role of anthracycline in the therapy of breast

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

Period Combination Regimens Risk Reduction

1970–1980 CMF-basedOral CMF

IV CMF26%

1980–1995Anthracycline-based

FAC x 6 FEC x 6 AC x 4 (USA)

30%

1995–Anthracyline and taxane-based

TAC x 6

3 FEC 3 T

AC x 4 P x 4 (q3w)

AC x 4 P q wk

25-30%

Early-Stage Breast Cancer Evolution

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

Stephen E. Jones, MDBaylor-Sammons Cancer Center, Dallas, TX

US Oncology Research, Houston, Texas

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1.

Agenda2.ppt

US Oncology 9735:

Study Design

• N=1016

• 71% ER+

• 48% N–

AC x 4 q3w

Doxorubicin (60 mg/m2)

Cyclophosphamide (600 mg/m2)

n=510

TC x 4 q3w

Taxotere (75 mg/m2)

Cyclophosphamide (600 mg/m2)

n=506

Eligibility: Stage I, II, or III disease

R

Jones et al. J Clin Oncol. 2006;24:5381-5387.

Chemotherapy doses based on actual

BSA (no cap)

Chemotherapy given prior to radiation

Tamoxifen for all ER+ patients after

chemotherapy +/- radiation

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 anthracyclinesto 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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Agenda2.ppt

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 AC60/600 mg/m2

4 x Taxotere100 mg/m2

6 x Taxotere and Carboplatin75 mg/m2 AUC 6

1 Year Trastuzumab

N=3222

1 Year Trastuzumab

ACT

ACTH

TCH

HER2+(Central FISH)

N+

or high

risk N-

4 x AC60/600 mg/m2

4 x Taxotere100 mg/m2

Stratified by Nodes

and Hormonal

Receptor Status

DFS Subpopulations

1.00.0 2.0

AC-TH

better

AC-T

better

Subgroup

Node neg

Node pos

HR -

HR +

T size <2cm

T size ≥2cm

AC-TH vs AC-T

1.00.0 2.0

Subgroup

Node neg

Node pos

HR -

HR +

T size <2cm

T size ≥2cm

TCH vs AC-T

TCH

better

AC-T

better

Slamon et al. SABCS 2006. Abstract 52.

Overall Survival Subpopulations

1.00.0 2.0

AC-TH

better

AC-T

better

Subgroup

Node neg

Node pos

HR -

HR +

T size <2cm

T size ≥2cm

AC-TH vs AC-T

1.00.0 2.0

Subgroup

Node neg

Node pos

HR -

HR +

T size <2cm

T size ≥2cm

TCH vs AC-T

TCH

better

AC-T

better


BCIRG 006: Cardiac Deaths and

CHF

AC-T

n=1050

AC-TH

n=1068

TCH

n=1056

Cardiac-related death 0 0 0

Cardiac left ventricular

function (CHF) Grade 3-4 4 20 4

p=.0015

Second Interim Analysis, per Independent Review


BCIRG 006: >10% Relative LVEF

Decline

AC-T

n=1014

AC-TH

n=1042

TCH

n=1030

Patients 102 189 89

% 10 18 8.6

p<0.0001 p<.0001

p=.5


Second Interim Analysis

BCIRG 006: Mean LVEF - All Observations

58

59

60

61

62

63

64

65

66

0

LV

EF

Po

ints

%

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


Second Interim Analysis

BCIRG 006: Therapeutic Index

Most Recent Data n=3222

In addition, 23 patients randomized to AC-TH never received trastuzumab due to LVEF decline following doxorubicin

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.


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


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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Agenda2.ppt

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


Disease Free Survival by Treatment

CEF

CMF

Probability(%)

40

60

80

100

CEF

CMF

0 10

Probability(%)

40

60

80

100

5

Time (years)

Over-expression of topo proteinp-value=0.01

Normal expression of topo proteinp-value=0.6

0 5 10

Disease Free Survival

Test for interaction chi2 = 13.7 p < 0.001

non anthra better

0.34 - 0.800.71 - 1.17

0.520.91NCIC MA-5

0.61 - 0.830.90 - 1.11

0.53 - 1.06 0.60 - 1.05

0.46 - 1.490.91 - 1.64

0.65 - 1.080.86 - 1.20

0.44 - 0.820.75 - 1.23

0.711.00Overall

0.750.79DBCCG-89-D

0.831.22Milan

0.34 - 1.270.93 - 1.97

0.651.35Brussels

NSABP B15

0.600.96

NSABP B11

0.841.02

heterogeneity c25 = 5.3, p = 0.38heterogeneity c25 = 7.6, p = 0.18

Study HR 95% CI anthra better

0.6 1 2 50.4

p < 0.0001

p = 1.0

0.9

HER2 positive

HER2 negative

A.Gennari, et.al. JNCI, 2008, 100

0.82 - 0.980.90Total p = 0.01

Topo IIa, HER2, and Anthracycline

Sensitivity in Breast Cancers:

Rational Therapeutic Implications

Dennis J. Slamon, MD, PhDUniversity of California at Los Angeles, USA

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Agenda2.ppt

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?

van Dalen EC et al. Cochrane Database Syst Rev 2006

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

Ryberg et al. J Clin Oncol. 2007;25:39s ;1029 (abstr)

Outcome: Clinical Heart Failure

Cardiotoxicity

0

10

20

30

40

50

60

70

80

90

100

Ewer et al. J Card Fail. 2005;11

Mathematical Curve% CHF = X2/Y

X=n cycles chemotherapy

Y

Doxorubicin 50 mg/m2 16

Doxorubicin 60 mg/m2 11.5

Epirubicin 90 mg/m2 20

600 700 800 900

Von Hoff

Cumulative Doxorubicin Dosage (mg/m2)

MD Anderson

5004003002001000

Anthracycline-Associated Heart Failure

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

Risk Factors for Anthracycline-Associated

Cardiotoxicity

0

10

20

30

40

50

60

70

80

90

100

0 100 200 300 400 500 600 700 800 900

MD Anderson

Von Hoff

CH

F (

%)

Doxorubicin Cumulative Dose (mg/m2)

• Cumulative dose of doxorubicin

• Combination chemotherapy

• Prior/concomitant mediastinal radiotherapy

• Age

• Previous cardiac disease

• Hypertension

Anthracycline Cardiotoxicity: How to prevent?

Dexrazoxane (Zinecard)

Antioxidants

Bolus vs Continuous Infusion

Shapira et al. Cancer 1990; 65: 870-873

Liposomal Doxorubicin

O’Brien et al. : Ann Oncol. 2004;15:440-9

Anthracyclines Cardiotoxicity

Incidence and Age

Swain et al. Cancer. 2003,97:2869.

B B B B BB B B B

B

B

B

B B B B

J J J J J J JJ

JJ

J J J J J J

100 200 300 400 500 600 700 8000

10

20

30

40

50

60

70

80

90

100

Do

xo

rub

icin

Re

late

d C

HF

(%

)

Cumulative Dose of Doxorubicin (mg/m2)

B < 65 years

J > 65 years

HR 2.25 (1.04, 4.96)

p=.029

Trastuzumab Cardiotoxicity:

Risk Factors

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

Anthracyclines

Type I Cardiotoxicity

(myocardial damage)

Trastuzumab

Type II Cardiotoxicity

(myocardial dysfunction)

Combination chemotherapy Prior/concomitant

anthracyclines

Prior/concomitant

mediastinal radiotherapy

Age > 70 Age > 50 years

Previous cardiac disease Previous cardiac disease

Hypertension Hyperlipidemia

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. SuterSwiss Cardiovascular Center, Bern, Switzerland

PACS 01: treatment protocol

S

U

R

G

E

R

Y

R

6FE100C

Fluorouracil 500 mg/m² d1

Epirubicin 100 mg/m² d1

Cyclophosphamide 500 mg/m² d1

6 cycles q21d

3FE100C–3Taxotere®

3 cycles of FEC 100 mg/m2 q21d

followed by

3 cycles of Taxotere® 100 mg/m² d1

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

Stratified by:

Centre

Age: <50; ≥50 y

Nodes: 1–3; ≥4

N=1999

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


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

PACS 01: events, ITTPatients % 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


PACS 01: 5-year DFS (ITT)

0.00

0.25

0.50

0.75

1.00

0 1 2 3 4 5 6 7 8

3FE100C–3T 78.3%

6FE100C 73.2%

Cum

ula

tive p

robabili

ty

Time (years)

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


Relapses=482

218 (21.7%)

264 (26.5%)

PACS 01: DFS by age (ITT)Age 50 yearsAge <50 years

Kapla

n–

Meie

r estim

ate

Log-rank p value=0.690

HR (Cox model)=0.98 [0.77–1.25]

0.00

0.25

0.50

0.75

Survival time (years)

0 1 2 3 4 5 6 7 8

6FE100C

3FE100C–3T

1.00

Log-rank p value=0.001

HR (Cox model)=0.67 [0.51–0.88]

0.00

0.25

0.50

0.75

1.00

Survival time (years)

0 1 2 3 4 5 6 7 8

6FE100C

3FE100C–3T

Multivariate interaction test

HR=0.66 [0.46–0.95] p value=0.026


PACS 01: disease free survival by

hazard ratio

3FE100C–3T better 6FE100C better

SBR I (n=228)

SBR II (n=868)

SBR III (n=773)

SBR grade

HR-positive (n=1560)

HR-negative (n=413)

Hormone receptor status

<20 mm (n=673)

≥20 mm (n=1154)

Pathological tumour size

1–3 (n=1236)

≥4 (n=762)

Number of positive nodes

<50 years (n=1004)

≥50 years (n=994)Age

Hazard ratio with 95% CI

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

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

PACS 01: overall survival (ITT)

Cum

ula

tive p

robabili

ty

Time (years)

3FE100C–3T 90.7%

6FE100C 86.7%

0.00

0.25

0.50

0.75

1.00

0 1 2 3 4 5 6 7 8

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

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

Death=235

100 (10.0%)

135 (13.5%)

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

Taxit216 972 E→ CMF HR=0.79

p=.08

HR=0.72

p=.08E→D→CMF

E1199 4950 AC→P q3wk 77 87

AC→P qwk 82 90

AC→D q3wk 81 87

AC→D qwk 78 86

BIG 02-98 2887 A x 4→ CMF x 3

A x 3→ D x 3 → CMF x 3

AC x 4 → CMF x 3

AD x 4 → CMF x 3

HR=0.79

p= .035NR

NR

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role of anthracycline in the therapy of breast

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