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Estrogen Receptor and EGFR/HER2 Pathways Cross Talk in Breast Cancer Endocrine Resistance. Rachel Schiff Breast Center Baylor College of Medicine. 2/2003. Endocrine Therapies. Lower E level in tumor. Selective ER modulators; antagonist vs. agonist activity.

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rachel schiff breast center baylor college of medicine

Estrogen Receptor and EGFR/HER2 Pathways Cross Talk in Breast Cancer Endocrine Resistance

Rachel Schiff

Breast Center

Baylor College of Medicine

2/2003

slide2

Endocrine Therapies

  • Lower E level in tumor.
  • Selective ER modulators; antagonist vs. agonist activity.
  • ER modulators with pure antagonist activity.
  • High dose estrogens, progestins, androgens.
slide3

Tamoxifen (SERM)

  • Agonist activity: bone, endometrium, liver, brain (cognitive function), clotting.
  • Antagonist activity: breast, vagina, brain (hot flashes).
  • Breast cancer – treatment benefit:
  • Adjuvant therapy: 50% reduction in recurrence.
  • Metastatic disease: disease control.
  • prevention: 50% reduction.
slide5

Major Problem

  • RESISTANCE
  • De novo
  • Acquired
slide6

ER Function – 2002/3

Classical

E

Coregulators

Activators

Repressors

ER

ER

E

E

Tumor Growth

ER

ER

mRNA

ERE

TARGET GENE

slide7

ER

Fos

Jun

mRNA

ER Function – 2002/3 (con’t)

Non Classical

ER

ERK 1,2

PI3K

AP-1

GROWTH

slide8

ER Function – 2002/3 (con’t)

Growth Factor Crosstalk

P

P

ERSignaling

ER - CoA =

ERK 1,2 Proliferation

AKT Survival

JNK, p38 MAPK Stress, Cytokines

slide9

Breast Tumor Growth

E

ER- CoA

Growth

GF

Stress

slide10

Activation of the EGFR/HER2

Signaling Pathway Leads to

Tamoxifen Resistance

  • Clinical studies
  • HER2 overexpression predicts a poor response to tamoxifen therapy
  • Preclinical studies
  • Overexpression of HER2 or its stimulation by HRG leads to tamoxifen resistance de novo
  • Acquired tamoxifen resistance in MCF-7 cells is associated with EGFR overexpression
slide11

De novo Tam-R

Tam-S

Tam-R

MCF7

MCF7/HER2

In vivo Model of Endocrine Resistance

Ovx Athymic Mice

Tumor

volume

(mm3)

1200

E2

1000

800

600

Tam

400

200

0

0

21

49

77

105

Days

(Benz, et al., Breast Cancer Res Treat, 1992)

slide12

Agonist activity

GF

ER-GF Cross-Talk and CoAs in and the

Agonist/ Antagonist Activity of Tamoxifen

CoR

Antagonist activity

P

E2

ER

CoA

slide13

Agonist activity

ER-GF Cross-Talk and CoAsin the

Agonist/ Antagonist Activity of Tamoxifen

CoR

Antagonist activity

P

Tam

ER

CoA

slide14

P

P

HER-2

Genomic

Non-genomic

ER-GF Cross-Talk and CoAsin the

Agonist/ Antagonist Activity of Tamoxifen

CoR

Antagonist activity

P

Tam

ER

CoA

Agonist activity

slide16

Tam

ER- CoA

Breast Tumor Endocrine Resistance

+

EGFR/HER2

slide17

Tam

Hormonal Resistance

ER- CoA

Tumor Growth

Breast Tumor Endocrine Resistance

+

EGFR/HER2

slide18

Hypothesis (1)

Coactivators

Corepressors

ER

Agonist

Antagonist

Tamoxifen

GF Signaling

Tumors with high levels of

HER2andcoactivators

should be relatively resistant to tamoxifen

slide19

AIB1 / SRC-3

  • CoA in SRC family.
  • Binds ER; augments ER signaling.
  • Overexpressed in 65% breast cancer.
  • Amplified in 5-10%.
  • Phosphorylated (activated) by ERK1/2, JNK, p38.
  •  tam agonist activity.
slide20

AIB1 and Tamoxifen Benefit in the Adjuvant Setting

  • 316 patients, primary breast ca, N+
  • -119 no adjuvant systemic therapy
      • -187 adjuvant tamoxifen
      • -median follow-up 8 years
  • Western blot analyses for AIB1
  • Correlated with patient and tumor variables HER-2
  • Effect on DFS
slide21

AIB1 and DFS

No Adjuvant Therapy

Tamoxifen Adjuvant Therapy

1.00

1.00

0.75

0.75

Low

High

n=141

n = 29

Proportion DFS

0.50

0.50

High

n=46

0.25

0.25

Low

n = 90

0.00

0.00

0

20

40

60

80

100

120

0

20

40

60

80

100

120

Time in months

Time in months

p-value=0.018

p-value=0.22

Osborne et al. ASCO 2002

slide22

AIB1 / HER-2 and DFS Tamoxifen Adjuvant Therapy

1.00

0.75

All others

Proportion DFS

0.50

n = 162

0.25

AIB1 high / HER2 high

n = 25

p-value=0.0024

0.00

0

20

40

60

80

100

120

Time in months

slide23

Summary

  • AIB1 with HER-2, is a strong predictive marker of tam resistance.
  • Blocking GF pathways and/or AIB1 may reverse tam resistance.
slide24

Tam

Hormonal Resistance

ER- CoA

Tumor Growth

Breast Tumor Endocrine Resistance

+

EGFR/HER2

slide25

Iressa (ZD1839, Gefitinib)

  • Selective EGFR tyrosine kinase inhibitor
  • Blocks EGFR and HER2 signaling

Hypothesis (2):

Iressa can block tamoxifen- stimulated growth of HER2 overexpressing tumors by eliminating the cross-talk that causes tamoxifen’s agonist activity

slide26

De novo Tam-R

Tam-S

Tam-R

MCF7

MCF7/HER2

In vivo model of endocrine resistance

Tumor

volume

(mm3)

1200

1000

800

600

Tam

400

200

0

0

21

49

77

105

Days

(Benz, et al., Breast Cancer Res Treat, 1992)

slide28

Experimental design

(Endocrine sensitivity of HER2+ tumors)

E2

Randomize

E2

_E2

TAM

MCF-7 HER2

endocrine sensitivity of her2 tumors
Endocrine sensitivity of HER2 tumors

1400

1200

E2

1000

800

Tumor volume

600

400

200

0

1 30 60 90 120

Days

endocrine sensitivity of her2 tumors1
Endocrine sensitivity of HER2 tumors

1400

1200

E2

1000

800

Tumor volume

600

400

-E2

200

0

1 30 60 90 120

Days

endocrine sensitivity of her2 tumors2
Endocrine sensitivity of HER2+ tumors

1400

1200

TAM

E2

1000

800

Tumor volume

600

400

-E2

200

0

1 30 60 90 120

Days

slide32

Response to letrozole and tamoxifen in the neoadjuvant setting

EGFR/HER2EGFR/HER2

_+

Letrozole 54% 88%

Tamoxifen 42% 21%

Ellis et al., J Clin Oncol. (2001) 19 3808-16

slide33

Experimental design

(Iressa effect on endocrine treatment of HER2+ tumors)

Iressa

+

E2

-

Randomize

E2

+

_E2

-

+

TAM

-

MCF-7 HER2

slide34

Iressa effect on endocrine treatment of HER2 tumors

1400

1200

E2

1000

E2+Iressa

800

Tumor volume

600

400

200

0

1 30 60 90 120

Days

slide35

Iressa effect on endocrine treatment of HER2 tumors

1400

1200

TAM

E2

1000

E2+Iressa

800

Tumor volume

600

400

TAM+Iressa

200

0

1 30 60 90 120

Days

slide36

Iressa effect on endocrine treatment of HER2 tumors

1400

1200

TAM

E2

1000

E2+Iressa

800

Tumor volume

600

400

TAM+Iressa

200

0

1 30 60 90 120

Days

slide37

Iressa effect on endocrine treatment of HER2 tumors

1400

1200

E2

1000

E2+Iressa

800

Tumor volume

600

- E2

400

-E2+Iressa

200

0

1 30 60 90 120

Days

slide38

Hypothesis (3):

Targeting the EGFR/HER2 pathway will delay the development of acquired resistance to tamoxifen in tumors with normal levels of EGFR/HER2.

Tam-S

Tumor

volume

(mm3)

Tam-R

1200

1000

800

Tam

600

400

200

0

0

21

49

77

105

Days

slide39

-

-

-

Experimental Design

(Iressa and endocrine treatment of MCF-7 tumors)

Iressa

E2

+

Randomize

E2

+

_E2

TAM

+

MCF-7

iressa effect on e2 stimulated mcf 7 xenografts
Iressa Effect on E2-StimulatedMCF-7 Xenografts

1400

1200

E2+ Iressa

E2

1000

800

Tumor volume

600

400

200

0

0

14

28

42

56

70

84

98

112

126

140

154

168

182

196

210

Days

zd1839 effect on tamoxifen therapy in mcf 7 xenografts
ZD1839 Effect on Tamoxifen Therapy in MCF-7 Xenografts

1400

1200

E2+ Iressa

TAM

E2

1000

800

Tumor volume

TAM+Iressa

600

400

200

0

0

14

28

42

56

70

84

98

112

126

140

154

168

182

196

210

Days

iressa effect on tamoxifen therapy in mcf 7 xenografts
Iressa Effect on Tamoxifen Therapy in MCF-7 Xenografts

1400

1200

E2+ Iressa

TAM

E2

1000

800

Tumor volume

TAM+Iressa

600

400

200

0

0

14

28

42

56

70

84

98

112

126

140

154

168

182

196

210

Days

slide43

Iressa Effect on Estrogen Deprivation

1400

-E2

1200

E2+ Iressa

E2

1000

800

Tumor volume

- E2+ Iressa

600

400

200

0

0

14

28

42

56

70

98

84

126

154

112

140

Days

conclusions
Conclusions
  • Molecular cross-talk increases tamoxifen agonist activity in tumors with high HER-2 (de novo resistance).
  • Cross-talk also contributes to tamoxifen agonist activity acquired during treatment
  • (low HER-2).
  • Receptor TKIs can block this cross-talk, improve tamoxifen performance, and overcome or delay resistance.
conclusions1
Conclusions

HER2+ breast tumors

  • Tamoxifen stimulates growth as a mechanism of de novo resistance
  • Estrogen deprivation inhibits tumor growth

Iressa

  • Modestly affects as a monotherapy
  • Inhibits tamoxifen-stimulated growth
  • Delays resistance to estrogen deprivation
conclusions2
Conclusions

Breast tumors with normal low HER2

  • Tamoxifen is an effective antiestrogen, but tumors will acquire resistance

Iressa

  • No effect as a monotherapy
  • Delays acquired resistance to tamoxifen
  • No significant benefit when combined with estrogen deprivation
conclusion
Conclusion
  • ER-targeted therapy combined with EGFR/HER2 inhibitors like Iressa should be tested in clinical trials to delay

de novo and acquired resistance.

?

Agonist

Breast/ Uterus

“Optimal

SERM”

SERM + TKI

Agonist

Bone/LM

slide48

Collaborators

  • Baylor Breast Center
  • Shou Jiang
  • Suleiman Massarweh
  • Margaret DiPietro
  • Kent Osborne
  • Powel Brown
  • Syed Mohsin/Craig Allred
  • Sue Hilsenbeck
  • AstraZeneca
  • Alan Wakeling
slide50

P-ER, HER2, MAPK, AIB1

Iressa

Proliferation

ER-dependent transcription

Effect of Iressa on ER and GF Pathways

MCF7

(Tam sensitive)

MCF7/HER2

(Tam resistant)

slide51

Phosphorylation of ER, HER2 and p-MAPK

in MCF7 and MCF7/HER2 Cells

MCF7

MCF7/HER2

C

E2

HRG

Tam

C

E2

HRG

Tam

Iressa

- - + - + - +

- - + - + - +

p-ER (Ser118)

p-HER2 (Tyr1248)

p-MAPK

-actin

slide52

AIB1 Phosphorylation in MCF-7 and HER -2 Cells

(Western Blot Analysis)

S

HRG

E2

Tam

MCF-7

MCF-7/HER-2

PPase

Iressa

slide53

Iressa Inhibition of Anchorage-independent Growth

MCF7

MCF7/HER2

No. of

colonies

120

120

100

100

80

80

60

60

E2

Ctr

Tam

E2

Ctr

Tam

40

40

20

20

0

0

0 0.1 1.0 10

0 0.1 1.0 10

Iressa concentration (µM)

slide54

Effect of Iressa on ER-dependent Transcription in MCF-7 and MCF-7/HER2 Cells

MCF-7

MCF-7/HER-2

--(C)

E2

Tam

--(C)

E2

Tam

5

5

4

4

3

3

Fold of Induction (E2)

Fold of Induction (E2)

2

2

1

1

0

0

Ir - + - + - + - + - + - + - + - + - + - + - + - +

GF

HRG

HRG

HRG

HRG

HRG

HRG

Treatment

Treatment