DISCLAIMERDISCLAIMERThis slide deck in its original and unaltered format is for educational purposes and is

current as of August 2012. All materials contained herein reflect the views of thefaculty, and not those of IMER, the CME provider, or the commercial supporter. Thesematerials may discuss therapeutic products that have not been approved by the US

Food and Drug Administration and off-label uses of approved products. Readersshould not rely on this information as a substitute for professional medical advice,

diagnosis, or treatment. The use of any information provided is solely at your own risk,and readers should verify the prescribing information and all data before treating

patients or employing any therapeutic products described in this educational activity.

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DISCLAIMERDISCLAIMERParticipants have an implied responsibility to use the newly acquired information

to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for

patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by

clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s

product information, and comparison with recommendations of other authorities.

DISCLOSURE OF UNLABELED USEDISCLOSURE OF UNLABELED USEThis educational activity may contain discussion of published and/or investigational

uses of agents that are not indicated by the FDA. Albert Einstein College of Medicine and IMER do not recommend the use of any agent outside of the labeled

indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Albert Einstein College of Medicine and IMER. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclosure of Conflicts of InterestDisclosure of Conflicts of Interest

Eleni Andreopoulou, MD, reported a financial interest/relationship or affiliation in the form of: Speakers' Bureau, Amgen, Inc.

Harold J. Burstein, MD, PhD, has no real or apparent conflicts of interest to report. Dr. Burstein has disclosed that he will discuss or present information that is related to an off-label or investigational use of fulvestrant, aromatase inhibitors (Als), estradiol, and tamoxifen.

Community Oncology Clinical Community Oncology Clinical Debates in Breast Cancer:Debates in Breast Cancer:

Advanced ER-Positive Disease Advanced ER-Positive Disease

Harold J. Burstein, MD, PhDDana-Farber Cancer Institute

Learning ObjectivesLearning ObjectivesUpon completion of this activity, Upon completion of this activity,

participants should be better able to:participants should be better able to:

Identify predictive factors and markers associated with response or resistance to endocrine therapy

Examine current data regarding the mechanisms of endocrine resistance and the rationale for therapeutic strategies to overcome resistance

Apply optimal sequencing of current and novel agents used in the treatment of advanced ER+ breast cancer

Identify current, emerging, and investigational therapeutic approaches for frontline and refractory ER+ breast cancer, including endocrine therapies and combination strategies using targeted agents

Explain common crosstalks between ER and growth factor signaling pathways and the rationale for targeting these pathways in advanced ER+ breast cancer

Describe the efficacy, safety, and tolerability of novel and emerging therapies demonstrated in recent clinical trials, including their clinical implications

ER = estrogen receptor.

Activity AgendaActivity Agenda Activity Overview (5 mins)

Interdisciplinary Debates and Interactive Discussion (50 mins)

– Can we predict response or resistance patterns to endocrine therapy in ER+ breast cancer?

– What is the optimal frontline therapy for a patient with advanced ER+ breast cancer?

– What is the optimal therapy for patients with advanced or metastatic ER+ endocrine-resistance who progressed after previous lines of therapies?

Questions & Answers (5 mins)

OutlineOutline

Overview of approach for advanced breast cancer

Predictors of outcome with endocrine therapy

Premenopausal and postmenopausal women

Role of AIs, fulvestrant, progestins, estradiol

mTOR inhibitors

ER+/HER2+ tumors

PI3K mutations

Can We Predict Response or Can We Predict Response or Resistance Patterns to Endocrine Resistance Patterns to Endocrine Therapy in ER+ Breast Cancer? Therapy in ER+ Breast Cancer?

Case Study 1Case Study 1

A 57-yr-old woman has recently been diagnosed withER+ MBC. She had been diagnosed with node+ breast cancer 6 yrs ago, and after her surgery, received adjuvant AC/T chemotherapy, radiation, and 5 yrs of an aromatase inhibitor.

She developed lower back discomfort and an MRI showed lesions suspicious for metastatic disease

A CT-guided bone biopsy confirmed metastatic carcinoma, ER+, PR-, HER2-, consistent with advanced breast cancer. Staging studies showed multiple bone abnormalities throughout the axial skeleton, borderline enlarged mediastinal lymph nodes, and no evidence for visceral metastases.

AC/T = doxorubicin, cyclophosphamide, paclitaxel; MBC = metastatic breast cancer; MRI = magnetic resonance imaging; CT = computed tomography; PR = progesterone receptor; HER2 = human epidermal growth factor receptor 2. NCCN, 2012.

Question 1Question 1

Which of the following are predictors of outcome for endocrine therapy for advanced breast cancer?

1) Extent of prior endocrine therapy

2) Disease-free interval

3) Overexpression of HER2

4) Quantitative levels of ER

5) PR negativity

6) All of the above

7) 1, 3, 4

NCCN, 2012.

Advanced Breast Cancer Is Treated Advanced Breast Cancer Is Treated Based on the Biology of the TumorBased on the Biology of the Tumor

Advanced Breast Cancer Requiring Therapy

Advanced Breast Cancer Requiring Therapy

HER2+Chemotherapy + Anti-HER2

Agents

HER2+Chemotherapy + Anti-HER2

Agents

Refractory to Hormonal Therapy

Refractory to Hormonal Therapy

ER and/or PR PositiveHormonal Treatment

ER and/or PR PositiveHormonal Treatment

ER and/or PR NegativeChemotherapy

ER and/or PR NegativeChemotherapy

HER2-Chemotherapy

HER2-Chemotherapy

Interdisciplinary Debates Interdisciplinary Debates and Interactive Discussion and Interactive Discussion

Clinical Predictors of Outcome Clinical Predictors of Outcome for ER+ Breast Cancerfor ER+ Breast Cancer

Disease-free interval

Prior endocrine therapy

– Clinical history radically different now than 20+ yrs ago with widespread use of adjuvant therapy

Quantitative ER expression

Bone-only vs. visceral metastases

HER2 expression

PR negativity

Oh et al, 2006; Rakha et al, 2007; Sainsbury et al, 1987; Loi et al, 2008; Ross et al, 2008; Weigel et al, 2010; Taneja et al, 2010; Niikura et al, 2011; Kurebayashi et al, 2000.

Jatoi et al, 2011.

Time Dependence of Breast Cancer Recurrence Time Dependence of Breast Cancer Recurrence in Subsets Defined by Genomic Assaysin Subsets Defined by Genomic Assays

Intrinsic/PAM50

MammaPrint

OncotypeDX

Rel

apse

-Fre

e S

urvi

val (

%)

Time After Diagnosis (yrs)

ER+ Metastatic Breast Cancer ER+ Metastatic Breast Cancer Goals of TherapyGoals of Therapy

Individual Goals Extend survival Improve or maintain QOL Clinical trial end points have

only some relationship to these goals

Clinician Goals Maximize QOL Minimize treatment related

symptoms and impact on patient lifestyle

Practice the “art” of oncology

Clinical Trial Outcomes Response rate Response duration TTP TTF OS QOL

QOL = quality of life; TTP = time to disease progression; TTF = time to treatment failure; OS = overall survival.

RESISTANCE

RESISTANCE

40%40% 30%30% 25%25% 15%15%

Response/Benefit Rates Response/Benefit Rates Over TimeOver Time

First Line

Second Line

ThirdLine

FourthLine

Harvey, 2000.

How Important Is Response in ER+ MBC?How Important Is Response in ER+ MBC?

0

100

0 1 2 3 4

Time (yrs from randomization)

80

60

40

20

At 2-YrRisk Deaths Estimate

CR or PR 33 10 85%

Stable ≥ 24 wks78 23 86%

Other 152 118 35%

CR = complete response; PR = partial response.

Robertson et al, 1999.

Su

rviv

al (

%)

Metastatic Breast Cancer:Metastatic Breast Cancer:Chemo or EndocrineChemo or Endocrine

ANZBCTG* Taylor

Tam AC Tam CMF

N 339 181

CR + PR (%)

TTP (mos)

OS (mos)

22

3

23

45

11

20

45

6.2

23

38

6.2

21

Trials Included ER- Patients

*The Australian and New Zealand Breast Cancer Trials Group (ANZBCTG).

AC = doxorubicin, cyclophosphamide; TAM = tamoxifen; CMF = cyclophosphamide, methotrexate, fluorouracil.

ANZBCTG, 1986; Taylor et al, 1986.

NCCN Database: Univariate Logistic NCCN Database: Univariate Logistic Regression for Site of First Recurrence*Regression for Site of First Recurrence*

NCCN = National Comprehensive Cancer Network; TN = triple negative; OR = odds ratio; CI = confidence interval.Lin et al, 2012.

Sites of Recurrence by SubsetSites of Recurrence by SubsetBritish Columbia Registry 1986–1992British Columbia Registry 1986–1992

Kennecke et al, 2010.

Brain (%) Liver (%) Lung (%) Bone (%) LN (%)

Pleura /

Peritoneum

(%)

LuminalA 8 29 24 67 16 28

B 11 32 30 71 23 35

HER2+ER+ 15 44 37 65 22 34

ER- 29 46 47 60 25 32

TN

Basal 25 21 43 39 40 30

Non-

Basal 22 32 36 43 36 28

ER Status and Response ER Status and Response to Tamoxifento Tamoxifen

Relationship of ER to Response to Endocrine Relationship of ER to Response to Endocrine Therapy in Advanced Breast CancerTherapy in Advanced Breast Cancer

Jensen, 1980.

Early Clinical Correlations

Quantitative Estrogen Receptor Analysis: Quantitative Estrogen Receptor Analysis: The Response to Endocrine and Cytotoxic The Response to Endocrine and Cytotoxic

Chemotherapy in Human Breast Cancer and Chemotherapy in Human Breast Cancer and Disease-Free IntervalDisease-Free Interval

Response Rate to Endocrine Therapy as a Function of ER Correlation

Lippman et al, 1980.

Value of Estrogen and Progesterone Receptors Value of Estrogen and Progesterone Receptors in the Treatment of Breast Cancerin the Treatment of Breast Cancer

Osborne et al, 1980.

Quantitative ER and the Response to Endocrine Therapy

Response to Endocrine Therapy as a Function of ER and PgR

PgR = progesterone receptor.

ER Status and Response to Tamoxifen ER Status and Response to Tamoxifen in Advanced Breast Cancerin Advanced Breast Cancer

*p = .04; A vs. B.**ER measurements were low positive in 1 biopsy, and negative in another taken simultaneously.Manni et al, 1980.

Clinical Correlation Between ER Measurements and Response to Tamoxifen

Quantitative ER and PR as Predictors of Response Quantitative ER and PR as Predictors of Response to Tamoxifen in Advanced Breast Cancerto Tamoxifen in Advanced Breast Cancer

*Includes 9 patients with ER concentration < 3 fmol/mg of protein and 13 patients with ER of 3 fmol/mf of protein.Bezwoda et al, 1991.

Correlation Between ER, PR, and Response to Tamoxifen

Significant Rate of Discordancy Significant Rate of Discordancy Between Primary and MetastasesBetween Primary and Metastases

Amir et al, 2010; Curigliano et al, 2011; Karlsson et al, 2010; Lindstrom et al, 2010.

Key Takeaways:Key Takeaways:Can We Predict Response or Resistance Patterns to Can We Predict Response or Resistance Patterns to

Endocrine Therapy in ER+ Breast Cancer? Endocrine Therapy in ER+ Breast Cancer?

Familiar clinical factors predict likelihood of benefit from endocrine treatments

To date, other molecular diagnostics have not proven value in clinical management of advanced, ER+ breast cancer

Clinical history governs much of likely outcome

What Is the Optimal Frontline What Is the Optimal Frontline Therapy for a Patient With Therapy for a Patient With

Advanced ER+ Breast Cancer?Advanced ER+ Breast Cancer?

Case Study 2Case Study 2

A 47-yr-old premenopausal woman has been diagnosed with MBC. She had non-specific changes in the right breast which prompted MRI evaluation.

Extensive architectural abnormalities were noted in an area exceeding 5 cm in size, and a biopsy revealed invasive lobular carcinoma, grade 2, that was ER+, PR+, and HER2-

She underwent a mastectomy and axillary node dissection, and was found to have metastatic lobular cancer in 5 of 13 axillary lymph nodes with extranodal extension

Staging CT scan showed suspicious lesions in the bone, multiple, subcentimeter pulmonary nodules, and enlarged mediastinal lymph nodes

A bronchosopic biopsy of a hilar lymph node showed MBC consistent with her lobular tumor

NCCN, 2012.

Question 2 Question 2 The appropriate initial endocrine treatment is:

1) Tamoxifen

2) Ovarian suppression

3) Ovarian suppression and tamoxifen

4) Ovarian suppression and an aromatase inhibitor

5) Ovarian suppression and fulvestrant

NCCN, 2012.

Shifting Landscape of Therapy for Shifting Landscape of Therapy for ER+ Metastatic Breast CancerER+ Metastatic Breast Cancer

OA = ovarian ablation; AI = aromatase inhibitors; mTOR = mammalian target of rapamycin.

Treatment Options for Treatment Options for Premenopausal Women WithPremenopausal Women WithER+ Advanced Breast CancerER+ Advanced Breast Cancer

Endocrine Therapy of Breast Cancer Endocrine Therapy of Breast Cancer in the 19th Centuryin the 19th Century

Randomized Trial of Single Vs. Randomized Trial of Single Vs. Combination Endocrine Therapy Combination Endocrine Therapy

Klijn et al, 2000.

Tamoxifen Vs.

Buserelin Vs.

Combination

O N No. Patients At Risk Treatment 43 54 29 11 2 1 LHRH-A 35 53 39 23 11 4 LHRH-A+TAM 44 54 34 16 6 0 TAM

0 2 4 6 8 10

100

80

60

40

20

0

Per

cen

t (%

)

Time (yrs)

LHRH-A + TAMLHRH-ATAM

Premenopausal Women With ER+ Advanced Breast Cancer

Treatment Options for Treatment Options for Postmenopausal Women With Postmenopausal Women With ER+ Advanced Breast CancerER+ Advanced Breast Cancer

Endocrine Agents for Endocrine Agents for Postmenopausal Breast CancerPostmenopausal Breast Cancer

SERMs– Tamoxifen

– Toremifene

– Raloxifene

Estrogens– Estradiol

– DES, EE2

ER-Down Regulator– Fulvestrant

Aromatase Inhibitors– Anastrozole

– Letrozole

– Exemestane

Progestins– Megestrol Acetate

– MPA

Androgens– Fluoxymesterone

0 6 12 18 24 30 36

Time (mos)

Pro

port

ion

Pro

gres

sion

Fre

e (%

)

0 12 24 36 48 60

0

10

20

3

0

4

0

5

0

6

0

70

80

90

1

00

Cum

ulat

ive

Pro

port

ion

Sur

viva

l (%

)

Time (mos)

Megesterol Acetate Vs. Tamoxifen Megesterol Acetate Vs. Tamoxifen for Advanced Breast Cancerfor Advanced Breast Cancer

Phase III Study of the Piedmont Oncology Association

Muss et al, 1988.

Summary: First-Line Randomized Summary: First-Line Randomized Studies AI Vs. TamoxifenStudies AI Vs. Tamoxifen

Fulvestrant Vs. Anastrozole: Trial DesignFulvestrant Vs. Anastrozole: Trial Design

Postmenopausal women with advanced breast cancer receiving prior endocrine treatment for early or advanced breast cancer

Anastrozole 1 mg qdoTrial 0020 (n = 229)Trial 0021 (n = 194)

Fulvestrant 250 mg im qmTrial 0020: 1 x 5 mL (n = 222)

Trial 0021: 2 x 2.5 mL (n = 206)

Trials 0020 and 0021: Recruitment between May 1997 and August 1999

Robertson et al, 2003.

Median TTP: Fulvestrant = 5.5 mos Anastrozole = 4.1 mos

Trial 0020: International, randomized 1:1, open, parallel-groupTrial 0021: North American, randomized 1:1, double-blind, double-dummy, parallel-group

Howell et al, 2002.

Time to Progression (mos)

Pro

po

rtio

n W

ith

ou

t P

rog

ress

ion

(%

)

Fulvestrant Vs. Anastrozole Fulvestrant Vs. Anastrozole After SERMs After SERMs

Duration of Response: Duration of Response: Without or With Visceral MetastasesWithout or With Visceral Metastases

Duration of Objective Response (days)

0 200 400 600 800 1,000

Fulvestrant 250 mg (n = 52)

Anastrozole 1 mg (n = 45)

0.0

0.2

0.4

0.6

0.8

1.0

Without Visceral Metastases

Pro

po

rtio

n W

ith

O

bje

ctiv

e R

es

po

ns

e

0 200 400 600 800 1,000

0.0

0.2

0.4

0.6

0.8

1.0

Fulvestrant 250 mg (n = 30)

Anastrozole 1 mg (n = 25)

With Visceral Metastases

Mauriac et al, 2003.

Di Leo et al, 2010.

CONFIRM: Fulvestrant 500 Vs. 250CONFIRM: Fulvestrant 500 Vs. 250PFS Curves by Treatment ArmPFS Curves by Treatment Arm

4 12 20 28 36 44

1.0

0.8

0.6

0.4

0.2

Time (mos)

Pro

po

rtio

n o

f P

atie

nts

P

rog

ress

ion

Fre

e (%

)

No. Patients At Risk Fulvestrant 500 mg 362 216 163 113 90 54 37 19 12 7 3 2 0 Fulvestrant 250 mg 374 199 144 85 60 35 25 12 4 3 1 1 0

PFS = progression-free survival.

Robertson et al, 2009.

FIRST Trial: Fulvestrant Vs. Anastrozole FIRST Trial: Fulvestrant Vs. Anastrozole in Endocrine-Naïve Breast Cancer in Endocrine-Naïve Breast Cancer

0 3 6 9 12 15 18 21

1.0

0.8

0.6

0.4

0.2

0

Pro

po

rtio

n N

ot

Pro

gre

ssed

(%

)

Time to Progression (mos)

No. Patients At Risk: Fulvestrant HD 102 96 76 46 31 17 7 5Anastrozole 1 mg 103 90 68 38 23 13 6 5

LTED = long term extrogen deprived.Brodie et al, 2005.

Combined Letrozole and Fulvestrant Delays Combined Letrozole and Fulvestrant Delays Emergence of Resistance to LTED in Emergence of Resistance to LTED in MCF-7MCF-7CaCa

XenograftsXenografts

0 4 8 12 16 20 24 28 32 36

800

600

400

200

Treatment Time (wks)

The Effect of the Letrozole and Fulvestrant Alone or in Combination on the Growth of MCF-7Ca Aromatase Xenograft

Bergh et al, 2012.

6 18 30 42 54

1.0

0.8

0.6

0.4

0.2

0

Time (mos)

PF

S (

%)

No. Patients At Risk: Anastrozole 256 148 108 57 31 16 10 5 4 1 Anastrozole 258 149 107 55 40 20 6 2 1 0+ Fulvestrant

Fulvestrant + Anastrozole (n = 258)

Anastrozole(n = 256)

No. Patients With Progression (%) 200 (77.5) 200 (78.1)

Median TTP (mos) 10.8 10.2

Primary TTP Analysis (log-rank test):HR* (95% CI)

0.99(0.81–1.20)

p Value .91

FACT Trial: AI +/- FulvestrantFACT Trial: AI +/- FulvestrantKaplan-Meier TTP and Median TTP in Mos (full analysis set) Kaplan-Meier TTP and Median TTP in Mos (full analysis set)

Mehta et al, 2012.

SWOG 0226:SWOG 0226:Anastrozole +/- Fulvestrant for MBCAnastrozole +/- Fulvestrant for MBC

Mehta RS et al, 2012

Progression-Free Survival, According to SubgroupsProgression-Free Survival, According to Subgroups

Combination Better

Anastrozole Alone Better

0.4 0.6 0.8 1.0 1.2 1.4

SoFEASoFEAPartially-Blind Phase III Randomized TrialPartially-Blind Phase III Randomized Trial

Johnston et al, 2012; Moser, 2012.US NIH, NCT00253422.

Only study of fulvestrant in the setting of acquired AI resistanceNone of the differences in RR, CBR, PFS or OS were statistically significant.

PFS

4.4 mosp = .98

4.8 mosp = .98

3.4 mosp = .56

Fulvestrant + AnastrozoleN = 241

Postmenopausal Women With ER+ Advanced Breast Cancer Following Progression on Non-Steroidal AIs

ExemestaneN = 247

Fulvestrant + PlaceboN = 230

OS

20.2 mosp = .61

19.4 mosp = .61

21.6 mosp = .68

CBR

33.7%

31.6%

26.9%

Comparison of AI ± F TrialsComparison of AI ± F Trials

FACT SWOG 0226

No. Patients 514 707

De Novo Metastatic Disease

13% 39%

Prior Adjuvant Chemotherapy

45% 33%

Prior Adjuvant Endocrine Therapy (TAM)

68% 40%

Mean PFS Range (m) 10–11 13–15

PFS Benefit No Yes

Mehta et al, 2012; Bergh et al, 2012.

Women With Advanced Breast Cancer

ER and/or PgR + Tumors

R A N D O M I Z E

Endocrine Therapy* po Daily +Bevacizumab 15 mg/kg IVPB q21days

Endocrine Therapy* po Daily + Placebo(for bevacizumab) 15 mg/kg IVPB

q21days

Restage q3cycles for first 18 cycles, then q4cycles

until first disease progressionCycle = 21 days

CALGB 40503CALGB 40503

CALGB = Cancer and Leukemia Group B.US NIH, NCT00601900.

Stratification:Planned Endocrine Tx

Letrozole / TamoxifenDisease Measurability

Yes / NoDisease-Free Interval

≤ 24 Mos / > 24 Mos

Choice of endocrine therapy is tamoxifen or the aromatase inhibitor letrozole Ovarian suppression is required, if premenopausal Ovarian suppression can be initiated at start

Key Takeaways:Key Takeaways:What Is the Optimal Frontline Therapy for a What Is the Optimal Frontline Therapy for a Patient With Advanced ER+ Breast Cancer?Patient With Advanced ER+ Breast Cancer?

Variety of treatment options for such patients

Premenopausal: OFS + TAM

Postmenopausal: AI, F, TAM

Role of combination anti-estrogen therapy unclear

– Maybe modest benefit in absolutely endocrine naïve populations

*OFS = ovarian function suppresion.NCCN, 2012.

What Is the Optimal Therapy for Patients What Is the Optimal Therapy for Patients With Advanced or Metastatic ER+ With Advanced or Metastatic ER+

Endocrine-Resistance Who Progressed Endocrine-Resistance Who Progressed After Previous Lines of Therapies?After Previous Lines of Therapies?

Case Study 3Case Study 3 A 64-yr-old woman is being treated for advanced ER+ breast

cancer. 14 yrs ago, she received AC chemotherapy for node-negative breast cancer.

She experienced chemotherapy-induced amenorrhea, and received 5 yrs of tamoxifen

3 yrs ago, she was diagnosed with recurrent breast cancer to bone and lymph node. She began treatment with bisphosphonates and aromatase inhibitor.

After 2 yrs, she had progression and began fulvestrant therapy. 10 mos later, she has again progressed with increased bone disease and enlarged axillary, chest, and abdominal lymph nodes.

She has mild bone pain in multiple locations and is fatigued but otherwise well

NCCN, 2012.

Case Study 3 (cont.)Case Study 3 (cont.)

You are discussing treatment options with her.

In comparison to exemestane alone, treatment with everolimus and exemestane is associated with an increased risk of all of the following, except:

1) Hyperglycemia

2) Stomatitis

3) Fatigue

4) Arthralgias

5) Pneumonitis / Dyspnea

Baselga et al, 2012; NCCN, 2012.

Summary: Second-Line Randomized Studies Summary: Second-Line Randomized Studies AI Vs. MAAI Vs. MA

*MA = megestrol acetate.Buzdar et al, 1996, 2001; Dombernowsky et al, 1998; Kaufmann et al, 2000.

NCCTG Study: Efficacy of Fulvestrant NCCTG Study: Efficacy of Fulvestrant Following Failure of an AI and TamoxifenFollowing Failure of an AI and Tamoxifen *Overall CBR: 35.0%, PR: 14.3%

Median duration of response: 11.4 mos

Median survival: 20.2 mos– 1-yr survival rate: 70.5%

CBR = clinical benefit rate.Ingle et al, 2006.

Adjuvant Advanced

AI

Tamoxifen

*Tamoxifen

Tamoxifen

AI

AI

AI

Tamoxifen

AI

Fulvestrant

FulvestrantN = 56

CBR 52.4%PR 28.6%

CBR 28.6%PR 8.9%

EFECT: Evaluation of Fulvestrant EFECT: Evaluation of Fulvestrant and Exemestane Clinical Trialand Exemestane Clinical Trial

Fulvestrant Loading Dose + Placebo for

Exemestane (n = 330)

Exemestane 25 mg Orally Daily + Placebo for

Fulvestrant (n = 330)

Progression

Survival

Progression

Survival

500 mg Day 1,250 mg Day 14, 28, and Monthly

Prior Nonsteroidal AI Failure

Analysis After 580 Events (progression or death)

Chia et al, 2008.

Chia et al, 2008.

EFECT: EXE Vs. Fulvestrant Following EFECT: EXE Vs. Fulvestrant Following Nonsteroidal AI TherapyNonsteroidal AI Therapy

Kaplan-Meier Estimates for TTP

1.0

0.8

0.6

0.4

0.2

0 100 200 300 400 500 600 700 800

Time to Progression (days)

Pro

po

rtio

n o

f P

atie

nts

P

rog

ress

ion

-Fre

e (%

)

Days 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 Fulvestrant At Risk 351 301 191 127 89 67 46 29 23 13 10 4 4 2 0 Exemestane At Risk 342 305 184 130 86 56 37 24 21 13 10 8 8 6 2

“The oestrogens thus provide a further example of the relation (only apparently paradoxical) that compounds possessing growth-retarding properties in certain circumstances may also have either with the physiological stimulation of growth or with the induction of tumors.”

Haddow et al, 1944.

Sir Alexander Haddow 1944Sir Alexander Haddow 1944

BJ Kennedy, 1957BJ Kennedy, 1957

“The findings suggest that some advanced primary breast cancers not originally thought to be susceptible to palliative operative attack may be so rendered after significant regression under hormonal therapy.”

Kennedy et al, 1957.

“When the tumor reactivated a hormone therapy was reinstituted and eight months of therapy lead to a further tumor regression for 18 months.”

Stoll, 1973.

Basil Stoll 1973Basil Stoll 1973

Tamoxifen Vs. DiethylstilbestrolTamoxifen Vs. Diethylstilbestrol

Ingle et al, 1981.

Estradiol Induced ApoptosisEstradiol Induced Apoptosis

Estradiol deprivation sensitizes MCF7 cells to estradiol induced apoptosis in vitro

Tamoxifen resistant MCF7 cells are sensitive to estradiol induced apoptosis

in vivo

Images courtesy of Matthew Ellis.Song et al, 2001; Liu et al, 2003.

E2 Concentration (nM)

Cel

l Num

ber

(x10

6 /w

ell)

1 2 3 4 5 6 7 8 9

Time (wks)

Cro

ss S

ectio

nal T

umor

Are

a (c

m2)

1.2

0.8

0.4

0

Estradiol After AIEstradiol After AI

PostmenopausalER+ and/or PR+ 30 mg estradiol

(10 mg tid)

6 mg estradiol

(2 mg tid)

Response to AI

CR, PR, or SD*

or

2 yrs before relapse

on AI

RANDOMIZE

*Progression-free at 24 wks.Ellis et al, 2009.

Acquired AI Resistance

RR CBR

3% 28%

9% 29%

ER and mTOR / PI3K: ER and mTOR / PI3K: CrosstalkCrosstalk

PI3K = phosphatidyl inositol 3-kinase; AKT = protein kinase B. Rugo et al, 2012.

Schematic of the PI3K/AKT/mTOR Pathway Schematic of the PI3K/AKT/mTOR Pathway

ECOG = Eastern Cooperative Oncology Group.Baselga et al, 2012.

Exemestane ±Everolimus 10 mg Day

ER+ and HER2-

AI Refractory

ECOG 0–2

BOLERO-2: Phase 3 RCT StudyBOLERO-2: Phase 3 RCT StudyKaplan-Meier Plot of PFS

*With at least 10% incidence in the everolimus-exemestane group.AE = adverse event.Baselga et al, 2012.

BOLERO-2: Phase 3 RCT StudyBOLERO-2: Phase 3 RCT StudyAEs Irrespective of Relationship to Study Treatment*AEs Irrespective of Relationship to Study Treatment*

AEs with most relevant toxicity difference between both groups

SD = stable disease; PD = progressive disease. Baselga et al, 2012.

BOLERO-2: Phase 3 RCT StudyBOLERO-2: Phase 3 RCT StudyEfficacy Analysis Local/Central AssessmentEfficacy Analysis Local/Central Assessment

ITT = intent-to-treat.Bachelot et al, 2012.

TAMRAD TrialTAMRAD Trial TTP in the ITT population for (I) the overall patient population and patients with (II) primary and (III) secondary hormone resistance

Pro

babi

lity

of S

urvi

val (

%)

Time (mos)

TT

P P

roba

bilit

y (%

)

Time (mos)

I

III

II

Overall Response Rate: 9%Clinical Benefit Rate: 14%

Chan et al, 2005.

1.0

0.5

0.6

0.8

0.7

0.9

0.1

0.3

0

0.2

24

0.4

16 32 40 56488

Time (wks from first dose)

Temsirolimus in Heavily Pretreated MBCTemsirolimus in Heavily Pretreated MBC

Letrozole +/- TemsirolimusLetrozole +/- Temsirolimus

Estratification by:

Geographic Regions

United States Western Europe, Australia, New Zealand, India, Canada Asia-Pacific, Eastern Europe, Africa, South America

Temsirolimus, 30 mg VOQD

for 5 days q2wks

+

Letrozole, 2.5 mg VOQD

(n = 556)

Letrozole, 2.5 mg VOQD

(n = 556)

RANDOMIZE

Chow, 2006.

Enrollment open from May 2004 to March 2006

1,112 patients randomly assigned

Patients treated until evidence of PD or as long as tolerated

TEMSR + LET: LET = comparisons for stratified log-rank p value and HR.Chow, 2006.

Letrozole +/- Temsirolimus EfficacyLetrozole +/- Temsirolimus Efficacy

ER and EGFR: CrosstalkER and EGFR: Crosstalk

Reciprocal Crosstalk Between ERReciprocal Crosstalk Between ERαα and and Growth Factor Receptor Signaling PathwaysGrowth Factor Receptor Signaling Pathways

Miller et al, 2011.

Osborne et al, 2011.

Stratum 1. Tam-SensitiveTam ± GefitinibRR: T, 15%; T+G, 12%

Stratum 1. HER2+ Cases

Stratum 1, By Prior Endocrine Rx

Stratum 2. AI-ResistantRR: T, 0%; T+G, 0%PFS: T, 7.0 m; T+G, 5.7 m

Tamoxifen ± Gefitinib for ER+ MBCTamoxifen ± Gefitinib for ER+ MBCP

ropo

rtio

n P

FS

(%

)

Time (yrs)

Cristofanilli et al, 2010.

PFS: Endocrine-Naïve

Anastrozole ± Gefitinib for ER+ MBCAnastrozole ± Gefitinib for ER+ MBC

PFS – OverallRR: A, 12%; A+G, 2%Median PFS: A, 8.4 m; A+G 14.7 m

Time (mos)

Pro

babi

lity

of P

FS

(%

)

Time (mos)

Pro

babi

lity

of P

FS

(%

)

PFS: Endocrine-Treated

Time (mos)

Pro

babi

lity

of P

FS

(%

)

ER and HER2: CrosstalkER and HER2: Crosstalk

Crosstalk Between Signal Transduction Pathways and Crosstalk Between Signal Transduction Pathways and ER Signaling in Endocrine-Resistant Breast Cancer, ER Signaling in Endocrine-Resistant Breast Cancer,

With Opportunities for Targeted InterventionWith Opportunities for Targeted Intervention

Adapted from Johnston, 2010.

SOSRAS

RAF

BasalTranscription

Machineryp160

ERE ER Target Gene Transcription

ER CBPPP P P

ER

Pp90RSK

AktP

MAPKP

CellSurvival

Cytoplasm

Nucleus

ER

PI3-KP

P

PPP

P

CellGrowth

MEKP

PlasmaMembrane

EGFR/HER2

IGFRGrowth FactorEstrogen

mTOR

.

Gutierrez et al, 2005.

HER2 Upregulation in Tamoxifen-Resistant HER2 Upregulation in Tamoxifen-Resistant Breast CancersBreast Cancers

3 Cases From 30 That Were ER+ and HER2- at Baseline3 Cases From 30 That Were ER+ and HER2- at Baseline

Kaufman et al, 2009.

TANDEM: Anastrozole +/- TrastuzumabTANDEM: Anastrozole +/- Trastuzumab

PF

S (

pro

ba

bili

ty)

TT

P (

pro

ba

bili

ty)

OS

(p

rob

ab

ility

)

Time (mos)

Johnston et al, 2009.

Letrozole +/- LapatinibLetrozole +/- LapatinibA

live

With

ou

t P

rog

ress

ion

(%

)

Time Since Random Assignment (mos)

0 10 20 30 40 50

100

80

60

40

20

0

Patients At Risk: Letrozole 642 438 294 208 120 78 51 26 11 2+ LapatinibLetrozole 644 403 291 212 140 80 53 23 13 7

CR PR SD > 6 mos ORR CBR

70

50

30

10

Pat

ient

s (%

)

Johnston et al, 2009.

Letrozole +/- Lapatinib:Letrozole +/- Lapatinib:Clinical Efficacy in Human EGFR2+ PopulationClinical Efficacy in Human EGFR2+ Population

Aliv

e W

itho

ut

Pro

gre

ssio

n (

%)

Time Since Random Assignment (mos)

Patients At Risk: Letrozole 110 69 33 20 12 8 4 1 1+ LapatinibLetrozole 108 43 26 18 12 7 5 2 2

Pa

tien

ts (

%)

Su

rviv

ing

(%

)

Time Since Random Assignment (mos)

Patients At Risk: Letrozole 111 104 89 80 64 48 32 19 9 4+ LapatinibLetrozole 108 93 76 69 59 38 31 15 8 2

Optimizing Chemotherapy-Free SurvivalOptimizing Chemotherapy-Free Survival

The 2 most prominent biological targets in breast cancer that are used for therapy and research are ER and HER2

50% of all HER2+ breast cancer cases also express ER, so 10% of all breast cancer

ER and HER2 pathways crosstalk and thereby synergize in tumor progression

Therefore, targeting both at the same time, potentially with other compounds and dual HER2 targeting, may increase clinical efficacy and improve long-term outcomes of patients with MBC

Several clinical trials are supporting this preclinical hypothesis

Gluck et al, 2011.

Postmenopausal women ER and/or PgR + tumors Prior Tx with AI

Stratification: Prior tamoxifen Tx

Yes/no Bone disease only

Yes/no

R A N D O M I Z E

Double-Blinded

Fulvestrant D1, 15 (Cycle 1 only) Lapatinib D1-28

Fulvestrant D1, 15 (Cycle 1 only) Placebo D1- 28

Restage q2cycles Continue study Tx until PD or undue toxicity

Cycle duration = 28 days Follow -up: Follow all patients registered to this study, including those who do not receive any

protocol treatment, for first PD, any new primaries and survival for 5 yrs from study entry or until death, whichever comes first

CALGB 40302CALGB 40302

Burstein et al, 2010.

Median PFS

Lapatinib 5.2 mPlacebo 4.0 m

Logrank p Value .94

Burstein et al, 2010.

CALGB 40302 (cont.)CALGB 40302 (cont.)

Median PFSLapatinib 4.1 mPlacebo 4.0 m

Median PFSLapatinib 5.9 mPlacebo 2.8 m

Interaction test: HER2 status and treatmentin Cox proportional hazard model2-sided p value = .23

CALGB 40302 (cont.)CALGB 40302 (cont.)

Months from Study Entry

Pro

b. A

live

& P

rog

ress

ion

-Fre

e

PFS: HER2-negative Tumors

0 6 12 18 24 30

0.0

0.2

0.4

0.6

0.8

1.0

93 52 24 13 10 5 4 1 0 0 085 46 24 13 5 3 1 1 1 0 0

Number of Patients at RiskLapatinibPlacebo

LapatinibPlacebo

Months from Study Entry

Pro

b. A

live

& P

rog

ress

ion

-Fre

e

PFS: HER2-positive Tumors

0 6 12 18 24 30

0.0

0.2

0.4

0.6

0.8

1.0

23 16 9 6 3 3 3 3 2 1 128 12 8 5 5 4 3 2 2 1 0

Number of Patients at RiskLapatinibPlacebo

LapatinibPlacebo

Burstein et al, 2010.

Key Takeaways:Key Takeaways:What Is the Optimal Therapy for Patients With What Is the Optimal Therapy for Patients With

Advanced or Metastatic ER+ Endocrine-Advanced or Metastatic ER+ Endocrine-Resistance Who Progressed After Previous Resistance Who Progressed After Previous

Lines of Therapies?Lines of Therapies?

Variety of options for endocrine-refractory breast cancer including AIs, fulvestrant, progestins, estrogens, treatment withdrawal

Strategies to overcome resistance

– Anti-EGFR shows no clinical benefit

– Anti-HER2 shows modest gains

– Anti-mTOR improves PFS but with side effects

Key Takeaways (cont.)Key Takeaways (cont.)

Management of ER+ breast cancer is the art of oncology

A variety of endocrine options available

After more than 100 yrs, new options still emerging