1. 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

2. ASCO 2005 Breast Cancer Update
Abstract #/ Session Title/ Subject
E2197: Adjuvant AT vs. AC
ECTO: A->CMF vs AT->CMF
MoAB Ed N9831/ NSABP B31 Joint Analysis – Adjuvant Trastuzumab
MoAB Ed N9831 – Adjuvant Trastuzumab
MoAB Ed HERA: Adjuvant Trastuzumab
MoAB Ed E2100: T +/- bevacizumab MBC

3. 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.
On behalf of ECOG and the US Intergroup, thank you for allowing me to present the first results of E2197, a randomized trial comparing adriamycin plus docetaxel to adriamycin plus cyclophosphamide for node positive and hi risk node negative breast cancer.

4. E2197 Rationale Phase II Studies Anthracyline + Taxane
Study A/Por D mg/m2 RR % CHF %
Gianni/ 60/P
Dombernowsky
Sledge E /P
Sparano E /P
Sparano E /D
Cresta 60/D
Misset 50/D
Given their single agent activity, relative non-cross resistance, partially non-overalpping toxicities and different mechanisms of action, there was a clear rationale for combining the taxanes with doxorubicin. The encouraging results of the combination of doxorubicin and palcitaxel were associated with a risk of cardiac toxicity related to cumulative doxorubicin dose and alteration of doxorubicin pharmacokinetcs by paclitaxel which was highly sequence dependent
Here are some of the Phase II trial s in metastatic breast cancer. The combination of doxorubicin and docetaxel was selected for E2197 based on the relative cardiac safety of this combination.

5. E2197 Rationale Phase III Studies:Anthracyline + Docetaxel
MBC AT (50/75) AC (60/600)
RR% p=.012
TTPwk p=.015
CHF % 2 4
FN%
No difference OS 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
Subsequent to the initiation of E2197 several randomized trials were published supporting the investigation of this combination in the adjuvant treatment of early stage breast cancer.
Here one can see that AT resulted in an increased response rate and time to tumor progression compared to AC in metastatic breast cancer with a low incidence of CHF. As you can also see the AT combination is associated with significant febrile neutropenia when given without growth factor support.
These data are also supported by the comparison of TAC vs FAC. While TAC resulted in an increased response rate there was no improvement in time to progression when compared to FAC in metastatic breast cancer.
However, in the adjuvant setting, TAC was superior to FAC in terms of both disease free and overall survival.

6. E2197: Schema R A N D O M I Z E IV q 3wk x 4 Cipro 500mg
po. bid D8 x 10d
Adriamycin 60mg/m2
Docetaxel (T) 60mg/m2
T1-3 N0-1 M0
No then
T> 1.0cm
Adriamycin 60mg/m2
Cyclophosphamide 600mg/m2
IV q 3wk x 4
Tamoxifen 20mg daily x 5 years
post chemotherapy for ER and/or
PR positive tumor
Stratified:
Nodal Status
HR Status (ER+PR+,ER+PR-,
ER-PR+,ER- PR-,ER/PR unknown)
Menopausal Status
*G-CSF -
per ASCO guidelines

7. 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.
At ASCO 2003 we reported no difference in LVEF bewteen AT and AC.

8. 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: including an estimated 10% ineligible
Primary Analysis: Intent-to-treat analysis on eligible patients.
The primary endpoint was DFS defined a recurrence, new breast cancer, or death without recurrence.
With 2778 patients (inlcuding 10% ineligible) this study had 83% power to detect a 25% reduction in DFS hazard rate using AT
This was an intent to treat analysis.
__________________________________________________________________________________________________________________
(assuming a 5 yr 78% DFS on the AC arm OR
The ability to detect a 5% absolute improvement in 5 yr DFS from 78% to 83%.
2 interims and a final analysis planned (total information=420 DFS failures)
The information time was defined by the number of eligible patients who recur, have a new breast cancer primary or die without recurrence whichever occurred first.

9. 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

10. E2197: Patient Characteristics
Balanced for age, HR, menopause, nodes, surgery, grade and size
Age range 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
The arms were balanced for age, hormone receptors, menopause, nodes, surgery, grade and size.
The Age range was , with a Median age of 51
64% were ER +
65% were LN-
For Grade: 10% were low, 38% int., and 46% high
For Size:the range was 0.1 – 12.5 cm; with a Median size of 2.0 cm

11. E2197: Toxicity Summary AT AC Feb/Infxn/N 28% 10% AML/MDS 7 7
Lethal Events
Related 4
Unrelated
As noted in other studies of the AT combination, the neutropenia associated with fever and infection was significant at 28% compared to AC where the rate was 10%. Again noted is that growth factor was not given prophylactically, but rather by ASCO guidelines.
There were 7 cases of AML/MDS on each arm.
There were 7 deaths during or within 30 days of chemo and One death at 42 days.
4 were related to treatment with AT, one with visceral ishcemia( ischemic bowel), 2 secondary to sepsis and one cardiac in a patient with a cardiac history.
Ages 62-70).
AT Unrelated:
Cardiac – h/o cardiac disease (77)
Sudden death (60)
AC Unrealted
Angioedema of the larynx post endoscopy
MI post chemo

12. E2197 Cardiac Safety AT AC Grade 3 4 5 3 4 CHF 15 2 1 10 Total 18 10%
No statistically significant difference
There 18 and 10 cases of CHF on the AT and AC arms respectively, with no significant difference between the 2 arms.

13. 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 Median follow-up = 59 months
432/ 2885 (15%) recurred, developed second breast cancer or died.
At the Fall 2004 DMC, the study was at full information and the ECOG DMC released the study for presentation and publication.
The current data are as of April 2005.
At 59 month median follow-up, 432 of 2885 patients recurred, developed second breast cancers or died.

14. E2197: DFS/OS Hazard Ratio HR > 1 favors AT HR (adjusted)
DFS ( ), p=0.70
OS ( ), p=0.49
As of 4/4/05, 242 deaths
With a Hazard ratio greater than 1 favoring AT there was no significant difference in disease free or overall survival between the 2 arms.
The Hazard ratio was adjusted for age, nodes, ER, menopausal status, surgery, grade, size. The unadjusted HR’s were not significantly different.

15. E2197 Disease-Free Survival
Percent 10 20 30 40 50 60 70 80 90
100
Months 12 24 36 48 72 AT AC
1444
213
1441
219 N
Events 87
(1)
4-Yr %
(S.E.)
E2197 Disease-Free Survival
The K-M curves are overlappiing for a disease free survival.
The 4 year DFS was 87% for both arms.

16. Percent 10 20 30 40 50 60 70 80 90
100
Months 12 24 36 48 72 AT AC
1444
117
1441
125 N
Events 94
(1) 93
4-Yr %
(S.E.)
E2197 Overall Survival
Similarly, the curves overlap for overall survival with 94% survival at 4yrs.

17. E2197: DFS Subgroup Analysis
No significant effect within any of the following subgroups :
Nodes
Size
Age
Menopausal Status
Grade
Type of Surgery
Race
No significant effect was observed within any of the following subgroups :
Nodes
Size
Age
Menopausal Status
Grade
Type of Surgery
Race
NB: There were no significant interactions between treatment and any of these variables.

18. E2197 Disease-Free Survival:ER-/PR- 10 20 30 40 50 60 70 80 90
100
100 90 80 70 60
Percent
Percent 50 40 30 20 10 12 24 36 48 60 72 12 24 36 48 60 72
Months
Months N
Events
4-Yr %
(S.E.) N
Events
4-Yr %
(S.E.) AT
454 85 83 83 83
(2)
(2)
(2) AT 52 14 77
(6) AC
463
109 79 79 79 79 79 79 79 79
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2) AC 38 3 95
(4)
E2197 Disease-Free Survival:ER+/PR-
E2197 Disease-Free Survival:ER+/PR+
100
100 90 90 80 80 70 70 60
The ER/PR subgroups were prespecified stratification groups at randomization designed to balance the treatment arms.
And are not powered to detect differences between the subgroups.
While there is no statistically significant difference in the ER+ and ER- tumors, these curves illustrate the 4 prespecified ER/PR subgroups.
In the ER-/PR- and the ER+/PR – seen on the left side of the slide, there were fewer events in the AT arm.
For the ER-/PR- group, the 4 yr DFS was 83% for AT and 79% for AC.
For the ER+/PR- group, the DFS was 90 % and 83% respectively for AT and AC, acknowledging that this subgroup is quite small.
On the top right, the ER-/PR+ subgroup was extremely small and may represent lab error for ER and therefore this curve could be collapsed into the ER+/PR+ curve below it showing no difference between the 2 arms, and this represents the majority of patients. 60
Percent 50
Percent 50 40 40 30 30 20 20 10 10 12 24 36 48 60 72 12 24 36 48 60 72
Months
Months N
Events
4-Yr %
(S.E.) N
Events
4-Yr %
(S.E.) AT
162 22 90
(2) AT
767 91 90 90 90 90 90 90 90
(1)
(1)
(1)
(1)
(1)
(1)
(1) AC
164 34 81 83 81
(3)
(3)
(3) AC
770 73 92 92 92 92 92 92 92
(1)
(1)
(1)
(1)
(1)
(1)
(1)

19. 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)
Here the same subgroup data are illustrated in this forest plot of DFS where anything to the right of 1 favors AT.
Again the largest group is the ER+/PR+ group with the very small ER-/PR+ group likely collapsing into it.
This again suggests that the PR – tumors may potentially benefit from AT but the study was not powered to statistically detect these differences.
The same pattern is seen for OS, data not shown.
These data support the hypothesis presented by Don Berry at San Antonio, that the in the ER positive tumors the large benefit provided by Tamoxifen, overwhelms the potential benefit to chemo, or that the prognosis of these tumors is so good it is difficult to detect a difference between the 2 chemotherapy arms.
Taken together along with the Genomic Health data, this data supports the hypothesis that the biology of the tumor may predict the benefit to individual therapies.
ER+/PR+
0.79 (0.58, 1.10)
0.1
0.2
0.5 1 2 5
Favors AC
Favors AT

20. 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.
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.

21. 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
Would longer f/u change these results? Unlikely
Observed DFS = 87% at 4 yrs.
Expected DFS = 78% at 4yrs.
The better than anticipated DFS may represent the continued improved prognosis over time that we have observed in Intergroup trials.
In fact the predecessor to this trial, 9313, there was an 80% 5 yr DFS.
What about the Aromatase Inhibitor Affect:
60% started Tam; About half have finished; with a Median of 41 mo on tamoxifen; AI info collected since 2004 for future analysis
Subset analysis of prespecified ER/PR stratifications: lead to the
Hypothesize that the biology of the primary tumor predicts outcome and benefit to specific therapies.
Central review of ER/PR/Her 2 is ongoing
With support from Genomic Health and Sanofi-Aventis we will perform the following analyses
Oncotype
Genomic profiling
to Use these data as training set for validation with E1199
In addition to Pharmacogenomics
In addition, These data support the design of the PACCT –1 trial
Program for the assessment of clinical cancer tests – Phase III validation study of genomic profiling
Intergroup 9313 AC vs. A->C; at median f/u of 5.3 yrs,, the estimated 5 yr DFS was 80%.
Refer to NSABP studies of eight + years f/u to see differences in low risk population of tumors< 1 cm. B 13, 19, 14 and 20.
Fisher at al. JNCI 93(2): Jan 17, 2001
Prognosis and treatment of patient with breast tumors one cm or less and negative axillary nodes.
ER - = 235: surgery +/- ctx
ER + = 1024: surgery, tam +/- ctx
8yr RFS for ER -: Surgery = 81%; surgery + ctx = 90%; p=.06
Survival similar in both groups: 93 and 91%; p= .65.
8 yr RFS for ER+:
Surgery = 86%
Surgery/tam = 93%; p= .01
Surgery/tam/ctx = 95%; p= .07 compared with tam
Survival was 90%, 92% ( p=,41). and 97% respectively. P=.01 in the latter 2 groups.
Although the majority of tumor recurrences occur in the first decade of f/u, the proportion of recurrences that occur in the second decade of f/u increases in women with small tumors. Consequently a follow-up longer than 8 years is likely necessary to allow for a more meaningful assessment of the outcome of these patients. Mortality at 8 yrs f/up was 8% for t< 1 cm. I/2 of deaths were related to breast cancer. Therefore the findings in these patients with short follow-up should be viewed with caution.
Would longer follow-up change these results? Statistically no, even though the entire group did better that anticipated compared to historical controls.
PACCT-1 Program for the assessment of clinical cancer tests – Phase III validation study of genomic profiling

22. Anne O’Neill, Deborah Namande, Eric Ross
Thank You
Patients
Data managers/ CRA’s
CALGB, NCCTG, SWOG, EPP
Anne O’Neill, Deborah Namande, Eric Ross