Current Situation of Breast Cancer Current Situation of Breast Cancer Treatment in USTreatment in US

Stefan Glück MD PhDProfessor of Medicine

Clinical DirectorBraman Family Breast Cancer Institute

UMSylvester Comprehensive Cancer CenterUniversity of Miami, Miller School of Medicine

Available Regimens Available Regimens (Level I Evidence)(Level I Evidence)

~Equivalent Regimens CMF AC CAF FEC50

Study Bonadonna NSABP-B15, 23 SECSG, Spain ICCG

ImprovementCEF120

(E - CMF)AC - T

DD TAC FEC100

RR ~20-35% ~30% ~20% ~30%

Study NCIC MA.05 CALGB9741 BCIRG001 FASG05

Further Improvement

DD EC - T DD AC - TG E-T-C DD and DI

FEC100 Doc

Study NCIC MA.21 NSABP-B38 AGO PACS01

+ TAM if >50 yrs.

AC x 4

Operable Breast Cancer

Stratification• Age• Clinical Tumor Size• Clinical Nodal Status

Operation

+ TAM if >50 yrs.

AC x 4

Operation

NSABP B-18: Trial DesignNSABP B-18: Trial Design

Fisher et al. J Clin Oncol. 1998;16(8):2672-2685.

NSABP B-18 NSABP B-18 ConclusionsConclusionsSurvival benefit was equivalent for pre-operative or

post-operative therapy

pCR correlates with a significant increase in disease free survival (p=0.00005) and overall survival (p=0.0008)

Pre-operative chemotherapy increases the rate of breast conserving surgeries

Primary OutcomesPrimary Outcomes

Neoadjuvant vs Neoadjuvant vs adjuvant therapyadjuvant therapy

NSummary risk ratio % (95% NSummary risk ratio % (95% CI), random effects analysisCI), random effects analysis pp-value-value

DeathDeath 1.0 (0.90-1.12)1.0 (0.90-1.12) ––

Disease progressionDisease progression 0.99 (0.88-1.11)0.99 (0.88-1.11) ––

Distant recurrencesDistant recurrences 0.94 (0.83-1.06)0.94 (0.83-1.06) ––

Locoregional Locoregional recurrencesrecurrences 1.22 (1.03-1.44)1.22 (1.03-1.44) 0.0180.018

Mauri D et al. J Natl Cancer Inst 2005;97(3):188-94.

NSABP B-27: DesignNSABP B-27: Design

Operable Breast Cancer

Randomization

Surgery

Surgery

Surgery

AC X 4Tam X 5 yrs

AC X 4Tam X 5 yrs

AC X 4Tam X 5 yrs

Docetaxel X 4

Docetaxel X 4

I II IIIBear et al. Breast Cancer Res Treat. 2004;88(Suppl 1):S16. Abstract 26.

NSABP B-27: Pathologic NSABP B-27: Pathologic Complete Responses in Complete Responses in

BreastBreast

9.1

18.9

9.9

3.7

7.2

4.4

02468

101214161820

Grp. I Grp. II Grp. III

No tumor

DCIS only

Per

cen

tag

e (

% )

*P < 0.001 for test of heterogeneity across groups

(n=764) (n=767)

12.8%*

26.1%*

14.3%*

(n=775)

Bear et al. Breast Cancer Res Treat. 2004;88(Suppl 1):S16. Abstract 26.

NSABP B-27: Overall SurvivalNSABP B-27: Overall SurvivalpCR versus non-pCR PatientspCR versus non-pCR Patients

% S

urv

ivin

g

Years after surgery

Treatment N DeathsNon pCR 1899 396pCR 409 31 HR=0.33 P<0.0001

Bear et al. Breast Cancer Res Treat. 2004;88(Suppl 1):S16. Abstract 26.

40

50

60

70

80

90

100

0 1 2 3 4 5

ErbB Family of Tyrosine Kinase ErbB Family of Tyrosine Kinase ReceptorsReceptors

Family of evolutionarily conserved type Family of evolutionarily conserved type I receptor tyrosine kinasesI receptor tyrosine kinases

Four members:Four members:

– ErbB-1 (EGFR/HER1)ErbB-1 (EGFR/HER1)

– ErbB-2 (HER2)ErbB-2 (HER2)

– ErbB-3 (HER3)ErbB-3 (HER3)

– ErbB-4 (HER4)ErbB-4 (HER4)

Extracellular Domain(Binds Ligand)

TMDomain

Cytoplasmic Domain(Kinase Activity)

ErbB-2 or HER2 ErbB-2 or HER2

Also known as HER2/Also known as HER2/neuneu

No known ligandsNo known ligands

Activation thought to occur through Activation thought to occur through heterodimerization with other ErbB family heterodimerization with other ErbB family membersmembers

ErbB-2 is the preferred heterodimerization ErbB-2 is the preferred heterodimerization partner with other family memberspartner with other family members

Most resistant to intracellular degradation, Most resistant to intracellular degradation, slower to inactivate compared to other slower to inactivate compared to other family membersfamily members

ErbB-2 overexpression in tumors correlates ErbB-2 overexpression in tumors correlates with poor prognosis and decreased survival with poor prognosis and decreased survival timestimes

Poorer Survival of Patients With Poorer Survival of Patients With HER2+ Primary Breast CancerHER2+ Primary Breast Cancer

0 2 4 6 8 10 12 14 16Years

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0P

rop

ort

ion

su

rviv

ing

P<0.0001

HER2–

HER2+

0

0.1

Witton et al. J Pathol. 2003;200:290.

N=220 (majority >1 cm); all patients received standard therapy

4 cycles

4 cycles

Dox/Cyc

Pax HD q 3 wk

Trastuzumab

Pax HD q 3 wk

4 cycles

4 cycles 52 wksNSABP B-31

NCCTG 9831

Dox/Cyc

Pax LD/wk

Trastuzumab

Pax LD/wk Trastuzumab

Pax LD/wk

12 wks 52 wks 64 wks

HERA

Trastuzumab

No therapy

StandardChemoRx

1 Yr 2 Yr

BCIRG 006

Dox/Cyc

4 cyclesDocetaxel

Docetaxel

Trastuzumab

Docetaxel

Carboplatin

Trastuzumab

Trastuzumab

Summary of Adjuvant Trastuzumab Summary of Adjuvant Trastuzumab TrialsTrials

Combined Analysis: Overall Combined Analysis: Overall SurvivalSurvival

ACACTHTH94%94%

91%91%

87%

92%ACT

N DeathsACT 1679 92ACTH 1672 62

HR=0.67, 2P=0.015

Years From Randomization B31/N9831

Complexity of HER SignalingComplexity of HER Signaling

Adapted from Yarden and Sliwkowski. Nat Rev Mol Cell Biol. 2001;2:127.

MycSp1Jun

Fos Elk Egr1 Stat

MigrationApoptosis Growth Adhesion Differentiation

SrcCbl

PLCPI(3)K Shp2 GAP

Shc

Nck Vav Grb7Crk

Jak

Grb2

Sos Rac

Transcription factors

Cascades

Adaptors andenzymes

Receptor dimers

Ligands

Signal-processing layer

Input layer

Output layer

Ras-GDP

Ras-GDP

PKC Bad

AktS6K

RAFMER

MAPK

PAK

AblJNKKJNK

LPA, thrombin, ET, etc

TGF(1)

EGF(1)

Epiregulin(1,4)

-cellulin(1)

HB-EGF(1,4)

Amphi-regulin

(1)

NRG1(3,4)

NRG2(4)

NRG3(4)

CytokinesNRG4

(4)

Multiple pathway interactions (eg, ER)

Summary and Summary and ConclusionConclusion There is increased clarity regarding adjuvant treatment of node-positive There is increased clarity regarding adjuvant treatment of node-positive

breast cancerbreast cancer

– Use of an anthracycline and taxane is a standard if not Use of an anthracycline and taxane is a standard if not THETHE standard standard

– Adjuvant trastuzumab improves outcomes and became standardAdjuvant trastuzumab improves outcomes and became standard

Neoadjuvant treatment is the treatment of choice for patients with locally Neoadjuvant treatment is the treatment of choice for patients with locally advanced breast cancer, and a resonable option for patients with operable advanced breast cancer, and a resonable option for patients with operable breast cancerbreast cancer

Novel combinations hold promise for improving outcomes for women in Novel combinations hold promise for improving outcomes for women in high risk settingshigh risk settings

Genomic data and DNA microarray analysis will gain increasing importance Genomic data and DNA microarray analysis will gain increasing importance in clinical investigation as well as clinical management of breast cancerin clinical investigation as well as clinical management of breast cancer