Clinical Updates
Hormonally Sensitive, Early-Stage Breast Cancer
Overcoming Resistance in Hormonally
Sensitive Breast Cancer
Ruth M. O’Regan, MD
Associate 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
Mechanisms of SERM Resistance
IGF1R
MoAb
EGFR/HER2
TKI
VEGFR
P
AB P
P
P
MoAb
P
P SOS
TKI
PI3-K
TKI
MEK
Akt
CCI RAD
RAS
RAF
p90RSK
MAPK
Increased signaling
through PI3-K pathway
SERD
AI
ER
T
Increased upstream
signaling through
EGFR and/or IGF-IR
and or VEGFR
E2
PP P P
Cytoplasm
ERER p160 CBP
ERE
Plasma
Membrane
Basal
Transcription
Machinery
ER Target Gene Transcription
Nucleus
Cell
Growth
Mechanisms of intrinsic and acquired resistance is likely similar
Johnston CCR 2005
ER+ Cancers
Are Heterogenous in Outcome
ER+
ER+
Copyright ©2003 by the National Academy of Sciences
Sorlie et al PNAS 2003
1.0
1.0
0.8
0.8
DRFS
DRFS
Efficacy of Tamoxifen Varies
in ER+ Cancers
0.6
0.4
Low Risk (RS<18)
0.2
Placebo
Tamoxifen
N
171
142
0.6
0.4
Int Risk (RS 18-30)
0.2
Placebo
Tamoxifen
0.0
N
85
69
0.0
0
2
4
6
8
10
12
14
16
Years
0
2
4
6
8
10
12
14
16
Years
1.0
DRFS
0.8
TAM-resistant
0.6
0.4
High Risk (RS≥31)
0.2
Placebo
Tamoxifen
Interaction P=0.06
N
99
79
0.0
0
2
4
6
8
Years
10
12
14
16
Paik et al SABCS 2004
Correlation Between Recurrence Score
and Intrinsic Subtype
Recurrence
Luminal A
Luminal B
Score
(n = 123)
(n = 55)
Low
62
1
Intermediate
25
4
High
36
50
Fan et al NEJM 2006
Oncotype DX 21
Gene Recurrence Score (RS) Assay
16 Cancer and 5 Reference Genes From 3 Studies
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
GSTM1
INVASION
Stromolysin 3
Cathepsin L2
HER2
GRB7
HER2
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
BAG1
ESTROGEN
ER
PR
Bcl2
SCUBE2
CD68
Reference
Beta-actin
GAPDH
Category
RS (0 – 100)
Low risk
RS < 18
Int risk
RS ≥ 18 and < 31
High risk
RS ≥ 31
RPLPO
GUS
TFRC
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
Overall Survival According to Tumor Receptor
Status in Women Treated with Tamoxifen
PR is prognostic or predictive for patients treated with tamoxifen
Cui, X. et al. J Clin Oncol; 23:7721-7735 2005
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
LUM A
LUM B
ER
PR
HER2
RS
Low Ki-67
Hormone-sensitive
High Ki-67
Hormone-resistant
Mechanisms of SERM Resistance
IGF1R
MoAb
EGFR/HER2
TKI
VEGFR
P
AB P
P
P
MoAb
P
P SOS
TKI
PI3-K
TKI
MEK
Akt
CCI RAD
RAS
RAF
p90RSK
MAPK
SERD
AI
Increased upstream
signaling through
EGFR and/or IGF-IR
and or VEGFR
Increased signaling
through PI3-K pathway
ER
T
E2
PP P P
Cytoplasm
ERER p160 CBP
ERE
Plasma
Membrane
Basal
Transcription
Machinery
ER Target Gene Transcription
Nucleus
Cell
Growth
Johnston CCR 2005
Increase in EGFR and HER2 Protein in
Tamoxifen-resistant Breast Cancers in vivo
Copyright ©2008 American Association for Cancer Research
Massarweh, S. et al. Cancer Res 2008;68:826-833
TAnDEM Study Design
HER2-positive,
HR+ MBC
(n=208)
Anastrozole 1 mg daily +
Trastuzumab 4 mg/kg loading dose 
2 mg/kg qw until
disease progression
R
Anastrozole
1 mg daily until
disease progression
•
Crossover to receive trastuzumab was actively offered to
all patients who progressed on anastrozole alone
HR, hormone receptor; MBC, metastatic breast cancer; R, randomisation
Trastuzumab + AI
Progression-free Survival
Probability
1.0
0.8
Events
0.6
Median PFS 95% CI P value
4.8 months
2.4 months
87
99
0.4
3.7, 7.0
2.0, 4.6
0.0016
0.2
0.0
0
5
10
15
20
25
30
35
40
45
50
55
60
Months
No. at risk
A+T
A
103
48
31
17
14
13
11
9
4
1
1
0
0
104
36
22
9
5
4
2
1
0
0
0
0
0
CI, confidence interval
PFS = time from randomisation to date of progressive disease or death
Kaufmann ESMO 2006
Trastuzumab + AI
Clinical benefit
Patients
(%)
60
P=0.026
50
42.7%
A + T (n=103)
A (n=104)
40
30
27.9%
20
10
0
Clinical benefit
Clinical benefit with single agent trastuzumab 48%
Vogel JCO 2002, Kaufmann ESMO 2006
Letrozole ± Lapatinib in HR+ MBC
Eligibility criteria:
Postmenopausal
ER+/PgR+
HER2+/HER2-/unknown
Stage IIIb, IIIc, and IV
breast cancer
No prior treatment for
metastatic disease
R
A
N
D
O
M
I
Z
E
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)
1° endpoint: PFS (investigator) in HR+/HER2 pts
Johnston et al., SABCS 2008, abstract 46
Letrozole ± Lapatinib in HR+ MBC
ITT
PFS
(months)
HER2+
let
(n=644)
let + lap
(n=642)
let
(n=108)
let + lap
(n=111)
let
(n=474)
let + lap
(n=478)
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
28%
15%
32%
ORR
30%
P =.262
51%
CBR
29%
P =.096
32.3
33%
P =.726
48%
56%
P =.003
NR
NR
28%
P =.021
56%
NR
OS (months)
HER2-
58%
P =.761
33.3
HR 0.74; P =.113
NR
NR
NR
Johnston et al., SABCS 2008, abstract 46
Progression-free Survival
HER2+ Population
LET
(N = 108)
LET+ LAP
(N = 111)
89 (82%)
88 (79%)
Median PFS, mo
3.0
8.2
Hazard ratio (95% CI)
0.71 (0.53, 0.96)
Progressed or died
P-value
0.019
Progression-free Survival
ITT and HER2-ve Populations
ITT
Progressed or died
Median PFS, mo
Hazard ratio (95% CI)
P-value
HER2-ve *
LET
(N = 644)
LET + LAP
(N = 642)
476 (74%)
413 (64%)
10.8
11.9
0.86 (0.76, 0.98)
0.026
Progressed or died
Median PFS, mo
Hazard ratio (95% CI)
P-value
LET
(N = 474)
LET + LAP
(N = 478)
342 (72%)
294 (62%)
13.4
13.7
0.90 (0.77, 1.05)
0.188
*Centrally confirmed
Letrozole ± Lapatinib in HR+ MBC
 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
Median PFS (months)
CBR
<6 months since
discontinuation of TAM
LET
(n=370)
LET + LAP
(n=382)
LET
(n=104)
LET + LAP
(n=96)
15.0
14.7
3.1
8.3
HR 0.94; P = .522
64%
62%
Hormone-sensitive
HR 0.78; P = .117
32%
44%
Hormone-refractory
Johnston et al., SABCS 2008, abstract 46
Phase II Anastrozole ± Gefitinib in Newly
Diagnosed HR+ MBC
Anastrozole 1 mg PO daily
Post menopausal women
Newly diagnosed, ER and / or
PR-positive MBC, No prior
hormonal therapy, measurable
disease
Gefitinib 250 mg PO Daily
R
Anastrozole 1 mg PO daily
Placebo
 Multi-center, randomized, double-blind trial
 Primary objective: PFS
 Enrollment stopped early due to low accrual
Cristofanilli M, et al. J Clin Oncol. 2008;26(15S): Abstract 1012.
Anastrozole ± Gefitinib in HR+ MBC
Efficacy
Anastrozole + Gefitinib
Median PFS (months)
(n = 43)
Anastrozole + placebo
(n = 50)
14.5
8.2
HR (95% CI) = 0.55 (0.32 – 0.94)
Objective response rate
2%
12%
Clinical benefit rate
49%
34%
Cristofanilli et al, ASCO 2008, abstract # 1012
IGF-1R Signaling
Pollak et al Nature Reviews 2004
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
Randomized Phase II Trial of IMC-A12 ± Hormonal
Therapy in Hormone-resistant Metastatic Breast Cancer

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 PRpositive
IMC-A12
(n = 30)
R
IMC-A12 10 mg/kg every 2 weeks
IMC-A12 +
most recent
endocrine
therapy
(n = 60)
Pilot Study of Letrozole + Bevacizumab
MSKCC/UCSF
Bevacizumab
15 mg/kg IV
Week
0
3
6
9
12
2.5 mg orally each day
Letrozole
 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)
Traina, Dickler, Rugo, Hudis et al., ASCO Abstract 3050, 2006
Best Response by RECIST
Feasibility 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
1.0
Progression-free Survival
N = 43
0.2
0.4
0.6
Median wks on AI therapy pre-bevacizumab =
15.4 weeks (range 1-216 wks)
0.0
Progression-free survival
0.8
Median PFS: 17.1 months [95% CI: (8.5, 26.2)]
0
12
24
Time (months) from Treatment start
36
48
Dickler ASCO Breast 2008
Proof of Concept Study
CALGB 40503 First-line Endocrine Rx
± Bevacizumab for MBC
R
A
N
D
O
M
I
Z
E
Endocrine Rx + Bevacizumab
(15 mg/kg IV q 3 wks)
N = 442
Endocrine Rx + Placebo
 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
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