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