1. CLINICAL CASE Highlights in the Management of Breast Cancer
Rome, May 25-26, 2007
CLINICAL CASE
Dott.ssa Jamara Giampietro
Cattedra di Oncologia Medica
Università “G. D’Annunzio” Chieti-Pescara
Direttore: Prof. Stefano Iacobelli

2. Core needle biopsy: ductal infiltrating carcinoma, G3
69 years old, female
Comorbility: hypertension and osteoporosis
December 2006: mammogram and breast ultrasound showed a 4.3 cm mass
Core needle biopsy: ductal infiltrating carcinoma, G3
ER=80% PR=10% HER2+++
Chest immaging Bone scan negative
Abdominal ultrasound
Echocardiogram LVEF:55%

3. The best therapeutic approach?
primary systemic therapy
immediate surgery

4. Randomized phase III trials comparing neoadjuvant with adjuvant therapy using the same chemotherapy regimen
Sachelarie et al, The Oncologist 2006;11:
The goals of PST in breast cancer are to treat occult systemic disease, decrease the tumor bulk (optimally to a complete pathologic response), and reduce the extent of local surgery to allow breast-conserving surgery.

5. Mauri et al, JNCI 2005;3:

6. The best therapeutic approach?
primary chemotherapy
primary hormonotherapy ?

7. Primary efficacy endpoint: overall objective response.
Secondary efficacy endpoint: percentage of patients who underwent BCS.
Munich et al, Ann of Oncology 2001;12:

8. Munich et al, Ann of Oncology 2001;12:1527-1532

9. The best therapeutic approach?
Anthracycline-based chemoterapy
Taxane-based chemoterapy
Anthracycline-taxane-based
chemoterapy
Trastuzumab ?

10. Randomized trials comparing different neoadjuvant
chemotherapy regimen
Sachelarie et al, The Oncologist 2006;11:
The sequential use of an anthracycline with a taxane is associated with better results than their concurrent use. However, it is impossible to determine whether the observed benefit is a result of the sequential use or because of differences in total delivered dose of chemotherapy(higher in the sequential arm) or treatment duration ( longer in the sequential arm).

11. [ 4 P* + 4 FE(75)C ] + H weekly Clinical stage II and IIIa
HER2 FISH 3+
or HIC +
4 P* + 4 FE(75)C
[ 4 P* + 4 FE(75)C ] + H weekly
* Paclitazel was administered at 225 mg/mq as a 24-hours continuous infusion.
The primary objective of the study was to compare pCR rate between the two arms.

12. Budzar et al, JCO 2005; 23:

13. BCIRG 006 ACT ACTH TCH 4 x AC 60/600 mg/m2 4 x Docetaxel Her 2+
(Central FISH) N+
or high
risk N-
4 x AC 60/600 mg/m2
4 x Docetaxel
100 mg/m2
ACTH
1 Year Trastuzumab
6 x Docetaxel and Carboplatin
75 mg/m2 AUC 6
N=3,222
TCH
Stratified by Nodes and Hormonal Receptor Status
1 Year Trastuzumab
Slamon D., SABCS 2006

14. Endpoints Primary Secondary - Disease-free Survival - Overall Survival
- Toxicity
- Pathologic & Molecular Markers

15. Disease Free Survival 2nd Interim Analysis
Absolute DFS benefits
(from years 2 to 4):
ACTH vs ACT: 6%
TCH vs ACT: 5%
1.0
93%
0.9
92%
87%
83%
86%
87%
0.8
82%
81%
% Disease Free
77%
0.7
Patients
Events
1073
192
AC->T
0.6
1074
128
AC->TH
HR (AC->TH vs AC->T) = 0.61 [0.48;0.76] P<0.0001
1075
142
TCH
HR (TCH vs AC->T) = 0.67 [0.54;0.83] P=0.0003
0.5 1 2 3 4 5
Year from randomization
Slamon D., SABCS 2006

16. Overall Survival 2nd Interim Analysis
1.0
99%
97%
98%
97%
95%
92%
93%
0.9
91%
86%
% Survival
0.8
0.7
Patients
Events
0.6
1073 80
AC->T
1074 49
AC->TH
HR (AC->TH vs AC->T) = 0.59 [0.42;0.85] P=0.004
1075 56
TCH
HR (TCH vs AC->T) = 0.66 [0.47;0.93] P=0.017
0.5 1 2 3 4 5
Year from randomization
Slamon D., SABCS 2006

17. DFS Lymph Node Negative 2nd Interim Analysis
1.0
99%
95%
97%
94%
94%
93%
0.9
92%
88%
86%
0.8
% Disease Free
0.7
Patients
Events
0.6
309 35
AC->T
310 12
AC->TH
HR (AC->TH vs AC->T) = 0.32 [0.17;0.62] P=0.0007
309 17
TCH
HR (TCH vs AC->T) = 0.47 [0.26;0.83] P=0.0096
0.5 1 2 3 4 5
Year from randomization
Slamon D., SABCS 2006

18. Overall Survival Lymph - Node Negative 2nd Interim Analysis
100%
100%
1.0
98%
99%
98%
97%
98%
96%
93%
0.9
% Survival
0.8
0.7
Patients
Events
307 12
AC->T
0.6
309 2
AC->TH
HR (AC->TH vs AC->T) = 0.16 [0.04;0.73] P=0.018
307 5
TCH
HR (TCH vs AC->T) = 0.42 [0.15;1.2] P=0.106
0.5 1 2 3 4 5
Year from randomization
Slamon D., SABCS 2006

19. DFS - Subpopulations AC-TH vs AC-T TCH vs AC-T AC-TH better AC-T
1.0
0.0
2.0
AC-TH
better
AC-T
Subgroup
Node neg
Node pos
HR -
HR +
Tsize <2cm
Tsize ≥2cm
AC-TH vs AC-T
1.0
0.0
2.0
Subgroup
Node neg
Node pos
HR -
HR +
Tsize <2cm
Tsize ≥2cm
TCH vs AC-T
TCH
better
AC-T

20. Cardiac Deaths and CHF as per Independent Review Panel
AC-T
n=1,050
AC-TH
n=1,068
TCH
n=1,056
Cardiac related death
Cardiac left ventricular function (CHF)
Grade 3 / 4 3 17 4
second interim analysis
/ 0
/ 4
/ 20
P =
first interim analysis
Data from follow_time.sas
Summary Statistics for Time: rando_lastfup_cens_mon
Slamon D., SABCS 2006

21. Patients with >10% relative LVEF decline
AC-T
n = 1012
AC-TH
n = 1040
TCH
n = 1029
Patients 91
180 82 % 9
17.3 8
P <0.0001
P = 0.5
second interim analysis
/102
/189
/89
/10
/18
/8.6
/1014
/1042
/1030
P = 0.002
P <0.0001
Data from follow_time.sas
Summary Statistics for Time: rando_lastfup_cens_mon
first interim analysis
P = 0.5
Slamon D., SABCS 2006

22. Mean LVEF - All Observations 2nd Interim Analysis66 65
TCH 64
AC->T 63
LVEF points % 62
AC->TH 61 60 59 58
100
200
300
400
500
600
700
800
900
1000
AC->T (N=1014)
AC->TH (N=1042)
Time since randomization (days)
TCH (N=1030)
Slamon D., SABCS 2006

23. NEOADJUVANT TREATMENT
January 2007 – April 2007: Trastuzumab + Docetaxel + Carboplatin x 6 cycles
May 2007 QUART SE
minimal residual disease ; 15 N –
Trastuzumab for a total of 1 year course
+ aromatase inhibitor