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Current Situation of Breast Cancer Treatment in US. Stefan Glück MD PhD Professor of Medicine Clinical Director Braman Family Breast Cancer Institute UMSylvester Comprehensive Cancer Center University of Miami, Miller School of Medicine.

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Current Situation of Breast Cancer Treatment in US


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current situation of breast cancer treatment in us

Current Situation of Breast Cancer Treatment in US

Stefan Glück MD PhD

Professor of Medicine

Clinical Director

Braman Family Breast Cancer Institute

UMSylvester Comprehensive Cancer Center

University of Miami, Miller School of Medicine

nsabp b 18 trial design

AC x 4

+ TAM if >50 yrs.

NSABP B-18: Trial Design

Operable Breast Cancer

Stratification

• Age

• Clinical Tumor Size

• Clinical Nodal Status

Operation

AC x 4

+ TAM if >50 yrs.

Operation

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

nsabp b 18 conclusions
NSABP B-18 Conclusions
  • Survival 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 outcomes
Primary Outcomes

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

nsabp b 27 design
NSABP B-27: Design

Operable Breast Cancer

Randomization

AC X 4

Tam X 5 yrs

AC X 4

Tam X 5 yrs

AC X 4

Tam X 5 yrs

Surgery

Docetaxel X 4

Surgery

Docetaxel X 4

Surgery

I

II

III

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

nsabp b 27 pathologic complete responses in breast
NSABP B-27: Pathologic Complete Responses in Breast

26.1%*

14.3%*

12.8%*

Percentage ( % )

(n=764)

(n=767)

(n=775)

*P < 0.001 for test of heterogeneity across groups

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

nsabp b 27 overall survival pcr versus non pcr patients
NSABP B-27: Overall SurvivalpCR versus non-pCR Patients

100

90

80

% Surviving

70

Treatment N Deaths

Non pCR 1899 396

pCR 409 31 HR=0.33 P<0.0001

60

50

40

0

1

2

3

4

5

Years after surgery

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

erbb family of tyrosine kinase receptors
ErbB Family of Tyrosine Kinase Receptors

Extracellular Domain

(Binds Ligand)

  • Family of evolutionarily conserved type I receptor tyrosine kinases
  • Four members:
    • ErbB-1 (EGFR/HER1)
    • ErbB-2 (HER2)
    • ErbB-3 (HER3)
    • ErbB-4 (HER4)

TM

Domain

Cytoplasmic Domain

(Kinase Activity)

erbb 2 or her2
ErbB-2 or HER2
  • Also known as HER2/neu
  • No known ligands
  • Activation thought to occur through heterodimerization with other ErbB family members
  • ErbB-2 is the preferred heterodimerization partner with other family members
  • Most resistant to intracellular degradation, slower to inactivate compared to other family members
  • ErbB-2 overexpression in tumors correlates with poor prognosis and decreased survival times
poorer survival of patients with her2 primary breast cancer
Poorer Survival of Patients With HER2+ Primary Breast Cancer

1.0

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

0.9

0.8

0.7

0.6

HER2–

Proportion surviving

0.5

0.4

0.3

HER2+

0.2

P<0.0001

0.1

0

0

2

4

6

8

10

12

14

16

Years

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

summary of adjuvant trastuzumab trials
Summary of Adjuvant Trastuzumab Trials

NSABP B-31

HERA

52 wks

1 Yr

2 Yr

4 cycles

Pax HD q 3 wk

4 cycles

No therapy

Trastuzumab

Standard

ChemoRx

Dox/Cyc

Trastuzumab

4 cycles

Pax HD q 3 wk

Trastuzumab

BCIRG 006

NCCTG 9831

52 wks

12 wks

64 wks

Docetaxel

4 cycles

Trastuzumab

Pax LD/wk

Dox/Cyc

Docetaxel

Trastuzumab

4 cycles

Docetaxel

Dox/Cyc

Trastuzumab

Pax LD/wk

Carboplatin

Pax LD/wk

Trastuzumab

combined analysis overall survival
Combined Analysis: Overall Survival

ACTH

94%

91%

ACT

92%

87%

N Deaths

ACT 1679 92

ACTH 1672 62

HR=0.67, 2P=0.015

Years From Randomization

B31/N9831

complexity of her signaling

Ras-GDP

Ras-GDP

RAF

PAK

Akt

MER

JNKK

PKC

S6K

Abl

Bad

MAPK

JNK

Complexity of HERSignaling

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)

NRG4(4)

Cytokines

Ligands

Input layer

Receptor dimers

Adaptors andenzymes

Src

Jak

Cbl

Shc

Crk

PLC

Grb7

PI(3)K

Vav

Shp2

Grb2

Nck

GAP

Sos

Rac

Signal-processing layer

Cascades

Multiple pathway interactions (eg, ER)

Jun

Transcription factors

Sp1

Myc

Fos

Elk

Egr1

Stat

Output layer

Apoptosis

Migration

Growth

Adhesion

Differentiation

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

summary and conclusion
Summary and Conclusion
  • There is increased clarity regarding adjuvant treatment of node-positive breast cancer
    • Use of an anthracycline and taxane is a standard if not THE standard
    • Adjuvant trastuzumab improves outcomes and became standard
  • Neoadjuvant treatment is the treatment of choice for patients with locally advanced breast cancer, and a resonable option for patients with operable breast cancer
  • Novel combinations hold promise for improving outcomes for women in high risk settings
  • Genomic data and DNA microarray analysis will gain increasing importance in clinical investigation as well as clinical management of breast cancer