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Highlights in the Management of Breast Cancer
Rome, May 25-26, 2007
CLINICAL CASE
Dott.ssa Jamara GiampietroCattedra di Oncologia Medica
Università “G. D’Annunzio” Chieti-PescaraDirettore: Prof. Stefano Iacobelli
• 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 ultrasoundEchocardiogram LVEF:55%
The best therapeutic approach?
• primary systemic therapy
• immediate surgery
Randomized phase III trials comparing neoadjuvant with adjuvant therapy using the same chemotherapy regimen
Sachelarie et al, The Oncologist 2006;11:574-589
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.
Mauri et al, JNCI 2005;3:188-194
The best therapeutic approach?
• primary chemotherapy
• primary hormonotherapy
Munich et al, Ann of Oncology 2001;12:1527-1532
Primary efficacy endpoint: overall objective response.
Secondary efficacy endpoint: percentage of patients who underwent BCS.
Munich et al, Ann of Oncology 2001;12:1527-1532
The best therapeutic approach?
•Anthracycline-based chemoterapy
•Taxane-based chemoterapy
•Anthracycline-taxane-based chemoterapy
•Trastuzumab
Randomized trials comparing different neoadjuvant chemotherapy regimen
Sachelarie et al, The Oncologist 2006;11:574-589
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).
The primary objective of the study was to compare pCR rate between the two arms.
Clinical stageII 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.
Budzar et al, JCO 2005; 23: 3676-3685
4 x AC60/600 mg/m2
4 x Docetaxel100 mg/m2
6 x Docetaxel and Carboplatin75 mg/m2 AUC 6N=3,22
2
1 Year Trastuzumab
ACT
ACTH
TCH
Her 2+(Central FISH)
N+or high risk N-
4 x AC60/600 mg/m2
4 x Docetaxel100 mg/m2
Slamon D., SABCS 2006
BCIRG 006
Stratified by Nodes and Hormonal Receptor Status
1 Year Trastuzumab
Endpoints
Primary
- Disease-free Survival
Secondary
- Overall Survival
- Toxicity
- Pathologic & Molecular Markers
Disease Free Survival 2nd Interim Analysis
Absolute DFS benefits(from years 2 to 4):
ACTH vs ACT: 6%TCH vs ACT: 5%
% D
isea
se F
ree
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5
Patients Events
1073 192 AC->T1074 128 AC->TH1075 142 TCH
81%
87%
86%
77%
83%
82%87%
93%
92%
HR (AC->TH vs AC->T) = 0.61 [0.48;0.76] P<0.0001HR (TCH vs AC->T) = 0.67 [0.54;0.83] P=0.0003
Year from randomization
Slamon D., SABCS 2006
Overall Survival 2nd Interim Analysis
HR (AC->TH vs AC->T) = 0.59 [0.42;0.85] P=0.004
HR (TCH vs AC->T) = 0.66 [0.47;0.93] P=0.017
% S
urvi
val
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5
Patients Events1073 80 AC->T1074 49 AC->TH
1075 56 TCH
97%
99%98%
93%
97%
95% 92%
91%
86%
Year from randomizationSlamon D., SABCS 2006
DFS Lymph Node Negative2nd Interim Analysis
% D
isea
se F
ree
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5
Patients Events
309 35 AC->T310 12 AC->TH309 17 TCH
92%
99%
97%
88%
95%
94%
86%
94%
93%
HR (AC->TH vs AC->T) = 0.32 [0.17;0.62] P=0.0007
HR (TCH vs AC->T) = 0.47 [0.26;0.83] P=0.0096
Year from randomizationSlamon D., SABCS 2006
Overall Survival Lymph - Node Negative
2nd Interim Analysis %
Sur
viva
l0
.50
.60
.70
.80
.91
.0
0 1 2 3 4 5
Patients Events307 12 AC->T309 2 AC->TH
307 5 TCH
99%
100%
98% 96%
100%
98%
93%
97%
98%
HR (AC->TH vs AC->T) = 0.16 [0.04;0.73] P=0.018
HR (TCH vs AC->T) = 0.42 [0.15;1.2] P=0.106
Year from randomizationSlamon D., SABCS 2006
1.00.0 2.0
AC-THbetter
AC-Tbetter
Subgroup
Node neg
Node pos
HR -
HR +
Tsize <2cm
Tsize ≥2cm
AC-TH vs AC-T
1.00.0 2.0
Subgroup
Node neg
Node pos
HR -
HR +
Tsize <2cm
Tsize ≥2cm
TCH vs AC-T
TCHbetter
AC-Tbetter
DFS - Subpopulations
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 0 0 0
Cardiac left ventricular function (CHF)
Grade 3 / 4 3 17 4 first interim analysissecond interim analysis
/ 0 / 0 / 0
/ 4 / 20 / 4
P = 0.0015
Slamon D., SABCS 2006
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
first interim analysis
P <0.0001 P <0.0001
P = 0.5second interim analysis
/102 /189 /89
/10 /18 /8.6
/1014 /1042 /1030
P = 0.002 P <0.0001
P = 0.5
Slamon D., SABCS 2006
58
Mean LVEF - All Observations2nd Interim Analysis
59
60
61
62
63
64
65
66
0
LVEF
poin
ts %
100 200 300 400 500 600 700 800 900 1000
Time since randomization (days)AC->T (N=1014)AC->TH (N=1042)TCH (N=1030)
AC->T
TCH
AC->TH
Slamon D., SABCS 2006
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