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Endocrine resistance: molecular pathways and rational development of targeted therapies - PPT Presentation

Grazia Arpino Università di Napoli Federico II Current Endocrine Therapy Tamoxifen aromatase inhibitors Limited by denovo or acquired endocrine resistance ID: 780409

her2 tam anastrozole cancer tam her2 cancer anastrozole endocrine months fulvestrant tamoxifen egfr pfs median resistance progression akt genomic

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Slide1

Endocrine

resistance: molecular pathways and rational development of targeted therapies

Grazia Arpino

Università di Napoli Federico II

Slide2

Current

Endocrine

Therapy:Tamoxifen; aromatase inhibitorsLimited by “de-novo” or “acquired” endocrine resistanceDe Novo/Acquired Endocrine Resistance:ER expression & functionRole of Growth Factor Receptors (EGFR/HER2) in “Cross-Talk”Downstream intracellular signaling (ie. mTor, MAPK vs AkT)Signal Transduction Inhibitors, biology and clinical role:EGFR – erlotinib, gefitinibHER2 – trastuzumab, lapatinibmTOR – everolimus, temsirolimus

Enhancing Endocrine Therapy for Breast Cancer

Slide3

Current

Endocrine

Enhancing Endocrine Therapy for Breast Cancer

Slide4

Current

Endocrine

Enhancing Endocrine Therapy for Breast Cancer

Slide5

5 years of adjuvant

tamoxifen safely reduces 15-year risks of breast cancer recurrence and death

~5 years tamoxifen vs Not, ER+ patientsEBCTGC, Lancet 201110%

Slide6

Tam

EREGeneEREREGeneEREGenePromoter

Promoter

Transcription

mRNA

Protein

CoR

CoA

Tam

CoR

Mechanism

Action-Tamoxifen

Slide7

Mechanism

of Action-Aromatase Inhibitors

Slide8

However, almost one quarter of the patients with ER+ tumor develop resistance

~5 years

tamoxifen vs Not, ER+ patientsEBCTGC, Lancet 201125%

Slide9

Major Problem

(Endocrine Therapy)

ResistanceDe NovoAcquired

Slide10



Her2+ Better

Her2+ worse



Overall

1.44

(1.34 – 1.56)

Ellegde

1.21

(0.87 – 1.69)

Hayes

1.06

(0.47 – 2.38)

Houston

2.07

(1.57 – 2.73)

Lipton 1

1.42

(1.24 – 1.63)

Willsher

1.33

(0.56 – 3.16)

Wright

1.54

(0.86 – 3.74)

Yamauchi

1.66

(1.05 – 2.64)

Metanalysis

ER+

Patients

(N=1195)

Lipton 2

1.40

(1.25 – 1.56)

Relative Risk of

Treatment Failure (95%CI)

De Laurentiis M., et al.

Clin.Cancer Res., 2005.

Slide11

In Vivo

Model of

Tamoxifen ResistanceOsborne et al. JNCI 1994

Tam

De Novo

Tam-R

Tam-S

Acquired

Tam-R

1200

1000

800

600

400

200

105

Days

Tumor

volume

(mm

)

MCF7

MCF7 / HER2

Slide12

Basal

transcription machinery

p160CBPP

EGFR

HER2

IGFR

Cell stress cytokines

Genomic & non-genomic ER cross-talk

Slide13

Basal

transcription machinery

p160CBPGenomic & non-genomic ER cross-talk

EGFR

HER2

IGFR

Cell stress cytokines

MKK3/6

p38

Ras

Raf

CDC42

MEKK1

MLK3

Rac-1

MEK1/2

ERK1/2

p60rsk

Grb2

SOS

Bad

mTor

AKT

PI3k

Slide14

Basal

transcription machinery

p160CBP

EGFR

HER2

IGFR

Cell stress cytokines

MKK3/6

p38

Ras

Raf

CDC42

MEKK1

MLK3

Rac-1

MEK1/2

ERK1/2

p60rsk

Grb2

SOS

Bad

mTor

AKT

PI3k

Genomic & non-genomic ER cross-talk

Slide15

Effect of HER Family Inhibitors on Tam-Stimulated Growth

200

400

600

800

105

126

147

168

189

209

Days

Tam

Tam+Gef

Tam+T

Tam+P

MCF7/HER2 Tumors

Tumor Volumes (mm

)

Arpino, JNCI 2007

Hypothesis:

Resistance

is due to incomplete

blockade

of the

HER

signaling pathway (all HER

dimer

pairs).

Slide16

TanDEM

Study Design

Kaufman et

al, JCO 2009

Anastrozole

1 mg

daily

Trastuzumab

4 mg/kg

dose

 2 mg/kg

until

disease

progression

Anastrozole

1 mg

until

disease

progression

HER2-positive

HR-positive MBC

(n=208)

HR,

hormone

receptor

MBC,

metastatic

breast

cancer

randomisation

Crossover to receive trastuzumab was actively offered to all patients who progressed on anastrozole alone

Slide17

TanDEM

Progression-free Survival

0.20.40.60.81.0Probability0

Months

103

104

A + H

No. at risk

Events

Median

PFS

4.8

months

2.4

months

95%

3.7, 7.0

2.0, 4.6

value

0.0016

Kaufman

al, JCO 2009

Slide18

Patient Population

ER+

/PgR+ (HR+)PostmenopausalHER2+, HER2- or unknownStage IIIb/IIIc, IVNo prior treatment for MBCStratification

Disease

sites

Bone

only

othe

sites

Interval

since

prior

adjuvant

anti-estrogen

therapy

< 6 mo /

≥ 6 mo or None

Letrozole 2.5 mg daily

Lapatinib 1500 mg daily

Letrozole 2.5 mg daily

Placebo

EGF30008 – Study Design

n = 1286 pts (including n=219 HER2+)

Johnston S, et al JCO2009

Slide19

Progression-Free Survival:

HER2+ Population

Letrozole(N = 108)Letrozole + Lapatinib(N = 111)

Progressed or died

89 (82%)

88 (79%)

Median PFS, mo

3.0

8.2

Hazard ratio (95% CI)

0.71 (0.53, 0.96)

p-value

0.019

Slide20

Patient

PopulationER+/PgR+ (HR+)PostmenopausalHER2+, No prior treatment for MBCRAND

Letrozole

2.5 mg

daily

Trastuzumab

Letrozole

2.5 mg

daily

Placebo

ELECTRA

– Study Design

Huober

Breast

2009

Slide21

ELECTRA

– Study Design

Huober Breast 2012Treatment§NORR (%)CBR (%)

PFS (mo)

Letrozole

39**

3.3*

Letrozole

Trastuzumab

65**

14.1*

*hazard ratio 0.67; p = 0.23

odds ratio 2.99, 95% CI 1.01-8.84

Slide22

HER2

HER3

EGFRTumor growth and survival

HER2

Trastuzumab

Gefitinib

Pertuzumab

Lapatinib

HER Family Inhibitors

HER4

Heregulin

EGF TGF

Slide23

Effect of HER Family Inhibitors on Tam-Stimulated Growth

200

400

600

800

105

126

147

168

189

209

Days

Tam

Tam+P

Tam+P+T

Tam+P+T+G

Complete Responses

Tam+P

5/18

Tam+P+T 12/18

Tam+P+T+G 18/20

Tumor Volumes (mm

)

Arpino, JNCI 2007

Slide24

200

400

600

800

1000

Treatment Days

Tumor Volume (mm3)

Complete Regression

ED+T 4/13

ED+L 5/13

ED+L+T 11/13

0 50 100 150 200 250

ED+L+T

ED+L

ED+T

MCF7/HER2-18

Effect of HER Family Inhibitors on Estrogen Deprivation

Rimawi Cancer res in press

Slide25

TBCRC 006:

Neoadjuvant

Lapatinib & Trastuzumab Without Chemotherapy Lap (L) + Tras (T) + Endocrine Rx if ER+02812Bx

Lapatinib (1000 mg/day)

Trastuzumab (4 mg/kg load, 2 mg/kg q-weekly)

Surgery

Weeks

Slide26

Pathologic Response

pCR rates: 18/61 (30%)

ER pos: 8/39 (21%)ER neg: 10/22 (46%)pCR+npCR rates: 34/61 (56%)ER pos: 22/39 (56%)ER neg: 12/22 (55%)

Slide27

PERTAIN

Patients with HER2- and hormone receptor-positive advanced breast cancer not previously treated with systemic non-hormonal anticancer therapy in the metastatic setting

(n ~250)RUntil disease progression, unacceptable toxicity, withdrawal of consent, or death

Pertuzumab + trastuzumab

Investigational arm [Arm A]

Patients receiving induction chemotherapy

(investigator’s discretion)

Up to 18 weeks

Docetaxel

paclitaxel

(starting after induction chemotherapy phase)

Control arm [Arm B]

Until disease progression, unacceptable toxicity, withdrawal of consent, or death

Trastuzumab

Patients receiving induction chemotherapy

(investigator’s discretion)

Up to 18 weeks

Docetaxel

paclitaxel

(starting after induction chemotherapy phase)

Slide28

In Vivo

Model of

Tamoxifen ResistanceOsborne et al. JNCI 1994

Tam

De Novo

Tam-R

Tam-S

Acquired

Tam-R

1200

1000

800

600

400

200

105

Days

Tumor

volume

(mm

)

MCF7

MCF7 / HER2

Slide29

signaling

survivers:ER expressed, although function may changeEnhance ER activationReversible silencing of ER can also occurEnhanced growth factor signaling (EGFR, HER2) occurs:Cross-talk between GFR and ER:activation of genomic ER via AkT/MAPK induced phosphorylationnon-genomic association of ER with HER2 / EGFR / IGFRmTOR pathway activation disregulating ER genomic function

Acquired Endocrine Resistance

Slide30

Fulvestrant

: selective

estrogen receptor downmodulator Pure estrogen receptor antagonist: - high affinity for estrogen receptor - downregulates ER and blocks ER- mediated transcription - downregulates PgR Pre-clinical and clinical studies showed: - Fulvestrant is effective in tamoxifen-resistant tumorsIndications: - MBC progressing after other antiestrogen therapy in postmenopausal women

Slide31

Slide32

FIRST:

Fulvestrant

500 mg vs Anastrazole-TTP

Slide33

All eligible patients (n=694)

0.00

0.50

0.75

1.00

0.25

N at risk

199

193

114

349

345

AN + FV

Months since registration

Anastrozole 13.5 mos (95% CI 12.1-15.1)

Combination 15.0 mos (95% CI 13.2-18.4)

Median PFS

HR = 0.80 (95% CI 0.68-0.94)

Anastrozole + Fulvestrant (268 events)

Anastrozole (297 events)

Stratified log-rank p = 0.0070

SWOG 0226:

Progression-Free Survival

Slide34

Prior adjuvant

tamoxifen

(n=280)

0.00

0.50

0.75

1.00

0.25

N at risk

141

139

AN + FV

Months since registration

Anastrozole 14.1 mos (95% CI 12.0-16.8)

Combination 13.5 mos (95% CI 11.0-19.3)

Median PFS

HR = 0.89 (95% CI 0.69-1.15)

Anastrozole + Fulvestrant (114 events)

Anastrozole (119 events)

Log-rank p = 0.037

SWOG 0226:

Progression-Free Survival

Slide35

No prior adjuvant

tamoxifen

(n=414)

0.00

0.50

0.75

1.00

0.25

N at risk

125

113

208

206

AN + FV

Months since registration

Anastrozole 12.6 mos (95% CI 11.2-15.6)

Combination 17.0 mos (95% CI 13.8-19.9)

Median PFS

HR = 0.74 (95% CI 0.59-0.92)

Anastrozole + Fulvestrant (154 events)

Anastrozole (178 events)

Log-rank p = 0.0055

SWOG 0226:

Progression-Free Survival

Slide36

All

eligible

patients (n=694)

0.00

0.50

0.75

1.00

0.25

N at risk

315

306

259

239

145

136

349

345

AN + FV

Months since registration

Anastrozole 41.3 mos (95% CI 37.2-45.0)

Combination 47.7 mos (95% CI 43.0-55.7)

Median OS

HR = 0.81 (95% CI 0.65-1.00)

Anastrozole + Fulvestrant (154 deaths)

Anastrozole (176 deaths)

Stratified log-rank p = 0.049

SWOG 0226:

Overall Survival

Slide37

Prior

adjuvant

tamoxifen

(n=280)

0.00

0.50

0.75

1.00

0.25

N at risk

125

101

100

141

139

AN + FV

Months since registration

Anastrozole 44.5 mos (95% CI 38.0-54.8)

Combination 49.6 mos (95% CI 37.9-71.2)

Median OS

HR = 0.91 (95% CI 0.65-1.28)

Anastrozole + Fulvestrant (63 deaths)

Anastrozole (68 deaths)

Log-rank p = 0.59

SWOG 0226:

Overall Survival

Slide38

No prior adjuvant

tamoxifen

(n=414)

0.00

0.50

0.75

1.00

0.25

N at risk

190

181

158

139

208

206

AN + FV

Months since registration

Anastrozole 39.7 mos (95% CI 33.1-43.9)

Combination 47.7 mos (95% CI 43.4-58.3)

Median OS

HR = 0.74 (95% CI 0.56-0.98)

Anastrozole + Fulvestrant (91 deaths)

Anastrozole (108 deaths)

Log-rank p = 0.0362

SWOG 0226:

Overall Survival

Slide39

signaling

Acquired Endocrine Resistance

Slide40

hanges of ER and

PgR Expression in Primary vs. Subsequent Metestatic DiseaseCurigliano et al. Ann. Onc. 2011

Slide41

The discordance

rates for ER, PgR, andHER2

status between primary tumor and liver metastases were 14.5%, 48.6%, and13.9%, respectively, which led to change in therapy for 31 of 255 patients (12.1%).Rebiopsy??……YES if it safe!Curigliano et al. Ann. Onc. 2011

Slide42

Changes in Molecular Profile Subtype at the Development of Endocrine Resistance

Creighton et al Cancer Res. 2009

Slide43

ER+ve

Tamoxifen Resistance Cells (TAM-R) show Increased EGFR SignalingWTTAM-Rp-EGFRp-HER2p-ERK 1/2

Total-ERK 1/2

p-ERK 1/2

Knowlden

al.

Endocrinology

2003

Slide44

MEK

Raf

Changes in Growth Factor Receptor Expression and ER Activation in Acquired

TamR

WT cell lines

Type I growth factor receptors

(EGFR, ERBB2, ERBB3, ERBB4)

p EGFR

p ERBB2

Actin

EGFR

ERBB2

ERBB3

ERBB4

p ERK 1/2

ERK 1/2

pAKT (ser

173

)

AKT

pERa (ser

118

)

pERa (ser

167

)

total ERa

TamR

ERE

Target gene

Pancholi

al.

Endocr

Relat

Cancer

2008

p160

CBP

Basal

transcription machinery

Akt

PI3K

Ras

SoS

MAPK

p90

RSK

TamR

Slide45

Slide46

1839IL/0225 – A

randomised

phase II study of Tamoxifen ± Gefitinib in patients with ER+ve metastatic breast cancerOsborne et al. CCR 20100.20.40.60.81.0

0.0

100

200

300

400

500

600

700

800

900

1000

1100

time (days)

tamoxifen + gefitinib

tamoxifen + placebo

Treatment Group

Proportion progression-free

Time to Progression

STRATUM 1: (Endocrine Naive or > 12 m post adjuvant tamoxifen)

Tamoxifen +

Gefitinib

(n = 105)

Tamoxifen +

Placebo

(n = 101)

Median PFS (months)

8.8

10.9

HER2+ subset (n=37)

Median PFS (months)

5.8

6.7

HR of gefitinib to placebo = 0.84 (0.59, 1.18)

HR of gefitinib to placebo = 0.54 (0.25, 1.15)

Slide47

Randomised

phase II study of

Anastrozole

Gefitinib

in patients with

ER+ve

metastatic breast cancer

0.2

0.4

0.6

0.8

1.0

0.0

Months

Probability of PFS

Anastrozole +

Gefitinib

(n = 43)

Anastrozole +

Placebo

(n = 50)

Events

Median PFS (months)

8.2

14.5

HR (95% CI) = 0.55 (0.32, 0.94)

Cristofanilli

al.

CCR2012

Placebo

Gefitinib

At risk

Slide48

EGF30008

Progression-Free

Survival: ITT and HER2-ve PopulationsLetrozole (N=474)Letrozole +Lapatinib(N=478)

Progressed or died

342 (72%)

294 (62%)

Median PFS, mo

13.4

13.7

Hazard ratio (95% CI)

0.90 (0.77, 1.05)

p-value

0.188

Letrozole

644)

Letrozole +

Lapatinib

(N =

642)

Progressed or died

476 (74%)

413 (64%)

Median PFS, mo

10.8

11.9

Hazard ratio (95% CI)

0.86 (0.76, 0.98)

p-value

0.026

ITT

HER2-ve *

*Centrally confirmed

Slide49

EGF30008

PFS: HER2-ve Patients (N=952)

< 6 Mo Since D/C of TamMedian tam duration 2.8 yMedian time since d/c 1 moLet(N=370)Let + Lap(N=382)Median PFS, mo15.0

14.7

Hazard ratio

(95% CI),

p-value

0.94 (0.79, 1.13); p=0.522

Let

(N=104)

Let + Lap

(N=96)

Median PFS, mo

3.1

8.3

Hazard ratio (95% CI), p-value

0.78 (0.57, 1.07); p=0.117

≥ 6 Mo Since

D/C of Tam (33%)

or No Tam (67%)

Median tam duration 5 y

Median time since d/c 3.5 y

Slide50

Fulvestrant

Placebo

Fulvestrant

Lapatinib

Fulvestrant

Aromatase

In.

Placebo

Fulvestrant

Aromatase

In.

Lapatinib

2x2 Factorial Design

Over

Trial

Design

Slide51

Fulvestrant

Placebo

Fulvestrant

Lapatinib

Fulvestrant

Aromatase In.

Lapatinib

Fulvestrant

Aromatase In.

Lapatinib

Evaluation of Retaining the AI

Over

Trial

Design

Slide52

Evaluation of Adding Lapatinib

Fulvestrant

+Placebo

Fulvestrant

Lapatinib

Fulvestrant

Aromatase In.

Placebo

Fulvestrant

Aromatase In.

Lapatinib

Over

Trial

Design

Slide53

signaling

Acquired Endocrine Resistance

Slide54

ki67

4EBP1

elF4E-F-GRhebGDP

Rheb

GTP

Targeting

mTOR

& cell growth

inhibition

Atzori et al, ASCO 2008

IGF1R

IRS1

PI3K

PDK1

PIP2

PIP3

PTEN

Akt

TSC1

TSC2

mTOR

Everolimus

Temsirolimus

S6K

Proliferation

Slide55

The

mTOR Pathway Is Active in Breast Cancer

• Genetic alterations result in activation of the PI3K/AKT/mTOR pathway in breast cancer: – Loss of PTEN protein (~30% to 48%), PTEN mutation (<5%) – PI3K mutation (~21% to 33%)• ~30% to 40% of breast cancer cells exhibit AKT activation• Overexpression/mutation of receptor tyrosine-kinases (eg, HER-2, EGFR) also activates the PI3K/AKT/mTOR pathway1. Hennessy BT, et al. Nat Rev Drug Discov. 2005;4(12):988-1004. 2. Pérez-Tenorio G, et al. Clin Cancer

Res

. 2007;13(12):3577-3584. 3.

deGraffenried

LA,

al.

Ann

Oncol

. 2004;15(10):1510-1516. 4.

Bachman

KE,

al.

Cancer

Biol

Ther

. 2004;3(8):772-775. 5. Campbell IG,

al.

Cancer

Res

. 2004;64(21):7678-7681. 6.

Stemke-Hale

al.

Cancer Res. 2008;68(15):6084-6091. 7. Wu G,

et al. Breast Cancer

Res. 2005;7(5):R609-R616. 8. Lee JW, et al. Oncogene; 2005;24(8):1477-1480. 9. Liu

W, et al. Front Biosci. 2007;12:4011-4019. 10.

Basu A. Breast Cancer. 2008;2:11-16. 11.

Hynes NE, et al. Curr Opin

Cell Biol. 2009;21(2):177-184.

Slide56

TAMRAD

Study Design

Randomized phase II Metastatic patients with prior exposure to aromatase inhibitors (AI) • Stratification: primary or secondary hormone resistance – Primary: Relapse during adjuvant AI; progression within 6 months of starting AI treatment in metastatic setting – Secondary: Late relapse (≥6 months) or prior response and subsequent progression to metastatic AI treatment • No crossover planned Bachelot T, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-6, Bourgier C, et al. Eur J Cancer Suppl. 2011;47(Suppl 2): Abstract 5005.

Slide57

TAMRAD:

Clinical Benefit Rate and TTP

Clinical benefit rate P = .045 (exploratory analysis) Time to progression • TAM: 4.5 months • TAM + RAD: 8.6 months • HR (95% CI) = 0.54 (0.36-0.81) • P = .0021 (exploratory analysis) Bourgier C, et al. Eur J Cancer Su 2011;47(Suppl 2):

Slide58

TAMRAD:Time

to Progression as a Function of Intrinsic Hormone Resistance

Primary resistance -TAM: 3.8 months -TAM + RAD: 5.4 months -HR = 0.70 (0.40-1.21) -P = NS (exploratory analysis) Secondary resistance - TAM: 5.5 months - TAM + RAD: 14.8 months - HR = 0.46 (0.26-0.83) - P = .0087 (exploratory analysis) Bourgier C, et al. Eur J Cancer Suppl. 2011

Slide59

TAMRAD: Overall Survival

Bourgier C, et al.

Eur J Cancer Suppl. 2011

Slide60

BOLERO-2: Trial Design

Stratification:

1. Sensitivity to prior hormonal therapy 2. Presence of visceral disease No crossover Baselga J, et al. Eur J Cancer Suppl. 2011;47(Suppl 2): Abstract: 9LBA. Definition of hormone sensitivity : ≥24 months of hormone therapy before recurrence in adjuvant setting ; Response or stabilization for ≥24 weeks of hormonal therapy for advanced disease

Slide61

18-Months Update BOLERO

-2 Primary Endpoint: PFS

Slide62

Slide63

BOLERO-2: Most Common G3/4 AEs

Slide64

Inhibitors of PI3K-AKT-mTOR Signaling in Clinical Development

Engelman JA. Nat Rev Cancer. 2009;9(8):550-562.

Slide65

Modulation of Resistance to Endocrine Therapies: A Look Into the Future

ABC-1

Congress 2011

Slide66

Endocrine resistance:

ER still expressed, although function may change

Complex “cross-talk” exists between GFR and ERNon-genomic association of ER with HER2Targeted growth factor receptor therapies:Proof of concept on inhibiting growth/ER signaling/restoring endocrine sensitivityTargeting of EGFR/HER2 to treat/delay emergence of resistanceClinical trials combining STI’s + endocrine therapies:Appropriate selection of patients that may benefit is crucialCorrect clinical endpoints (ORR vs PFS) are importantNeo-adjuvant setting – some advantages for early developmentEndocrine Rx and STIs - Conclusions