Nugroho Prayogo

Dharmais Cancer Center-

Hematology & Medical Oncology Medical Faculty University of
Indonesia
Contain :
1. Introduction : history adjuvant chemoth.
2. A controversion , Anthracycline vs Non
Anthracycline regimen
3. Efficacy and toxicities
4. Role of topoisomerase IIa
5. Trials :Early Breast Cancer and Metastatic BC.
6. Conclusion.
Introduction.
 Several meta analisis treatment of Early breast
cancer :
I. Better overall survival
II. Fewer relaps

 Anthracycline based therapy :

I. backbone adjuvant th/ (. Undoubtely)
II. mayor driving force impovement.
III. But  cause longterm heart problem and
secondary leukemia in some patients
Early-Stage Breast Cancer Evolution

Period Combination Regimens Risk Reduction

Oral CMF
1970–1980 CMF-based 26%
IV CMF
FAC x 6
Anthracycline-
1980–1995 FEC x 6 30%
based
AC x 4 (USA)
TAC x 6
3 FEC  3 T 25-30%
Anthracyline and
1995–
taxane-based AC x 4  P x 4
(q3w)
AC x 4  P q wk
 Side effect Researchers :

Looking for :
 Non anthracycline regimens ,
 equally effective , and less toxic
 Equal:
 (PFS) Prolonged progression free survival
 (OS) overall survival .
Controversy .
 Expert pro :
1. ,, Anthracycline therapy may be avoidable in EBC
(R.Tuma; JNCI April 2, 2008 )
2. ,,Do we still need Anthracycline,, ? (ASCO
Educational book 2008)
3. Many women could be treated without
Anthra.cycline (S.Jones JNCI, April 2008)
 Expert contra:
 ,,Trial relative small, verry provocative,, very
sheldom change standard care base on 1000 (Edith
Perez)

JNCI April 2008

Contra anthracycline
TRIAL :
1. Stephen Jones (USON 9735 )
2. Denis Slamon , BCIRG 06
1.

Stephen E. Jones, MD
Baylor-Sammons Cancer Center, Dallas, TX
US Oncology Research, Houston, Texas

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 US Oncology 9735:
Study Design
AC x 4 q3w
Doxorubicin (60 mg/m2)
Cyclophosphamide (600 mg/m2)
n=510
R
TC x 4 q3w
• N=1016 Taxotere (75 mg/m2)
• 71% ER+ Cyclophosphamide (600 mg/m2)
• 48% N–
n=506
Chemotherapy doses based on actual
BSA (no cap)
Eligibility: Stage I, II, or III disease
Chemotherapy given prior to radiation
Tamoxifen for all ER+ patients after
chemotherapy +/- radiation
Jones et al. J Clin Oncol. 2006;24:5381-5387.
 Risk Versus Benefit in Context
With USON 9735

 (HER2 status unknown) n=1016

 TC superiority over AC
 (HR=0.67 for DFS)*
 (statistically significant)
 Only single centre.

*Jones et al. J Clin Oncol. 2006;24:5381-5387; Slamon et al. SABCS 2006. Abstract 52.
Result :
1. Taxanes have improved the effectiveness of several
adjuvant regimens

2. Until now the backbone of these regimens has been an

anthracycline

3. Recent evidence relates effectiveness of anthracyclines

to topoisomerase Iia

4. There are now 2 non-anthracycline regimens that

challenge the assumption that anthracyclines are
needed to treat breast cancer

5. Stay tuned!

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Why AC Remains a Standard
 4 cycles of AC became ‘standard’
 Until now, no treatment of 4 cycles in length was
superior to AC
 2. BCIRG 006: Study Design
4 x AC 4 x Taxotere
60/600 mg/m2 100 mg/m2

ACT
HER2+
(Central FISH) 4 x AC 4 x Taxotere
60/600 mg/m2 100 mg/m2

N+
or high ACTH
risk N-
1 Year Trastuzumab

6 x Taxotere and Carboplatin

75 mg/m2 AUC 6
N=3222
TCH
Stratified by Nodes
and Hormonal
Receptor Status
1 Year Trastuzumab
 DFS Subpopulations
AC-TH vs AC-T TCH vs AC-T
Subgroup Subgroup

Node neg Node neg

Node pos Node pos

HR - HR -
HR + HR +

T size <2cm T size <2cm

T size ≥2cm T size ≥2cm

0.0 1.0 2.0 0.0 1.0 2.0

AC-TH AC-T TCH AC-T
better better better better

Slamon et al. SABCS 2006. Abstract 52.

 Overall Survival Subpopulations
AC-TH vs AC-T TCH vs AC-T
Subgroup Subgroup

Node neg Node neg

Node pos Node pos

HR - HR -
HR + HR +

T size <2cm T size <2cm

T size ≥2cm T size ≥2cm

0.0 1.0 2.0 0.0 1.0 2.0

AC-TH AC-T TCH AC-T
better better better better

Slamon et al. SABCS 2006. Abstract 52.

 BCIRG 006: Cardiac Deaths and
CHF
Second Interim Analysis, per Independent Review

AC-T AC-TH TCH

n=1050 n=1068 n=1056
Cardiac-related death 0 0 0
Cardiac left ventricular
function (CHF) Grade 3-4 4 20 4

p=.0015

Slamon et al. SABCS 2006. Abstract 52.

 BCIRG 006: >10% Relative LVEF
Decline
Second Interim Analysis

AC-T AC-TH TCH

n=1014 n=1042 n=1030
Patients 102 189 89
% 10 18 8.6

p<0.0001 p<.0001

p=.5
Slamon et al. SABCS 2006. Abstract 52.
 BCIRG 006: Mean LVEF - All Observations
Second Interim Analysis
66

65

64
TCH
LVEF Points %

63 AC->T

62

61 AC->TH

60

59

58
0 100 200 300 400 500 600 700 800 900 1000

AC->T (N=1014) Time Since Randomization (days)

AC->TH (N=1042)
TCH (N=1030)
Slamon et al. SABCS 2006. Abstract 52.
 BCIRG 006: Therapeutic Index
Most Recent Data n=3222
AC-TH TCH
BrCa Recurrence 93 98
BrCa Deaths 44 47
Grade 3/4 CHF 20 4
Leukemia 4* 0
Total 161 149
* In both anthracycline-based arms.
 In addition, 23 patients randomized to AC-TH never
received trastuzumab due to LVEF decline following
doxorubicin

Slamon et al. SABCS 2006. Abstract 52.

 Implications for HER2-Negative and
HER2-Positive Breast Cancers
 HER2-negative population
 The benefit of anthracyclines is limited to patients with Topo IIa
amplification and/or overexpression
 Topo IIa amplification occurs only in patients with HER2 amplification
 What data support preferential use of anthracyclines in the HER2-
negative population which represents ~ 75% of breasts cancers?
 HER2-positive population
 Only 35% of patients with HER2 amplification also have Topo IIa
amplification (co expression )
 We now have trastuzumab and lapatinib which more than replace the
gained efficacy of anthracyclines in the 1/3 of patients with
coamplified Topo IIa without risking their toxicities

Slamon et al. SABCS 2006. Abstract 52.

Overall Conclusions
• Two adjuvant breast trials have demonstrated the efficacy
of non-anthracycline regimens:
• USO 9735: TC > AC (HER2 status unknown)
• BCIRG 006: efficacy of TCH in HER2-positive patients
• Molecular data from BCIRG 006 puts the role of
anthracyclines in adjuvant breast cancer treatment into
question
• Anthracyclines cause significant cardiotoxicity, which is
augmented with trastuzumab
• Optimal way to prevent cardiotoxicity is to eliminate the
key stressor: anthracyclines

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 Critical Question:

What is the Role of Anthracyclines

in the Adjuvant Treatment of Breast
Cancer?
Topo IIa Gene Amplification
is Responsible for Improved
Anthracycline Sensitivity
(NOT HER2 Overexpression)
The HER2 Gene
 Encodes a 185kd protein that is a member of the
type I receptor tyrosine kinase family with EGFR,
HER3 and HER4

 Functions
 Growth and proliferation
 Differentiation
 Cell survival
 Motility
 Angiogenesis
The Topo IIa Gene
 Encodes an enzyme which is critical in DNA
replication and function, including RNA transcription
 Functions
 DNA repair
 RNA transcription
 DNA replication
 DNA segregation, condensation and superhelicity

The Topo IIa protein is a major target of the

anthracyclines
 Analysis of >1600 patients in BCIRG 005
showed not a single case of Topo IIa
amplification (always co expression)

Topo IIa amplification does not occur

without HER2 amplification

Slamon et al. SABCS 2006. Abstract 52.

 Disease Free Survival by Treatment
100 Over-expression of topo protein
p-value=0.01
80 CEF
Probability
(%) 60

40 CMF

0 5 10
100 Normal expression of topo protein
p-value=0.6
80
Probability CEF
(%) 60
CMF
40

0 5 10
Time (years)
 Disease Free Survival HER2 positive
HER2 negative

Study HR 95% CI anthra better non anthra better

NSABP B11 0.60 0.44 - 0.82
0.96 0.75 - 1.23

NSABP B15 0.84 0.65 - 1.08

1.02 0.86 - 1.20
Brussels 0.65 0.34 - 1.27
1.35 0.93 - 1.97
Milan 0.83 0.46 - 1.49
1.22 0.91 - 1.64

DBCCG-89-D 0.75 0.53 - 1.06

0.79 0.60 - 1.05

NCIC MA-5 0.52 0.34 - 0.80

0.91 0.71 - 1.17

Total 0.90 0.82 - 0.98 p = 0.01

Overall 0.71 0.61 - 0.83 p < 0.0001

1.00 0.90 - 1.11 p = 1.0
heterogeneity c25 = 5.3, p = 0.38 0.4 0.6 0.9 1 2 5
heterogeneity c25 = 7.6, p = 0.18

Test for interaction chi2 = 13.7 p < 0.001

A.Gennari, et.al. JNCI, 2008, 100
Topo IIa, HER2, and Anthracycline
Sensitivity in Breast Cancers:
Rational Therapeutic Implications

Dennis J. Slamon, MD, PhD

University of California at Los Angeles, USA

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Circumstantial Evidence Linked HER2 Gene
Amplification to Anthracycline Sensitivity
 Pre-trastuzumab era
 Studies showed superior outcomes with anthracyclines
in patients with HER2-positive disease.
 CALGB 8541
 NSABP B11
 NSABP B15
 Intergroup 0100

 At least 6 subsequent retrospective analyses of

therapeutic trials showed similar results including those
using epirubicin instead of doxorubicin.
Does HER2 Overexpression Confer
Unique and/or Inherent Sensitivity to
Anthracyclines?
Type of Anthracycline :
 Doxorubicine ?
 Or
 Epirubicine ?
 Epirubicin Less Cardiotoxic Than Doxorubicin?
Outcome: Clinical Heart Failure

Retrospective Analysis 2007

1097 Consecutive Anthracycline Naïve Pts

Cumulative Epirubicin Dose Corresponding to

5% risk:

Age 40 = 806 mg/m2

Age 50 = 739 mg/m2
Age 60 = 673 mg/m2
Age 70 = 609 mg/m2

van Dalen EC et al. Cochrane Database Syst Rev 2006 Ryberg et al. J Clin Oncol. 2007;25:39s ;1029 (abstr)
 Cardiotoxicity
100

90
% CHF = X2/Y Mathematical Curve
80
X=n cycles chemotherapy
70 Y
MD Anderson
60 Doxorubicin 50 mg/m2 16
Doxorubicin 60 mg/m2 11.5
50 Epirubicin 90 mg/m2 20
40
Von Hoff
30

20

10

0
0 100 200 300 400 500 600 700 800 900
Cumulative Doxorubicin Dosage (mg/m2)
Ewer et al. J Card Fail. 2005;11
 Anthracycline-Associated Heart Failure

Adapted from Felker et al. N Engl J Med .2000;342: 1077–1084.

Risk Factors for Anthracycline-Associated
Cardiotoxicity

100
90
80
• Cumulative dose of doxorubicin
70 • Combination chemotherapy
CHF (%)

60
50 • Prior/concomitant mediastinal radiotherapy
40
MD Anderson • Age
30
Von Hoff
20 • Previous cardiac disease
10
0 • Hypertension
0 100 200 300 400 500 600 700 800 900
Doxorubicin Cumulative Dose (mg/m2)
 Anthracycline Cardiotoxicity: How to prevent?
Bolus vs Continuous Infusion Liposomal Doxorubicin

Shapira et al. Cancer 1990; 65: 870-873 O’Brien et al. : Ann Oncol. 2004;15:440-9
Antioxidants

Dexrazoxane (Zinecard)
 Anthracyclines Cardiotoxicity
Incidence and Age
100
Doxorubicin Related CHF (%)

90 B < 65 years
80 J > 65 years
70
HR 2.25 (1.04, 4.96)
60 J J J J J J

50 p=.029
B B B B
40
30 J
B
J
20 B
B
10 J
B B
JB JB JB
0 JB JB JB JB
100 200 300 400 500 600 700 800
Cumulative Dose of Doxorubicin (mg/m2)
Swain et al. Cancer. 2003,97:2869.
 Trastuzumab Cardiotoxicity:
Risk Factors
Anthracyclines Trastuzumab
Type I Cardiotoxicity Type II Cardiotoxicity
(myocardial damage) (myocardial dysfunction)
Combination chemotherapy Prior/concomitant
anthracyclines
Prior/concomitant
mediastinal radiotherapy
Age > 70 Age > 50 years
Previous cardiac disease Previous cardiac disease

Hypertension Hyperlipidemia

Singal et al. N Engl J Med. 1998;339:900-905; Suter TM. Breast. 2004;13:173–183.

To prevent cardiotoxicity
 Long term infuse , 48 h
 After 3 cycles, monitor sign CHF, consider non
anthracycline regimen
 Age> 65 yo  evaluation risk factor
 Do not given concomitantly anthracycline with
traztuzumab .
 Use antioxidant .

Thomas M. Suter
Swiss Cardiovascular Center, Bern, Switzerland
PACS 01: treatment protocol
6FE100C
S Fluorouracil 500 mg/m² d1
U N=1999 Epirubicin 100 mg/m² d1
R Cyclophosphamide 500 mg/m² d1
G 6 cycles q21d
E
R
R
Y 3FE100C–3Taxotere®
3 cycles of FEC 100 mg/m2 q21d
Stratified by:
followed by
 Centre
 Age: <50; ≥50 y
3 cycles of Taxotere® 100 mg/m² d1
 Nodes: 1–3; ≥4
q21d

 Radiotherapy delivered within 4 weeks after the last chemotherapy cycle

 Tamoxifen 20 mg/day for 5 years prescribed in menopausal hormone-receptor
positive patients after chemotherapy
Roché H, et al. Breast Cancer Res Treat. 2004;88 (Suppl 1):S16. Abstract 27.
PACS 01: cardiac toxicity
6FE100C 3FE100C–3T ² test

Patients n, (%) 13 (1.3) 4 (0.4) 0.027

Events, n

CHF 4 0

LVEF 4 1

Arrhythmia 2 0

Others§ 2 2

Cardiac death* 1 1
myocardial infarct, dyspnea / pericarditis, menace syndrome
*cardiogenic shock / sudden death

Roché H, et al. Breast Cancer Res Treat. 2004;88 (Suppl 1):S16. Abstract 27.
PACS 01: second cancers
Patients (n) 6FE100C 3FE100C–3T

Second cancers 25 17
Acute myeloid leukemia 3 1
Chronic myeloid leukemia 0 1
Lymphoma/myeloma 1 1
Endometrium 2 (tamoxifen) 1 (tamoxifen)
Ovary 1 3
GI tract 5 5
Head neck tumour 4 1
Skin 3 2
Miscellaneous 6 2

Roché H, et al. Breast Cancer Res Treat. 2004;88 (Suppl 1):S16. Abstract 27.
PACS 01: events, ITT
Patients % 6FE100C 3FE100C–3T p-value*

First event 28.1 22.8 0.006

Local relapse 4.7 3.1 0.064

Regional relapse 2.4 1.6 0.188

Distant relapse (n) 21.8 (217) 17.7 (178) 0.023

Deaths (n) 13.5 (135) 9.9 (100) 0.017

Contralateral breast cancer 3.0 2.4 0.427

Second cancer 2.6 1.7 0.131

* log-rank adjusted

Roché H, et al. Breast Cancer Res Treat. 2004;88 (Suppl 1):S16. Abstract 27.
 PACS 01: 5-year DFS (ITT)
1.00

3FE100C–3T 78.3%
Cumulative probability

0.75 Relapses=482
218 (21.7%)
264 (26.5%)
0.50
6FE100C 73.2%

0.25 Log-rank unadjusted p value=0.012

Log-rank adjusted p value=0.014
HR (Cox model)=0.83 [0.69–0.99], p value=0.041
0.00
0 1 2 3 4 5 6 7 8
Time (years)

Roché H, et al. Breast Cancer Res Treat. 2004;88 (Suppl 1):S16. Abstract 27.
 PACS 01: DFS by age (ITT)
Age <50 years Age 50 years
1.00 1.00
3FE100C–3T
3FE100C–3T
Kaplan–Meier estimate

0.75 0.75
6FE100C 6FE100C
0.50 0.50
Log-rank p value=0.690 Log-rank p value=0.001
HR (Cox model)=0.98 [0.77–1.25] HR (Cox model)=0.67 [0.51–0.88]

0.25 0.25
Multivariate interaction test
HR=0.66 [0.46–0.95] p value=0.026
0.00 0.00
0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8
Survival time (years) Survival time (years)

Roché H, et al. Breast Cancer Res Treat. 2004;88 (Suppl 1):S16. Abstract 27.
PACS 01: disease free survival by
hazard ratio
3FE100C–3T better 6FE100C better
Age ≥50 years (n=994)
<50 years (n=1004)
Number of positive nodes
≥4 (n=762)
1–3 (n=1236)
Pathological tumour size
≥20 mm (n=1154)
<20 mm (n=673)
Hormone receptor status
HR-negative (n=413)
HR-positive (n=1560)
SBR grade
SBR III (n=773)
SBR II (n=868)
SBR I (n=228)
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6
Hazard ratio with 95% CI
Roché H, et al. SABCS 2004, Abstr. 27.
 PACS 01: overall survival (ITT)
1.00 3FE100C–3T 90.7%

Death=235
100 (10.0%)
Cumulative probability

0.75
135 (13.5%) 6FE100C 86.7%

0.50

0.25 Log-rank unadjusted p value=0.013

Log-rank adjusted p value=0.017
HR (Cox model)=0.77 [0.59–1.00], p value=0.050
0.00
0 1 2 3 4 5 6 7 8
Time (years)

Roché H, et al. SABCS 2004, Abstr. 27.

Conclusions PACS 01 .
 This regimen is easily feasible without systematic
antibiotic and/or G-CSF prophylaxis
 Use of G-CSF in the 3FE100C–3T arm is decreased
by 50% compared with the 6FE100C arm
 Specific toxicity related to Taxotere® is easily
manageable
 Risks of acute and delayed cardiac events are
reduced by the 50% less exposure to anthracyclines
Reported Clinical Trials Evaluating Sequential Anthra.-Taxanes
Study N Regimen Outcome (5-year)
DFS(%) OS(%)
CALGB9344 3121 AC x 4 65 77
AC + P x 4 70 80
NSABP B28 3060 AC x 4 72 85

AC x 4→P x 4 76 85

GEICAM9906 1248 FEC x 6 79 92

FEC x 4→ P x 8 85 94
PACS01 1999 FEC x 6 73 87
FEC x 3→D x 3 78 91
BIG 02-98 2887 A x 4→ CMF x 3 HR=0.79 NR
A x 3→ D x 3 → CMF x 3 p= .035 NR
AC x 4 → CMF x 3 -- --
AD x 4 → CMF x 3 -- --
Taxit216 972 E→ CMF HR=0.79 HR=0.72
p=.08 p=.08
E→D→CMF
E1199 4950 AC→P q3wk 77 87
AC→P qwk 82 90
AC→D q3wk 81 87
AC→D qwk 78 86