Despite remarkable progress in the treatment of breast cancer in recent years, management of estrogen receptor (ER)-positive disease remains a challenge. Through didactic and case presentations, expert faculty will address clinical debates regarding optimal treatment selection and the incorporation of new classes of targeted therapies into practice to improve outcomes and overcome resistance in the management of ER-positive breast cancer
Target Audience
This activity has been designed to meet the educational needs of medical oncologists and other healthcare providers who are involved in the care and treatment of patients with advanced estrogen receptor (ER)-positive breast cancer.
Purpose
The goal is to optimize the clinical decision-making of clinicians involved in the treatment of advanced ER-positive breast cancer by providing updates on emerging data.
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This 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 the faculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should 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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This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply.
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Community Oncology Clinical Debates in Breast Cancer: Advanced ER-Positive Disease
1.
2. DISCLAIMER
This 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 the
faculty, and not those of IMER, the CME provider, or the commercial supporter. These
materials may discuss therapeutic products that have not been approved by the US
Food and Drug Administration and off-label uses of approved products. Readers
should 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.
Usage Rights
This slide deck is provided for educational purposes and individual slides may be
used for personal, non-commercial presentations only if the content and references
remain unchanged. No part of this slide deck may be published in print or
electronically as a promotional or certified educational activity without prior written
permission from IMER. Additional terms may apply. See Terms of Service on
IMERonline.com for details.
3. DISCLAIMER
Participants 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 USE
This 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.
4. Disclosure 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.
5. Community Oncology Clinical
Debates in Breast Cancer:
Advanced ER-Positive Disease
Harold J. Burstein, MD, PhD
Dana-Farber Cancer Institute
6. Learning Objectives
Upon completion of this activity,
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.
7. Activity 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)
8. Outline
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
9. Can We Predict Response or
Resistance Patterns to Endocrine
Therapy in ER+ Breast Cancer?
10. Case Study 1
A 57-yr-old woman has recently been diagnosed with
ER+ 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.
11. Question 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.
12. Advanced Breast Cancer Is Treated
Based on the Biology of the Tumor
Advanced Breast Cancer
Requiring Therapy
ER and/or PR Positive ER and/or PR Negative
Hormonal Treatment Chemotherapy
Refractory to Hormonal HER2+ HER2-
Therapy Chemotherapy Chemotherapy
+ Anti-HER2
Agents
14. Clinical Predictors of Outcome
for 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.
15. Time Dependence of Breast Cancer Recurrence
in Subsets Defined by Genomic Assays
Intrinsic/
PAM50
Relapse-Free Survival
MammaPrint
(%)
OncotypeDX
Time After Diagnosis (yrs)
Jatoi et al, 2011.
16. ER+ Metastatic Breast Cancer
Goals of Therapy
Individual Goals Clinical Trial Outcomes
Extend survival Response rate
Improve or maintain QOL Response duration
Clinical trial end points have TTP
only some relationship to these
goals TTF
OS
Clinician Goals QOL
Maximize QOL
Minimize treatment related
symptoms and impact on
patient lifestyle
Practice the “art” of
oncology
QOL = quality of life; TTP = time to disease progression; TTF = time to treatment failure;
OS = overall survival.
17. Response/Benefit Rates
Over Time
R
E
S
I
S
40% 30% 25% 15% T
A
N
C
First Second Third Fourth E
Line Line Line Line
Harvey, 2000.
18. How Important Is Response in ER+ MBC?
At 2-Yr
Risk Deaths Estimate
CR or PR 33 10 85%
100
Stable ≥ 24 wks78 23 86%
Other 152 118 35%
80
Survival (%)
60
40
20
0
0 1 2 3 4
Time (yrs from randomization)
CR = complete response; PR = partial response.
Robertson et al, 1999.
19. Metastatic Breast Cancer:
Chemo or Endocrine
Trials Included ER- Patients
ANZBCTG* Taylor
Tam AC Tam CMF
N 339 181
CR + PR (%) 22 45 45 38
TTP (mos) 3 11 6.2 6.2
OS (mos) 23 20 23 21
*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.
20. NCCN Database: Univariate Logistic
Regression for Site of First Recurrence*
Triple Negative vs. ER+ HER2+ vs. ER+
Site OR (95% CI)** p Value OR (95% CI) p Value
Distant vs.
Locoregional 1.32 (1.01, 1.74) .045 1.12 (0.83, 1.51) .45
Lung vs. Other 2.17 (1.47, 3.21) < .001 1.73 (1.13, 2.66) .012
Brain vs. Other 3.50 (2.10, 5.85) < .001 3.97 (2.35, 6.72) < .001
Bone vs. Other 0.26 (0.19, 0.36) < .001 0.39 (0.29, 0.54) < .001
Liver vs. Other 1.09 (0.74, 1.61) .67 1.48 (1.07, 2.33) .021
*Analysis based on cohort of 1,389 patients with documented recurrence (TN, n = 480;
HER+, n = 373; Luminal, n = 536) ER+ cohort used as the referent group for all analyses.
**OR; CI; Other refers to any/all distant/locoregional site.
NCCN = National Comprehensive Cancer Network; TN = triple negative; OR = odds ratio;
CI = confidence interval.
Lin et al, 2012.
21. Sites of Recurrence by Subset
British Columbia Registry 1986–1992
Pleura /
Brain (%) Liver (%) Lung (%) Bone (%) LN (%) Peritoneum
(%)
A 8 29 24 67 16 28
Luminal
B 11 32 30 71 23 35
ER+ 15 44 37 65 22 34
HER2+
ER- 29 46 47 60 25 32
Basal 25 21 43 39 40 30
TN Non-
Basal 22 32 36 43 36 28
Kennecke et al, 2010.
23. Relationship of ER to Response to Endocrine
Therapy in Advanced Breast Cancer
Early Clinical Correlations
Objective Remissions
Investigator Year Patients
Positive Borderline
and Negative
Jensen et al. 1970 26 4/6 1/20
1971 42 10/13 1/29
1973 54 13/17 2/37
Maass et al. 1972 21 6/7 0/14
1973 59 13/24 2/35
Englesman et al. 1973 37 14/17 2/20
Leung et al. 1973 20 10/10 2/10
Savlov et al. 1974 11 3/5 0/6
Total
(through 1974) 181 53/73 8/108
Jensen, 1980.
24. Quantitative Estrogen Receptor Analysis:
The Response to Endocrine and Cytotoxic
Chemotherapy in Human Breast Cancer and
Disease-Free Interval
Response Rate to Endocrine Therapy as a Function of ER Correlation
Response Rate
ER (fmol/mg cytoplasmic protein)
0 ≤ ER < 10 3/33 (9%) ----
10 ≤ ER < 20 3/10 (30%) p > .05
20 < ER < 50 7/11 (63%) p < .001
ER ≥ 50 24/31 (77%) p < .00001
Lippman et al, 1980.
25. Value of Estrogen and Progesterone Receptors
in the Treatment of Breast Cancer
Quantitative ER and the Response to Endocrine Therapy
Objective Response
Primary Biopsy Metastatic Biopsy
ER fm/mg
0–3 1/6 (17%) 4/47 (8%)
3–100 17/38 (45%) 26/65 (40%)
> 100 5/6 (83%) 22/36 (61%)
Response to Endocrine Therapy as a Function of ER and PgR
ER- PgR- ER- PgR+ ER+ PgR- ER+ PgR+
San Antonio 3/20 --- 14/45 16/20
Other Series 9/91 6/13 19/76 71/93
Total 12/111 (11%) 6/13 (46%) 33/121 (27%) 87/113 (77%)
PgR = progesterone receptor.
Osborne et al, 1980.
26. ER Status and Response to Tamoxifen
in Advanced Breast Cancer
Clinical Correlation Between ER Measurements and Response to Tamoxifen
Remissions No Change Failures
No. (%) No. (%) No. (%)
Status No.
A. ER
(Assay Not 80 34 43 13 16 33 41
Done)
B. ER+ 77 43 56* 5 6 29 38
C. ER- 6 0 0 0 0 6 100
D. ER+/-** 3 0 0 0 0 3 100
*p = .04; A vs. B.
**ER measurements were low positive in 1 biopsy, and negative in another taken
simultaneously.
Manni et al, 1980.
27. Quantitative ER and PR as Predictors of Response
to Tamoxifen in Advanced Breast Cancer
Correlation Between ER, PR, and Response to Tamoxifen
PR Level and Response to Tamoxifen
ER Level No. Percent
(fmol/mg of Patients 0–10 10.1–30 30.1–300 > 300 Total Response
protein)
<3 22* 1/20 0/1 0/1 --- 1/22 5
3.0–10 76 10/66 3/8 1/2 --- 14/76 18
10.1–30 219 24/86 43/107 10/20 3/6 80/219 37
30.1–300 63 6/11 25/31 14/17 3/4 48/63 78
> 300 35 4/6 12/15 7/8 4/6 27/35 77
Total 415 45/189 83/162 32/48 10/16 170/416
Percent 14 51 68 63 46
*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.
28. Significant Rate of Discordancy
Between Primary and Metastases
Amir Curigliano
2010 Studies Karlsson Lindstrom
(n ~ 270) (n ~ 250)
Comparing Primary (n ~ 470) (n ~ 118–459)
Prospective Retrospective
to Metastasis Retrospective Retrospective
Reanalyzed Liver Only
ER+ ER- 12% 11% 36% 26%
ER- ER+ 14% 25% 22% 7%
HER2- HER2+ 5% 6% nd 7%
HER2+ HER2- 12% 32% nd 3%
Amir et al, 2010; Curigliano et al, 2011; Karlsson et al, 2010; Lindstrom et al, 2010.
29. Key Takeaways:
Can We Predict Response or Resistance Patterns to
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
30. What Is the Optimal Frontline
Therapy for a Patient With
Advanced ER+ Breast Cancer?
31. Case 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.
32. 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.
33. Shifting Landscape of Therapy for
ER+ Metastatic Breast Cancer
Decade Adjuvant Metastatic
1980s None OA, Tamoxifen
1990s Tamoxifen AI
[AI, Tamoxifen]
2000s AI, Tamoxifen Fulvestrant
[AI, Tamoxifen]
Fulvestrant, mTOR
2010s AI, Tamoxifen Inhibition
OA = ovarian ablation; AI = aromatase inhibitors; mTOR = mammalian target of rapamycin.
36. Randomized Trial of Single Vs.
Combination Endocrine Therapy
100 LHRH-A + TAM
Premenopausal LHRH-A
Women With ER+ 80
TAM
Advanced Breast
Percent (%)
Cancer 60
Tamoxifen 40
Vs.
20
Buserelin
Vs. 0
Combination 0 2 4 6 8 10
Time (yrs)
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
Klijn et al, 2000.
39. Megesterol Acetate Vs. Tamoxifen
for Advanced Breast Cancer
Phase III Study of the Piedmont Oncology Association
Cumulative Proportion Survival (%)
Proportion Progression Free (%)
90 100
80
60 70
50
40
20 30
0 10
0 6 12 18 24 30 36 0 12 24 36 48 60
Time (mos) Time (mos)
Muss et al, 1988.
40. Summary: First-Line Randomized
Studies AI Vs. Tamoxifen
Anastrozole Letrozole
Exemestane
(2 studies) 60% ER+ 66% ER+
No. Patients 1,021 907 371
Daily Dosage 1 2.5 25
Significant Survival Not Yet vs.
Advantage vs. TAM (mos) None 35 vs. 32 ns 123 wks (.039)
10.7 vs. 6.4
TTP (mos) vs. TAM
(ER+ only, not ITT) 9.4 vs. 6.0 9.9 vs. 5.8
Clinical Benefit
(CR + PR + SD ≥ 24 wks)
vs. TAM (%) 56.8 vs. 50.0 50.0 vs. 38 NR
Response Rates**
(CR + PR) vs. % 29 vs. 27.1 32 vs. 21 46 vs. 31
Survival Impact No +/- No
41. Fulvestrant Vs. Anastrozole: Trial Design
Postmenopausal women with advanced breast cancer receiving prior
endocrine treatment for early or advanced breast cancer
Trials 0020 and 0021: Recruitment between May 1997 and August 1999
Trial 0020: International, randomized 1:1, open, parallel-group
Trial 0021: North American, randomized 1:1, double-blind, double-dummy, parallel-group
Fulvestrant 250 mg im qm Anastrozole 1 mg qdo
Trial 0020: 1 x 5 mL (n = 222) Trial 0020 (n = 229)
Trial 0021: 2 x 2.5 mL (n = 206) Trial 0021 (n = 194)
Median TTP: Fulvestrant = 5.5 mos
Anastrozole = 4.1 mos
Robertson et al, 2003.
42. Fulvestrant Vs. Anastrozole
Proportion Without Progression (%) After SERMs
Time to Progression (mos)
Howell et al, 2002.
43. Duration of Response:
Without or With Visceral Metastases
Without Visceral Metastases With Visceral Metastases
Fulvestrant 250 mg (n = 52) Fulvestrant 250 mg (n = 30)
Anastrozole 1 mg (n = 45) Anastrozole 1 mg (n = 25)
1.0 1.0
Objective Response
Proportion With
0.8 0.8
0.6 0.6
0.4 0.4
0.2 0.2
0.0 0.0
0 200 400 600 800 1,000 0 200 400 600 800 1,000
Duration of Objective Response (days)
Mauriac et al, 2003.
44. CONFIRM: Fulvestrant 500 Vs. 250
PFS Curves by Treatment Arm
1.0
Proportion of Patients
0.8
Progression Free (%)
0.6
0.4
0.2
4 12 20 28 36 44
Time (mos)
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.
Di Leo et al, 2010.
45. FIRST Trial: Fulvestrant Vs. Anastrozole
in Endocrine-Naïve Breast Cancer
1.0
Progressed (%)
Proportion Not
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21
Time to Progression (mos)
No. Patients At Risk:
Fulvestrant HD 102 96 76 46 31 17 7 5
Anastrozole 1 mg 103 90 68 38 23 13 6 5
Robertson et al, 2009.
46. Combined Letrozole and Fulvestrant Delays
Emergence of Resistance to LTED in MCF-7Ca
Xenografts
The Effect of the Letrozole and Fulvestrant Alone or in Combination
on the Growth of MCF-7Ca Aromatase Xenograft
800
600
400
200
0 4 8 12 16 20 24 28 32 36
Treatment Time (wks)
LTED = long term extrogen deprived.
Brodie et al, 2005.
47. FACT Trial: AI +/- Fulvestrant
Kaplan-Meier TTP and Median TTP in Mos (full analysis set)
1.0
0.8
PFS (%) 0.6
0.4
0.2
0
6 18 30 42 54
Time (mos)
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 Anastrozole
(n = 258) (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): 0.99
HR* (95% CI) (0.81–1.20)
p Value .91
Bergh et al, 2012.
48. SWOG 0226:
Anastrozole +/- Fulvestrant for MBC
Mehta et al, 2012.
49. Progression-Free Survival, According to Subgroups
Subgroup Hazard Ratio for Progression of Death (95% CI) P value for
interaction
Age .95
≥65 yr 0.79 (0.62-1.01)
<65 yr 0.79 (0.63-1.00)
HER2 status .22
positive 0.58 (0.33-1.03)
negative 0.81 (0.67-0.98)
Disease site .96
nonvisceral 0.84 (0.61-1.14)
visceral 0.79 (0.62-0.99)
bone only 0.77 (0.54-1.11)
Measurable disease .08
No 0.93 (0.73-1.19)
Yes 0.69 (0.55-0.86)
Time between diagnosis of primary and .22
metastatic disease
≥10 yr 0.59 (0.42-0.83)
5 to <10 yr 1.03 (0.70-1.48)
3 mo to <5 yr 0.84 (0.54-1.31)
none 0.84 (0.65-1.10)
Previous chemotherapy .80
No 0.81 (0.66-1.00)
Yes 0.75 (0.56-1.00)
Previous Tamoxifen .22
No 0.74 (0.59-0.92)
Yes 0.89 (0.69-1.15)
Overall 0.80 (0.68-0.94)
0.4 0.6 0.8 1.0 1.2 1.4
Combination Anastrozole
Better Alone Better
Mehta RS et al, 2012
50. SoFEA
Partially-Blind Phase III Randomized Trial
Postmenopausal Women With ER+
Advanced Breast Cancer Following
Progression on Non-Steroidal AIs
PFS OS CBR
Fulvestrant + Anastrozole 4.4 mos 20.2 mos 33.7
N = 241 p = .98 p = .61 %
RANDOMIZED
Fulvestrant + Placebo
N = 230 4.8 mos 19.4 mos
p = .98 p = .61 31.6
%
Exemestane
3.4 mos 21.6 mos
N = 247
p = .56 p = .68
26.9
%
Only study of fulvestrant in the setting of acquired AI resistance
None of the differences in RR, CBR, PFS or OS were statistically significant.
Johnston et al, 2012; Moser, 2012.
US NIH, NCT00253422.
51. Comparison of AI ± F Trials
FACT SWOG 0226
No. Patients 514 707
De Novo Metastatic 13% 39%
Disease
Prior Adjuvant 45% 33%
Chemotherapy
Prior Adjuvant Endocrine 68% 40%
Therapy (TAM)
Mean PFS Range (m) 10–11 13–15
PFS Benefit No Yes
Mehta et al, 2012; Bergh et al, 2012.
52. CALGB 40503
Stratification:
Women With Advanced
Planned Endocrine Tx
Breast Cancer
Letrozole / Tamoxifen
ER and/or PgR + Tumors
Disease Measurability
Yes / No
Disease-Free Interval
≤ 24 Mos / > 24 Mos
R Endocrine Therapy* po Daily +
A Bevacizumab 15 mg/kg IVPB q21days
N
D Restage q3cycles for first
O 18 cycles, then q4cycles
M until first disease progression
I Cycle = 21 days
Z Endocrine Therapy* po Daily + Placebo
E (for bevacizumab) 15 mg/kg IVPB
q21days
Choice of endocrine therapy is tamoxifen or the aromatase inhibitor letrozole
Ovarian suppression is required, if premenopausal
Ovarian suppression can be initiated at start
CALGB = Cancer and Leukemia Group B.
US NIH, NCT00601900.
53. Key Takeaways:
What Is the Optimal Frontline Therapy for a
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.
54. What Is the Optimal Therapy for Patients
With Advanced or Metastatic ER+
Endocrine-Resistance Who Progressed
After Previous Lines of Therapies?
55. Case 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.
56. 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.
57. Summary: Second-Line Randomized Studies
AI Vs. MA
Anastrozole Letrozole Letrozole Exemestane
No. Patients 263 vs. 253 199 vs. 201 174 vs. 189 366 vs. 403
Daily Dosage 1 mg 2.5 mg 2.5 mg 25 mg
Significant Yes No No Yes
Survival 26.7 vs. 22.5 28.6 vs. 26.2 25.8 vs. 21.5 vs. 28.4
Advantage vs. MA (p < .025) (NS) (p = .15) (p = .039)
(mos)
Median FU +33 mos +37 mos 45 mos 11 mos
TTP (mos) vs. MA 4.8 vs. 4.6 3.2 vs. 3.4 5.6 vs. 5.5 4.7 vs. 3.9
(NS) (p = .99) (p = .07) (p = .037)
Clinical Benefit 42 vs. 40 26.7% vs. 23.4 35 vs. 32 37 vs. 35
(CR + PR + SD ≥ (NS) (NS) (NS) (NS)
24 wks) vs. MA (%)
Response Rates 12.6 vs. 12.2 16.11 vs. 14.9 15 vs. 12.4 15 vs. 12.4
(CR + PR) vs. MA (NS) (NS) (p = .04) (NS)
(%)
*MA = megestrol acetate.
Buzdar et al, 1996, 2001; Dombernowsky et al, 1998; Kaufmann et al, 2000.
58. NCCTG Study: Efficacy of Fulvestrant
Following 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%
Adjuvant Advanced
AI Tamoxifen
Tamoxifen AI
Fulvestrant
AI Tamoxifen N = 56
CBR 28.6%
*Tamoxifen AI PR 8.9%
AI Fulvestrant CBR 52.4%
PR 28.6%
CBR = clinical benefit rate.
Ingle et al, 2006.
59. EFECT: Evaluation of Fulvestrant
and Exemestane Clinical Trial
500 mg Day 1,
250 mg Day 14, Prior Nonsteroidal AI Failure
28, and Monthly
Fulvestrant Loading
Exemestane 25 mg Orally
Dose + Placebo for
Daily + Placebo for
Exemestane
Fulvestrant (n = 330)
(n = 330)
Progression Progression
Survival Survival
Analysis After 580 Events
(progression or death)
Chia et al, 2008.
60. EFECT: EXE Vs. Fulvestrant Following
Nonsteroidal AI Therapy
Kaplan-Meier Estimates for TTP
1.0
Proportion of Patients
Progression-Free (%)
0.8
0.6
0.4
0.2
0 100 200 300 400 500 600 700 800
Time to Progression (days)
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
Chia et al, 2008.
61. Sir Alexander Haddow 1944
“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.
62. BJ 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.
63. Basil Stoll 1973
“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.
64. Tamoxifen Vs. Diethylstilbestrol
Event DES TAM
N = 74 N = 69
Emesis 18 (25%) 8 (12%)
Edema 39 (53%) 8 (12%)
Phlebitis 2 (3%) 0
Vag Bleed 11 (15%) 1 (1%)
CCF 2 (4%) 0
Hot 2 (3%) 20 (29%)
Flashes
Ingle et al, 1981.
65. Estradiol Induced Apoptosis
1.2
Cross Sectional Tumor Area (cm2)
Cell Number (x106/well)
0.8
0.4
0
1 2 3 4 5 6 7 8 9
Time (wks)
E2 Concentration (nM)
Estradiol deprivation sensitizes MCF7 cells Tamoxifen resistant MCF7 cells are
to estradiol induced apoptosis in vitro sensitive to estradiol induced apoptosis
in vivo
Images courtesy of Matthew Ellis.
Song et al, 2001; Liu et al, 2003.
66. Estradiol After AI
RR CBR
Postmenopausal
ER+ and/or PR+ 30 mg estradiol 3% 28%
R (10 mg tid)
A
Acquired AI Resistance
N
D
O
M
Response to AI
I 6 mg estradiol 9% 29%
CR, PR, or SD*
Z (2 mg tid)
or
E
2 yrs before relapse
on AI
*Progression-free at 24 wks.
Ellis et al, 2009.
68. Schematic of the PI3K/AKT/mTOR Pathway
PI3K = phosphatidyl inositol 3-kinase; AKT = protein kinase B.
Rugo et al, 2012.
69. BOLERO-2: Phase 3 RCT Study
Kaplan-Meier Plot of PFS
Exemestane ±
Everolimus 10 mg Day
ER+ and HER2-
AI Refractory
ECOG 0–2
ECOG = Eastern Cooperative Oncology Group.
Baselga et al, 2012.
70. BOLERO-2: Phase 3 RCT Study
AEs Irrespective of Relationship to Study Treatment*
AE Everolimus and Exemestane Placebo and Exemestane
(N = 482) (N = 238)
Toxicity % (any event)
Stomatitis 56 11
Rash 36 6
Diarrhea 30 16
Decreased Appetite 29 10
Dysgeusia 21 5
AEs with most
Weight Loss 19 5
relevant toxicity
Dyspnea 18 9 difference between
Anemia 16 4 both groups
Epistaxis 15 1
Edema 14 6
Pyrexia 14 6
Hyperglycemia 13 2
Pneumonitis 12 0
Thrombocytopenia 12 <1
Asthenia 12 3
Pruritus 11 3
*With at least 10% incidence in the everolimus-exemestane group.
AE = adverse event.
Baselga et al, 2012.
71. BOLERO-2: Phase 3 RCT Study
Efficacy Analysis Local/Central Assessment
Central Assessment Everolimus and Placebo and p Value HR
Exemestane (N = 485) Exemestane (N = 239) (95% CI)
Best Overall Response (%)
CR 0.0 0.0
PR 7.0 0.4
SD 74.6 64.4
PD 5.6 21.8
Unknown or Too Early 12.8 13.4
Objective Response (%; 95% CI) 7.0 (4.9–9.7) 0.4 (0.0–2.3) < .001
PFS
Events (No.; %) 114 (24) 104 (44) < .001 0.36 (0.27-0.47)
Duration (Mos Median) 10.6 4.1
95% CI 9.5–NR 2.8–5.8
Local Assessment Everolimus and Placebo and p Value HR
Exemestane (N = 485) Exemestane (N = 239) (95% CI)
Best Overall Response (%)
CR 0.4 0.0
PR 9.1 0.4
SD 70.1 58.6
PD 9.9 31.4
Unknown or Too Early 10.5 9.6
Objective response (%; 95% CI) 9.5 (7.0–12.4) 0.4 (0.0–2.3) < .001
PFS
Events (No.; %) 202 (42) 157 (66) < .001 0.43 (0.35-
Duration (Mos Median) 6.9 2.8 0.54)
95% CI 6.4–8.1 2.8–4.1
SD = stable disease; PD = progressive disease.
Baselga et al, 2012.
72. TAMRAD Trial
TTP in the ITT population for (I) the overall patient population and patients with
(II) primary and (III) secondary hormone resistance
I
Probability of Survival (%)
TTP Probability (%)
II
III
Time (mos)
Time (mos)
ITT = intent-to-treat.
Bachelot et al, 2012.
73. Temsirolimus in Heavily Pretreated MBC
1.0
0.9
0.8
Probability of PFS (%)
0.7
0.6
0.5
Overall Response Rate: 9%
0.4 Clinical Benefit Rate: 14%
0.3
0.2
0.1
0
8 16 24 32 40 48 56
Time (wks from first dose)
Chan et al, 2005.
74. Letrozole +/- Temsirolimus
Estratification by: R
Geographic Regions A Temsirolimus, 30 mg VOQD
N
for 5 days q2wks
United States D
Western Europe, O +
Australia, New
Zealand, India, M Letrozole, 2.5 mg VOQD
Canada I (n = 556)
Asia-Pacific, Z
Eastern Europe, E
Africa, South America Letrozole, 2.5 mg VOQD
(n = 556)
Enrollment open from May 2004 to March 2006
1,112 patients randomly assigned
Patients treated until evidence of PD or as long as tolerated
Chow, 2006.
75. Letrozole +/- Temsirolimus Efficacy
TEMSR + LET: LET = comparisons for stratified log-rank p value and HR.
Chow, 2006.
78. Tamoxifen ± Gefitinib for ER+ MBC
Stratum 1. Tam-Sensitive
Tam ± Gefitinib
RR: T, 15%; T+G, 12%
Stratum 1. HER2+ Cases
Proportion PFS (%)
Stratum 1, By Prior Endocrine Rx
Stratum 2. AI-Resistant
RR: T, 0%; T+G, 0%
PFS: T, 7.0 m; T+G, 5.7 m
Time (yrs)
Osborne et al, 2011.
79. Anastrozole ± Gefitinib for ER+ MBC
Probability of PFS (%)
Probability of PFS (%)
PFS – Overall Time (mos) Time (mos)
RR: A, 12%; A+G, PFS: Endocrine-Treated
2%
Median PFS: A,
Probability of PFS (%)
8.4 m; A+G 14.7
m
PFS: Endocrine-Naïve
Cristofanilli et al, 2010. Time (mos)
81. Crosstalk Between Signal Transduction Pathways and
ER Signaling in Endocrine-Resistant Breast Cancer,
With Opportunities for Targeted Intervention
Growth Factor IGFR
Estrogen
EGFR/HER2
Plasma P P
Membrane P P
P
P SOS
PI3-K RAS
RAF
Cell
Survival P
Akt MEK
P
ER
mTOR p90RSK MAPK
P P
Cytoplasm Cell
P P P Basal
P Transcription Growth
ER p160 CBP Machinery
ER
Nucleus ERE ER Target Gene Transcription
Adapted from Johnston, 2010.
82. HER2 Upregulation in. Tamoxifen-Resistant
Breast Cancers
3 Cases From 30 That Were ER+ and HER2- at Baseline
Gutierrez et al, 2005.
83. TANDEM: Anastrozole +/- Trastuzumab
PFS (probability)
TTP (probability)
OS (probability)
Time (mos)
Kaufman et al, 2009.
84. Letrozole +/- Lapatinib
100 70
Alive Without Progression (%)
80
50
Patients (%)
60
30
40
20
10
0
0 10 20 30 40 50 CR PR SD > 6 mos ORR CBR
Time Since Random Assignment (mos)
Patients At Risk:
Letrozole 642 438 294 208 120 78 51 26 11 2
+ Lapatinib
Letrozole 644 403 291 212 140 80 53 23 13 7
Johnston et al, 2009.
85. Letrozole +/- Lapatinib:
Clinical Efficacy in Human EGFR2+ Population
Alive Without Progression (%)
Surviving (%)
Time Since Random Assignment (mos) Time Since Random Assignment (mos)
Patients At Risk: Patients At Risk:
Letrozole 110 69 33 20 12 8 4 1 1 Letrozole 111 104 89 80 64 48 32 19 9 4
+ Lapatinib + Lapatinib
Letrozole 108 43 26 18 12 7 5 2 2 Letrozole 108 93 76 69 59 38 31 15 8 2
Patients (%)
Johnston et al, 2009.
86. Optimizing 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.
87. CALGB 40302
Postmenopausal women Stratification:
ER and/or PgR + tumors Prior tamoxifen Tx
Prior Tx with AI Yes/no
Bone disease only
Double-Blinded Yes/no
R Fulvestrant D1, 15 (Cycle 1 only)
A Lapatinib D1-28
N Restage q2cycles
D
O Continue study Tx until
M PD or undue toxicity
I
Z Fulvestrant D1, 15 (Cycle 1 only)
E Placebo D1-28
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
Burstein et al, 2010.
88. CALGB 40302 (cont.)
Median PFS
Lapatinib 5.2 m
Placebo 4.0 m
Logrank p Value .94
Burstein et al, 2010.
89. CALGB 40302 (cont.)
PFS: HER2-negativ e Tumors PFS: HER2-positiv e Tumors
1.0
1.0
Lapatinib Lapatinib
Placebo
Prob. Alive & Progression-Free
Placebo
Prob. Alive & Progression-Free
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
0.0
0.0
0 6 12 18 24 30 0 6 12 18 24 30
Months from Study Entry Months from Study Entry
Number of Patients at Risk Number of Patients at Risk
Lapatinib 93 52 24 13 10 5 4 1 0 0 0 Lapatinib 23 16 9 6 3 3 3 3 2 1 1
Placebo 85 46 24 13 5 3 1 1 1 0 0 Placebo 28 12 8 Median PFS 4 3 2
5 5 2 1 0
Median PFS
Lapatinib 5.9 m
Lapatinib 4.1 m
Placebo 2.8 m
Placebo 4.0 m
Interaction test: HER2 status and treatment
in Cox proportional hazard model
2-sided p value = .23
Burstein et al, 2010.
90. Key Takeaways:
What Is the Optimal Therapy for Patients With
Advanced or Metastatic ER+ Endocrine-
Resistance Who Progressed After Previous
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
91. 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