Nadia HarbeckBreast Center

University of Cologne, Germany

Evidence in Favor of Taxane Based Combinationsand No Anthracycline in Adjuvant and Metastatic

Settings

Evidence in Favor of Taxane Based Combinations and No Anthracycline in Adjuvant and Metastatic Settings

Evidence in Favor of Taxane Based Combinations and No Anthracycline in Adjuvant and Metastatic Settings

Personal Bias: To date, anthracycline-free chemotherapy NOT sufficientlyevaluated in order to replace our current standards in all patients

YESNONOT YET

Open questions

Consider different therapeutic goals: early Breast cancer: cure mBC: quality of life and prolongation of life

Early BC: anthracycline-free regimens sufficient independent of risk ?

Predictive factor(s) for anthracycline benefit – ready to use forclinical practice ?

…

Anthracyclines in breast cancer: Clinical concerns

Anthracyclines: Longterm toxicity*

* Data of the French Adjuvant Study Group (FASG), modified after M. Piccart, St. Gallen 2003

Cardiotoxicitysymptomatic LV - dysfunction

1.36%

0.2%

Risk factors• Age > 65 years• adipositas

p=0.004

n = 3577, follow-up 7 years(adjuvant epirubicin: n=2553)

n = 3633, follow-up 8 years(adjuvant epirubicin**: n=2589)

Secondary leucemia

N=7 0.3%

N=1 0.1%

** mainly FEC (50,75 oder 100) cumulative doses < 600mg/m2

no G-CSF support

Epi

no Epi

Epi

no Epi

CAF

none

AnnualCM incidence

CumulativeCM incidence

Anthracyclines in breast cancer: Clinical data

CMF

No CT19703.6% OS improvement

ANTHRACYCLINES19804.5% OS improvement

TAXANES

20006% OS improvement

Adjuvant Chemotherapy in Breast Cancer and Survival Improvements: Step by Step

CT + TT (trastuzumab)

6% OS improvement2006

heterogeneity c25 = 5.2, p = 0.39heterogeneity c25 = 5.5, p = 0.36

Test for interaction chi2 = 12.0,  p  < 0.001

non-anthra betteranthra better

0.6 1 2 50.4

p < 0.0001p = 0.86

0.9

A. Gennari , J Natl Cancer Inst. 2008;100:14‐20

p = 0.056

Study HR 95% CI

0.47 - 0.92NSABP B11

0.63 - 1.06NSABP B15

0.27 - 2.69GUN 3

0.32 - 1.16Milan

0.50 - 1.05DBCG-89-D

0.42 - 1.01NCIC MA-5

0.62 - 0.85Overall

0.83 - 1.00Total

0.69 - 1.18 0.90

1.07 0.88 - 1.30

1.64 0.85 - 3.15

0.610.89 - 1.79

0.82 0.59 - 1.13

1.06 0.80 - 1.40

1.03 0.92 - 1.16

0.66

0.82

0.85

1.260.73

0.65

0.910.73

HER2+ve HER2-ve

Overall survivalMeta-analysis of pts with known HER2 status received an anthracycline vs non-

anthracycline regimen

aBased on small subgroups of patients with HER2-positive breast cancer; bdistant DFSAC, doxorubicin, cyclophosphamide; P, paclitaxel; T, docetaxel; Carbo, carboplatin; V, vinorelbine; CEF, cyclophosphamide, epirubicin, 5-fluorouracil

Several studies demonstrate consistent DFS benefit for 1-year adjuvant Herceptin

3

4

5

4

3

3

Median follow-up, yearsDFS benefit

B-31 / N9831 ACPH

HERA CTxH 1 year

FinHera VH / THCEFb

PACS-04a CTxH 1 year

BCIRG 006 ACTH

TCarboH

n=231

n=528

NOAH CTx / HH 1 year 3

0 1 2FavoursHerceptin

Favours noHerceptinHR

Gianni et al 2009; Perez et al 2007;

Slamon et al 2006; Gianni et al 2008;

Joensuu et al 2009; Spielmann et al 2007

Design

OP

OP

CoreCore biopsybiopsy::uni/bilateral uni/bilateral cT2cT2--44cN0cN0--33sizesize 2 cm*2 cm*

DocetaxelDocetaxelAdriamycinAdriamycinCyclophosphamideCyclophosphamide+G+G--CSFCSF

NCNC

CR/CR/PRPR

OP

OP

TAC

Pal

patio

nP

alpa

tion

//so

nogr

aphy

sono

grap

hy

NX

TAC

TAC x 8

TAC x 6

RR

RR

**excludingexcluding lowlow riskrisk (T2 + ER/PR pos. + (T2 + ER/PR pos. + cNOcNO + G1/2 + > 35y.)+ G1/2 + > 35y.)

VinorelbineVinorelbineCapecitabineCapecitabine

NX

n=2090

von Minckwitz et al, SABCS 2006

Conclusions II

• Locally advanced and inflammatory breast cancer show similar

responses and do not need separate neoadjuvant trials.

• Significant predictors for path CR are:– Complete response after 2 cycles (40.7%)

– Triple negative tumors (40.7%)– High grade (37.9%)

– Hormone receptor negativity (33.5%)

– Age < 40 yrs (24.7%)

– Ductal type (17.3%)

von Minckwitz et al, SABCS 2006

Disease-free Survival by Treatment

Jones S, et al. SABCS 2007. Abstract 12.

Disease-free Survival by Treatmentand Age Group

Overall Survival by Treatment

Jones S, et al. SABCS 2007. Abstract 12.

Overall Survival by Treatmentand Age Group

Jones S, et al. SABCS 2007. Abstract 12.

Hematologic Toxicity by Treatment and Age

Adverse Event

< 65 Years ≥ 65 YearsTC

(N=428)AC

(N=428)TC

(N=78)AC

(N=82)Anemia <1 1 <1 5Neutropenia 60 54 52 59Thrombocytopenia <1 1 0 <1Febrile neutropenia 4 2 8 4

Grade 3/4 hematologic toxicities (%)

Jones S, et al. SABCS 2007. Abstract 12.

Anthracyclines in breast cancer: Predictive factors

BCIRG 006: HER2 and TOPO2A Co-amplification

HER2Core region

17 q 12 17 q 21.1 17 q 21.2

Non-Coamplified

Normal Amplified Deletion

TOPO2A region

Coamplified

N=2990

1788 pts (60%)

145 pts (5%)

1057 pts (35%)

2990 of 3222 patients analyzed

Slamon et al. SABCS 2006. Abstract 52.

0.50 1 2 3 4 5

Year From Randomization

0.6

0.7

0.8

0.9

1.0

Patients Events643 146643 87618 92

AC TAC THTCH

P < .001P < .001

83%

91%

90%

78%

85%

84%

71%

83%

81%

DFS Non-Coamplified Topo IIα by Arm: 2nd Interim Analysis

Slamon D, et al. SABCS 2006. Abstract 13.

Patie

nts

Dis

ease

Fre

e (%

)

Patie

nts

Dis

ease

Fre

e (%

)

0.50 1 2 3 4 5

Year From Randomization

0.6

0.7

0.8

0.9

1.095%

87%

89%

Patients Events328 42357 35359 42

AC TAC THTCH

P = .336P = .648

87%

85%83%83%

92%94%

DFS Coamplified Topo IIα by Arm: 2nd Interim Analysis

Slamon D, et al. SABCS 2006. Abstract 13.

HER2, TOP2A and AnthracyclinesRole of Anthracyclines in the Treatment of Early Breast Cancer

Gianni L, et al, J Clin Oncol epub ahead of print August 2009

Several trials show increased benefit for anthracyclines in HER2+ tumors Others show conflicting results Meta-anaylsis suggests DFS benefit for higher dose vs standard dose

anthracycline in HER2+ (not sig) Role of TOP2A as a predictive factor for anthracycline activity unclear Anthracyclines have mechanisms of action other than topoisomerase

inhibition Highly proliferating tumors generally more likely to respond to

chemotherapy TOP2A and HER2 may not be specific enough on their own to

discriminate between cytotoxic agents

© AGO e. V.in der DGGG e.V. sowie in der DKG e.V.

Guidelines BreastVersion 2009.1.0

Predictive Factors – Adjuvant Therapy

Treatment FactorEndocrine therapy ER/PgR Status 1a A ++

HER-2 2b D -Oncotype DXTM 2b B +/-*

Tamoxifen therapy Cyp2D6 polymorphism 2b B +/-*Ovarian ablation menopausal status 1c A ++Aromatase inhib. menopausal status 1c A ++Chemotherapy HER-2 2b D -

ER/PgR status 2a B +/-uPA/PAI-1 2a C +/-Oncotype DXTM 2b B +/-*

HER-2 directed therapies HER-2 2b D ++Anthracyclines Topoisomerase IIα 2ba B -

Oxford / AGO LoE / GR

*Study participation recommended

Furtherinformation

References

Anthracyclines in breast cancer: Current status

Evidence in Favor of Taxane Based Combinations and No Anthracycline in Adjuvant and Metastatic Settings

© AGO e. V.in der DGGG e.V. sowie in der DKG e.V.

Guidelines BreastVersion 2009.1.0

Non-Anthracycline Containing Regimenswithout Trastuzumab*

Equivalent OS efficacy to 4 x A / EC: 6 x CMF 1a A +/-

Superior OS efficacy to 4 x AC : 4 x DC 1ba B +

*Study participation for non-anthracycline regimens recommendedD = Docetaxel; C = Cyclophosphamide

Oxford / AGOLoE / GR

Furtherinformation

References

RANDOMISATION

TC x 6Docetaxel (75 mg/m2) + Cyclophosphamide (600 mg/m2)q3wk x 6

EC x 4 Doc x 4Epirubicin (90 mg/m2) + Cyclophosphamide (600 mg/m2)q3wk x 4 Docetaxel 100 mg/m2 q3w x 4

• HER2-negative breast cancer

• M0• T1-4• R0• adequate axillary

dissection• N+*• N- high risk*

n=2448

PlanB – a-free W S GW S G

*Risk-selection N0 and 1-3 LN: Recurrence Score (vs. uPA/PAI-1)Translational program: uPA/PAI-1 (NNBC-4), anthracycline-response(cooperation with SUCCESS studygroup), CTCs, etc.

© AGO e. V.in der DGGG e.V. sowie in der DKG e.V.

Guidelines BreastVersion 2009.1.0

Adjuvant Treatmentwith Trastuzumab: Schedules

Furtherinformation

References

Simultaneously with paclitaxel / docetaxel after AC / EC 1b B ++ with docetaxel and carboplatin 1ba B +

with anthracyclines 2b B +/- with taxanes dose-dense 2b B +/- with taxanes in other regimes 3ba B +/-

Radiotherapy concurrent with Trastuzumab 2 B +

Oxford / AGOLoE / GR

Evidence-based breast cancer therapy

www.karger.com/brc

AGO (DKG, DGGG) www.ago-online.org

Annually updated, evidence-basedguidelines for diagnosis and treatment

of breast cancer