 – 12.5 cm; Median – 2.0 cm
E2197: Toxicity Summary
Feb/Infxn/N
AML/MDS
Lethal Events
Related
Unrelated
AT
28%
7
AC
10%
7
4
2
2
E2197 Cardiac Safety
Grade
3
AT
4
5
CHF
15
2
1
AC
3
4
10
Total
18
10
%
.01
.006
No statistically significant difference
E2197: DFS
• Fall 2004 DMC (409/ 420 DFS failures)
• O’Brien-Fleming boundary had not been
crossed, there was not enough evidence
to suggest a significant difference
• April 2005 - Median follow-up = 59 months
• 432/ 2885 (15%) recurred, developed
second breast cancer or died.
E2197: DFS/OS
Hazard Ratio
HR > 1 favors AT
HR (adjusted)
DFS
1.03 (0.86-1.25), p=0.70
OS
1.09 (0.85-1.40), p=0.49
As of 4/4/05, 242 deaths
E2197 Disease-Free Survival
100
90
80
Percent
70
60
50
40
30
20
10
0
0
12
24
AT
AC
36
Months
N
Events
1444
213
1441
219
48
60
4-Yr % (S.E.)
87 (1)
87 (1)
72
E2197 Overall Survival
100
90
80
Percent
70
60
50
40
30
20
10
0
0
12
24
AT
AC
36
Months
N
Events
1444
117
1441
125
48
60
4-Yr % (S.E.)
94 (1)
93 (1)
72
E2197: DFS
Subgroup Analysis
No significant effect within any of the
following subgroups :
•Nodes
•Size
•Age
•Menopausal Status
•Grade
•Type of Surgery
•Race
E2197 Disease-Free Survival:ER-/PR-
E2197 Disease-Free Survival:ER-/PR+
90
90
80
80
70
70
60
60
Percent
100
Percent
100
50
40
50
40
30
30
20
20
10
10
0
0
0
12
24
36
N
454
463
AT
AC
48
Months
Events
85
109
60
0
72
4-Yr % (S.E.)
83 (2)
79 (2)
24
36
N
52
38
AT
AC
E2197 Disease-Free Survival:ER+/PR-
Months
Events
14
3
48
60
72
4-Yr % (S.E.)
77 (6)
95 (4)
E2197 Disease-Free Survival:ER+/PR+
90
90
80
80
70
70
60
60
Percent
100
100
Percent
12
50
40
50
40
30
30
20
20
10
10
0
0
0
12
24
AT
AC
36
N
162
164
Months
Events
22
34
48
60
4-Yr % (S.E.)
90 (2)
83 (3)
81
72
0
12
24
AT
AC
36
N
767
770
Months
Events
91
73
48
60
4-Yr % (S.E.)
90 (1)
92 (1)
72
Disease Free Survival
ER-/PR-
1.30 (0.96, 1.70)
ER-/PR+
0.30 (0.10, 0.95)
ER+/PR-
1.64 (0.96, 2.80)
ER+/PR+
0.79 (0.58, 1.10)
0.1
0.2
Favors AC
0.5
1
2
Favors AT
5
E2197 Conclusions
• These results show a better than expected
outcome for both regimens.
87%(obs) vs 78% (expected for AC) DFS at 4
yrs.
• At 59 mo median follow-up, there is no
difference in DFS or OS between AT and AC.
• Prespecified stratifications at randomization:
LN, menopause, ER/PR – no significant
difference between the 2 treatment arms.
• In PR negative tumors, a potential benefit to
AT may be suggested.
E2197: Issues for Discussion
Would longer f/u change these results? Unlikely
Observed DFS = 87% at 4 yrs.
Expected DFS = 78% at 4yrs.
Aromatase Inhibitor Affect:
60% on Tam; Median 41 mo; AI info collected; future
analysis
Subset analysis of prespecified ER/PR stratifications:
Hypothesize that the biology of the primary tumor
predicts outcome and benefit to specific therapies.
Central review of ER/PR/Her 2 pending
Genomic Health/ Sanofi-Aventis Analysis:
Oncotype
Genomic profiling
Use as training set for validation with E1199
Pharmacogenomics
PACCT- 1 Trial
Thank You
Patients
Data managers/ CRA’s
CALGB, NCCTG, SWOG, EPP
Anne O’Neill, Deborah Namande, Eric Ross