1. European Cooperative Trial in Operable Breast Cancer(ECTO): Improved freedom from progression from adding paclitaxel(T) to doxorubicin(A) followed by CMF
Luca Gianni
Abstract 513

2. ECTO: Schema Tumors > 2 cm randomized to :
SURG ->A 75 mg/m2 x 4 -> CMF x 4
SURG ->AT 60/ 200 x 4 -> CMF x 4
AT 60/ 200 x 4 -> CMF x 4 -> SURG
Tam for HR +
Analysis: FFP A vs B
B vs C

3. ECTO at 5 years Analysis A vs. B
Pts. Events HR p
A-CMF *
AT-CMF
Analysis B vs. C
S-AT-CMF
AT-CMF-S
Data super imposable so far, no significant difference, however pCR had improved FFP.

4. ECTO: Main Treatment Outcomes
A(%) B(%) C(%)
Total FFP
pCR
no pCR N N
N +> OS
No significant difference in OS.
No significant difference in cardiac toxicity

5. Combined Analysis of NSABP-B31/NCCTG-N9831
Doxorubicin and Cyclophosphamide Followed by Paclitaxel with or without Trastuzumab as Adjuvant Therapy for Patients with HER-2 Positive Operable Breast Cancer
Romond EH, Perez EA, Bryant J, Suman V, Geyer CE,
Davidson N, Tan-Chiu E, Martino S, Swain SM, Kaufman P, Fehrenbacher L, Pisansky T, Vogel V, Kutteh LA, Yothers G, Visscher D, Brown AM, Jenkins R, Seay TE, Mamounas E, Abrams J, Wolmark N
Combined Analysis of NSABP-B31/NCCTG-N9831

6. NSABP B-31 NCCTG N9831 Control: ACT Arm 1 Arm 2 Arm A Arm B Arm C
Investigational: ACT+H
Arm B
Arm C
= doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4
= paclitaxel (T) 175 mg/m2 q 3 wk x 4
= paclitaxel (T) 80 mg/m2/wk x 12
= trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51

7. Patient Eligibility
HER-2 positive by FISH or +++ by IHC verified centrally (N9831) or by approved reference lab (B-31)
Normal left ventricular ejection fraction
No past or active cardiac disease including:
History of myocardial infarction
History of congestive heart failure
Angina pectoris requiring medication
Arrhythmia requiring medication
Clinically significant valvular disease
Uncontrolled hypertension
LVH
Cardiomegaly on CXR

8. LVEF Evaluation Schedule
B-31 Arm 2 / N9831 Arm C
AC Paclitaxel + Trastuzumab
mo. 3
mos. 6
mos. 9
mos. 18
mos.
B-31 Arm 1 / N9831 Arm A
AC Paclitaxel
mo. 3
mos. 6
mos. 9
mos. 18
mos.

9. Relationship of LVEF to LLN
Asymptomatic Patients Rules for Trastuzumab Continuation Based on Serial LVEFs
Relationship of LVEF to LLN
Absolute Decrease
of < 10%
Absolute Decrease
of %
Absolute Decrease
of  16%
Within Normal Limits
1- 5 % below LLN
 6 % below LLN
Cont.
Cont.*
Cont.
Hold *
Hold *
Once the patients start Herceptin, they will be monitored at set intervals by MUGA scan. The above criteria must be followed for continuing or stopping Herceptin in patients who are asymptomatic. If a repeat MUGA scan is indicated, that MUGA scan must fall into one of the categories labeled “continue” (above) before the patient can proceed with further weekly Herceptin doses.
* Repeat LVEF assessment after 4 weeks
- If criteria for continuation met – resume trastuzumab
- If 2 consecutive holds, or total of 3 holds occur – discontinue trastuzumab

10. B-31: Trastuzumab Discontinuation Due to Asymptomatic or Symptomatic
Cardiac Dysfunction by Quarter

11. Patient and Tumor Characteristics (%)
AC  Paclitaxel
+ Trastuzumab
872
B-31
807
N9831
864
808
Age
<50
50-59
≥60 52 34 15 51 32 16 50 18
No. Pos Nodes
1-3
4-9
10+ 57 29 14 13 48 25 11
Hormone Receptors
ER+
ER-
PR+
PR- 53 47 41 58 46 39 60
Tumor Size
≤2.0 cm.
cm.
>4.0 cm. 43 40 37 44 17 38

12. Statistical Analysis
Median follow-up: 2.0 years (2.4 years on B-31/1.5 years on N9831)
Primary endpoint: DFS
analyzed by intent-to-treat
Secondary endpoints: OS and Time to 1st Distant Recurrence
Definitive analysis after 710 DFS events
First interim analysis after 355 DFS events
Stop trials only if equivalence is rejected at p= (2p=0.001)

13. Disease-Free Survival
ACTH
87%
85%
ACT
75% %
67%
N Events
ACT
ACTH
HR=0.48, 2P=3x10-12
Years From Randomization
B31/N9831

14. Forest Plot For Disease-Free Survival
ALL DATA
Age
≥60
50-59
40-49
≤39
Hormone
Receptor
Positive
Negative
Tumor
Size
≥ 4.1cm cm
<2.0 cm
No.
Positive
Nodes
10+
4-9
1-3
Protocol
N9831
NSABP B-31
0.2
0.4
0.6
0.8
1.0
1.2
1.4
Hazard Ratio

15. Disease-Free Survival1 2 3 4 5 50 60 70 80 90
100
B-31
N9831
ACTH
ACTH
87%
87%
85%
ACT
86%
ACT
78%
74% %
68%
66%
N Events
N Events
ACT
ACT
ACTH
ACTH
HR=0.55, 2P=0.0005
HR=0.45, 2P=1x10-9
Years From Randomization

16. Time to First Distant Recurrence
100
ACTH
AC->T+H
90%
90%
90%
90%
90%
90% 90
ACT
AC->T 80
81%
81%
81% %
74%
74% 70
74%
N Events
N Events
ACTH
ACT
AC->T 60
AC->T+H
HR=0.47, 2P=8x10-10
HR=0.47, 2P=8x10-10 50 1 2 3 4 5
Years From Randomization
B31/N9831

17. Hazard of Distant Recurrence
120
100
ACT 80
Rate per 1000 Women /Yr 60 40
ACTH 20 1 2 3 4
Years From Randomization
B31/N9831

18. B-31/N9831 Survival ACTH 94% 91% ACT 92% 87% N Deaths ACT 1679 92
HR=0.67, 2P=0.015
Years From Randomization
B31/N9831

20. B-31: Post-AC LVEF and Age Are Independent Predictors of Trastuzumab-Associated CHF
P(Age)=0.04
P(LVEF)<0.0001

21. Conclusions
For high risk HER-2 positive breast cancer, trastuzumab given concurrently with paclitaxel following AC chemotherapy, reduces the risk of a first breast cancer event at 3 years by 52%.
The relative risk reduction benefit was present and of similar magnitude in all subsets of patients analyzed. There is not, however, statistical power to establish efficacy in the node negative subset.
The addition of trastuzumab reduced the probability of distant recurrence by 53% at 3 years, and the hazard of developing distant metastases appears, thus far, to decrease over time.

22. Conclusions
4. Results at a median follow-up of 2 years show a statistically significant survival advantage with a relative risk reduction of 33%.
5. The combination of trastuzumab and chemotherapy has a notable risk of cardiac toxicity. Careful monitoring of cardiac function is of vital importance if trastuzumab is to be used in the adjuvant setting.