overcoming resistance in hormonally sensitive breast cancer ruth m. o’regan, md associate...

Overcoming Resistance in Hormonally Sensitive Breast Cancer

Ruth M. O’Regan, MDAssociate Professor, Hematology and Medical Oncology

Emory University School of Medicine

Director, Translational Breast Cancer Research Program

Director, Hematology and Medical Oncology Fellowship Program

Winship Cancer Institute

Atlanta, Georgia

Clinical UpdatesHormonally Sensitive, Early-Stage Breast Cancer

Mechanisms of SERM Resistance

Johnston CCR 2005

ER Target Gene Transcription

SOS

P P

P P

PI3-K

Akt

PP

RASRAF

MEK

MAPKp90RSK

ER

Pp160

BasalTranscription

MachineryCBPERERPPP

ERE CellGrowth

PlasmaMembrane

Cytoplasm

Nucleus

E2

SERD

AI T

IGF1REGFR/HER2

Increased signalingthrough PI3-K pathway

CCI RAD

MoAb

TKI

Increased upstream signaling throughEGFR and/or IGF-IRand or VEGFR

TKI

ABVEGFR

MoAb

TKI

Mechanisms of intrinsic and acquired resistance is likely similar

Copyright ©2003 by the National Academy of Sciences

ER+ Cancers Are Heterogenous in Outcome

Sorlie et al PNAS 2003

ER+

ER+

Efficacy of Tamoxifen Varies in ER+ Cancers

Low Risk (RS<18)N

171142

Int Risk (RS 18-30)N8569

Interaction P=0.06High Risk (RS≥31)N9979

0 2 4 6 8 14 16

Years

0.0

0.2

0.4

0.6

0.8

1.0

DR

FS

PlaceboTamoxifen

1210

0 2 4 6 8 14 16

Years

0.0

0.2

0.4

0.6

0.8

1.0

DR

FS

PlaceboTamoxifen

1210 0 2 4 6 8 14 16

Years

0.0

0.2

0.4

0.6

0.8

1.0

DR

FS

PlaceboTamoxifen

1210

Paik et al SABCS 2004

TAM-resistant

Correlation Between Recurrence Score and Intrinsic Subtype

Recurrence

Score

Luminal A

(n = 123)

Luminal B

(n = 55)

Low 62 1

Intermediate 25 4

High 36 50

Fan et al NEJM 2006

RS = + 0.47 x HER2 Group Score

- 0.34 x ER Group Score + 1.04 x Proliferation Group Score + 0.10 x Invasion Group Score + 0.05 x CD68 - 0.08 x GSTM1 - 0.07 x BAG1

Oncotype DX 21 Gene Recurrence Score (RS) Assay

PROLIFERATIONKi-67

STK15Survivin

Cyclin B1MYBL2

ESTROGENERPR

Bcl2SCUBE2

INVASIONStromolysin 3Cathepsin L2

HER2GRB7HER2

BAG1GSTM1

ReferenceBeta-actinGAPDHRPLPOGUSTFRC

CD68

16 Cancer and 5 Reference Genes From 3 Studies

Category RS (0 – 100)

Low risk RS < 18

Int risk RS ≥ 18 and < 31

High risk RS ≥ 31

Poor Outcome for Patients with HER2-positive MBC Treated with Endocrine Agents Alone

Agent Clinical Benefit PFS

Anastrozole 28% 2.4 months

Letrozole 29% 3.0 months

Kaufmann ESMO 2006, Johnston SABCS 2008

Cui, X. et al. J Clin Oncol; 23:7721-7735 2005

Overall Survival According to Tumor Receptor Status in Women Treated with Tamoxifen

PR is prognostic or predictive for patients treated with tamoxifen

Disease-free Survival by Ki-67 LI in BIG-1-98 (Letrozole and Tamoxifen)

• 1,252 (47%) expressed Ki-67 LI > 11% (high)

Viale G et al. SABCS 2007 Abs 64.

Possible Surrogate Markers for Hormone Resistance

ER

PR

HER2

LUM A LUM B

Low Ki-67 High Ki-67

Hormone-sensitive Hormone-resistant

RS

Mechanisms of SERM Resistance

Johnston CCR 2005

ER Target Gene Transcription

SOS

P P

P P

PI3-K

Akt

PP

RASRAF

MEK

MAPKp90RSK

ER

Pp160

BasalTranscription

MachineryCBPERERPPP

ERE CellGrowth

PlasmaMembrane

Cytoplasm

Nucleus

E2

SERD

AI T

IGF1REGFR/HER2

Increased signalingthrough PI3-K pathway

CCI RAD

MoAb

TKI

Increased upstream signaling throughEGFR and/or IGF-IRand or VEGFR

TKI

ABVEGFR

MoAb

TKI

Copyright ©2008 American Association for Cancer Research

Massarweh, S. et al. Cancer Res 2008;68:826-833

Increase in EGFR and HER2 Protein in Tamoxifen-resistant Breast Cancers in vivo

TAnDEM Study Design

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

HER2-positive, HR+ MBC

(n=208)R

Anastrozole 1 mg daily + Trastuzumab 4 mg/kg loading dose

2 mg/kg qw until disease progression

Anastrozole1 mg daily until

disease progression

HR, hormone receptor; MBC, metastatic breast cancer; R, randomisation

Trastuzumab + AIProgression-free Survival

103 48 31 17 14 13 11 9 4 1 1 0 0A + T

104 36 22 9 5 4 2 1 0 0 0 0 0A

CI, confidence intervalPFS = time from randomisation to date of progressive disease or death

Probability 1.0

0.8

0.6

0.4

0.2

0 5 10 15 20 25 30 35 40 45 50 55 60Months

95% CI

3.7, 7.02.0, 4.6

P value

0.0016

Median PFS

4.8 months2.4 months

Events

8799

0.0

No. at risk

Kaufmann ESMO 2006

Patients(%)

0

10

20

30

40

50

60P=0.026

Clinical benefit

A + T (n=103)

A (n=104)

Trastuzumab + AIClinical benefit

42.7%

27.9%

Vogel JCO 2002, Kaufmann ESMO 2006

Clinical benefit with single agent trastuzumab 48%

Johnston et al., SABCS 2008, abstract 46

1° endpoint: PFS (investigator) in HR+/HER2 pts

Letrozole ± Lapatinib in HR+ MBC

Arm A: LAP 1,500 mg/d p.o.+ LET 2.5 mg/d p.o.

(n = 642)

Arm B: LET 2.5 mg/day p.o.+ Placebo

(n = 644)

(n = 1,286)

RANDOMIZE

Eligibility criteria:Postmenopausal ER+/PgR+HER2+/HER2-/unknownStage IIIb, IIIc, and IV breast cancerNo prior treatment for metastatic disease


ITT HER2+ HER2-

let (n=644)

let + lap (n=642)

let (n=108)

let + lap (n=111)

let (n=474)

let + lap (n=478)

PFS (months)

10.8 11.9 3.0 8.2 13.4 13.7

HR 0.86; P =.026 HR 0.71; P =.019 HR 0.90; P =.188

ORR28% 30% 15% 28% 32% 33%

P =.262 P =.021 P =.726

CBR51% 56% 29% 48% 56% 58%

P =.096 P =.003 P =.761

OS (months)NR NR 32.3 33.3 NR NR

NR HR 0.74; P =.113 NR


Progression-free SurvivalHER2+ Population

LET

(N = 108)LET+ LAP(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

Progression-free SurvivalITT and HER2-ve Populations

LET

(N = 474)

LET + LAP

(N = 478)



Hazard ratio (95% CI) 0.90 (0.77, 1.05)

P-value 0.188

LET

(N = 644)

LET + LAP

(N = 642)



Hazard ratio (95% CI) 0.86 (0.76, 0.98)

P-value 0.026

ITT HER2-ve *

*Centrally confirmed

Preplanned stepwise exploratory Cox proportional hazard analysis for PFS:

– HER2+ population: HR for treatment = 0.65; P = .008

– HER2(-) population: HR for treatment = 0.77; P = .010

PFS in HER2(-) population based on interval since adjuvant TAM therapy

≥6 months since discontinuation of TAM or none

<6 months since

discontinuation of TAM

LET

(n=370)LET + LAP

(n=382)LET

(n=104)

LET + LAP

(n=96)

Median PFS (months)15.0 14.7 3.1 8.3

HR 0.94; P = .522 HR 0.78; P = .117

CBR 64% 62% 32% 44%


Hormone-sensitive Hormone-refractory


Phase II Anastrozole ± Gefitinib in Newly Diagnosed HR+ MBC

Cristofanilli M, et al. J Clin Oncol. 2008;26(15S): Abstract 1012.

Post menopausal women Newly diagnosed, ER and / or PR-positive MBC, No prior hormonal therapy, measurable disease

Anastrozole 1 mg PO daily

Gefitinib 250 mg PO Daily

Anastrozole 1 mg PO daily

Placebo

Multi-center, randomized, double-blind trial Primary objective: PFS Enrollment stopped early due to low accrual

R

Anastrozole ± Gefitinib in HR+ MBC Efficacy

Cristofanilli et al, ASCO 2008, abstract # 1012

Anastrozole + Gefitinib

(n = 43)Anastrozole + placebo

(n = 50)

Median PFS (months)14.5 8.2

HR (95% CI) = 0.55 (0.32 – 0.94)

Objective response rate 2% 12%

Clinical benefit rate 49% 34%

Pollak et al Nature Reviews 2004

IGF-1R Signaling

Role of IGF-1R Signaling in HR+ Breast Cancer

TAM initially inhibits IGF-1 but with the onset of resistance IGF-1R signaling is re-established

TAM-resistant cancers are more sensitive to IGF-1R signaling

Inhibitors of IGF-1R (TKI and mAB) prevent growth of TAM-resistant cells

Knowlden et al Endocrinology 2005 Massarweh, S. et al. Cancer Res 2008

Metastatic breast cancer

At least 1 prior endocrine Rx for ≥ 3 months

Disease progression within 12 months of starting last endocrine therapy ER and/or PR-positive

IMC-A12(n = 30)

IMC-A12 + most recentendocrine

therapy(n = 60)

Randomized Phase II Trial of IMC-A12 ± Hormonal Therapy in Hormone-resistant Metastatic Breast Cancer

IMC-A12 10 mg/kg every 2 weeks

R

Pilot Study of Letrozole + BevacizumabMSKCC/UCSF

N = 43

Primary endpoint: Safety/feasibility

Secondary endpoints: TTP, RR, SD > 6 mo.

Prior NS-AI allowed if no documented progression

Ovarian suppression allowed (medical or surgical)

2.5 mg orally each day

Week 0 3 6 9

Bevacizumab15 mg/kg IV

Letrozole

12

Traina, Dickler, Rugo, Hudis et al., ASCO Abstract 3050, 2006

Best Response by RECISTFeasibility Study of Letrozole Plus Bevacizumab

n (%)

Assessed for Response 43

Complete Response 0 (0%)

Partial Response 4 (9%)

Stable Disease > 24 weeks 29 (67%)

Clinical Benefit Rate 33 (76%)

Median # cycles/patient (range): 13 (1-56)Prior Rx on a NS-AI for MBC (median/range): 15 wks (1-126 wks)

Dickler ASCO Breast 2008

Progression-free Survival

Dickler ASCO Breast 2008Time (months) from Treatment start

Pro

gres

sion

-fre

e su

rviv

al

0 12 24 36 48

0.0

0.2

0.4

0.6

0.8

1.0

N = 43

Median PFS: 17.1 months [95% CI: (8.5, 26.2)]

Median wks on AI therapy pre-bevacizumab = 15.4 weeks (range 1-216 wks)

RANDOMIZE

Endocrine Rx + Bevacizumab (15 mg/kg IV q 3 wks)

Endocrine Rx + Placebo

Proof of Concept StudyCALGB 40503 First-line Endocrine Rx

± Bevacizumab for MBC

Primary Endpoint: Progression-free Survival Endocrine Rx: Physician choice of Letrozole or Tamoxifen For premenopausal women → ovarian suppression required (can start day 1 of

protocol therapy) Correlative studies: CTCs/CECs, pharmacogenomics, differential response by

luminal subtyping and PIK3CA mutation analysis

N = 442

Conclusions

HR+ cancers are clearly heterogeneous with divergent outcomes

Need to identify robust predictive factors for both luminal A and B cancers

Essential to establish molecular differences between luminal subtypes so that novel therapeutic approaches can be developed

overcoming resistance in hormonally sensitive breast cancer ruth m. o’regan, md associate...

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