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Endocrine resistance:
molecular pathways and
rational development of
targeted therapies
Grazia Arpino
Università di Napoli Federico II
Enhancing Endocrine Therapy for Breast
Cancer
● Current Endocrine Therapy:
• Tamoxifen; aromatase inhibitors
• Limited by “de-novo” or “acquired” endocrine resistance
● De Novo/Acquired Endocrine Resistance:
• ER expression & function
• Role 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, gefitinib
• HER2 – trastuzumab, lapatinib
• mTOR – everolimus, temsirolimus
Enhancing Endocrine Therapy for Breast
Cancer
● Current Endocrine Therapy:
• Tamoxifen; aromatase inhibitors
• Limited by “de-novo” or “acquired” endocrine resistance
● De Novo/Acquired Endocrine Resistance:
• ER expression & function
• Role 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, gefitinib
• HER2 – trastuzumab, lapatinib
• mTOR – everolimus, temsirolimus
Enhancing Endocrine Therapy for Breast
Cancer
● Current Endocrine Therapy:
• Tamoxifen; aromatase inhibitors
• Limited by “de-novo” or “acquired” endocrine resistance
● De Novo/Acquired Endocrine Resistance:
• ER expression & function
• Role 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, gefitinib
• HER2 – trastuzumab, lapatinib
• mTOR – everolimus, temsirolimus
~5 years tamoxifen vs Not, ER+ patients
10%
5 years of adjuvant tamoxifen safely reduces 15-year risks of breast
cancer recurrence and death
EBCTGC, Lancet 2011
Mechanism of Action-Tamoxifen
Protein
E2
E2
CoA
+
CoR
E2
Transcription
ER
mRNA
ERE
CoA
ER
ER
Promoter
ER
Gene
ERE
Gene
+
Tam
Tam
Tam
CoR
ER
ER
Transcription
ERE
Promoter
Gene
Mechanism of Action-Aromatase
Inhibitors
~5 years tamoxifen vs Not, ER+ patients
25%
However, almost one quarter of the patients with ER+ tumor develop
resistance
EBCTGC, Lancet 2011
Major Problem
(Endocrine Therapy)
Resistance
De Novo
Acquired
Metanalysis
ER+ Patients (N=1195)
Relative Risk of
Treatment Failure (95%CI)
Ellegde
1.21
(0.87 – 1.69)
Hayes
1.06
(0.47 – 2.38)
Houston
2.07
(1.57 – 2.73)
Lipton 1st
1.42
(1.24 – 1.63)
Lipton 2nd
1.40
(1.25 – 1.56)
Willsher
1.33
(0.56 – 3.16)
Wright
1.54
(0.86 – 3.74)
Yamauchi
1.66
(1.05 – 2.64)
Overall 1.44
Relative Risk
 Her2+ Better
Her2+ worse 
(1.34 – 1.56)
De Laurentiis M., et al. Clin.Cancer Res., 2005.
0,2
0,5
1
2
5
In Vivo Model of Tamoxifen Resistance
Tumor 1200
volume
(mm3)
1000
De Novo Tam-R
Tam-S
Acquired Tam-R
800
600
Tam
400
MCF7
MCF7 / HER2
200
0
0
21
49
77
105
Days
Osborne et al. JNCI 1994
Genomic & non-genomic ER cross-talk
EGFR
HER2
IGFR
Cell stress
cytokines
E2
P
P
P
p160 CBP
ER ER
E2
Basal
transcription
machinery
Genomic & non-genomic ER cross-talk
EGFR
HER2
IGFR
Cell stress
cytokines
Grb2
SOS
Ras
Rac-1
CDC42
ER
Raf
PI3k
MEKK1
MEK1/2
MLK3
AKT
ERK1/2
p60rsk
p38
MKK3/6
mTor
ER
ER
Bad
ER
P
P
P
p160 CBP
ER ER
E2
Basal
transcription
machinery
Genomic & non-genomic ER cross-talk
EGFR
HER2
IGFR
Cell stress
cytokines
Grb2
SOS
Ras
Rac-1
CDC42
ER
Raf
PI3k
MEKK1
MEK1/2
MLK3
AKT
ERK1/2
p60rsk
p38
MKK3/6
mTor
ER
ER
E2
Bad
ER
P
P
P
p160 CBP
ER ER
E2
Basal
transcription
machinery
Effect of HER Family Inhibitors on TamStimulated Growth
Tumor Volumes (mm3)
800
E2
600
MCF7/HER2 Tumors
Tam
400
Tam+Gef
Tam+P
Tam+T
200
0
1
21
42
63
84
105
126
147
168
189
209
Days
Hypothesis: Resistance is due to incomplete blockade of the
HER signaling pathway (all HER dimer pairs).
Arpino, JNCI 2007
TanDEM Study Design
HER2-positive
HR-positive MBC
(n=208)
Anastrozole 1 mg daily +
Trastuzumab 4 mg/kg Loading
dose  2 mg/kg qw until
disease progression
R
Anastrozole
1 mg until
disease progression
HR, hormone receptor
Crossover to receive trastuzumab was
actively offered to all patients who
progressed on anastrozole alone
MBC, metastatic breast cancer
R, randomisation
Kaufman et al, JCO 2009
TanDEM Progression-free Survival
1.0
Probability
0.8
Events
Median PFS
95% CI
p value
87
99
4.8 months
2.4 months
3.7, 7.0
2.0, 4.6
0.0016
0.6
0.4
0.2
0
No. at risk
A+H
A
5
10
16
20
25
30
35
40
45
50
55
60
Months
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
Kaufman et al, JCO 2009
EGF30008 – Study Design
Patient Population
• ER+/PgR+ (HR+)
• Postmenopausal
• HER2+, HER2- or unknown
• Stage IIIb/IIIc, IV
R
A
• No prior treatment for MBC
N
Stratification
D
• Disease sites
• Bone only/othe sites
• Interval since prior
adjuvant anti-estrogen
therapy
• < 6 mo / ≥ 6 mo or None
O
M
I
Z
Letrozole 2.5 mg daily
+
Placebo
Letrozole 2.5 mg daily
+
Lapatinib 1500 mg daily
n = 1286 pts (including n=219 HER2+)
Johnston S, et al JCO2009
Progression-Free Survival:
HER2+ Population
Letrozole
Progressed or died
Median PFS, mo
Hazard ratio (95% CI)
p-value
(N = 108)
Letrozole +
Lapatinib
(N = 111)
89 (82%)
88 (79%)
3.0
8.2
0.71 (0.53, 0.96)
0.019
ELECTRA – Study Design
Patient
Population
• ER+/PgR+ (HR+)
• Postmenopausal
• HER2+,
• No prior treatment for
MBC
R
A
N
Letrozole 2.5 mg daily
+
Placebo
D
O
M
I
Z
E
Letrozole 2.5 mg daily
+
Trastuzumab
Huober Breast 2009
ELECTRA – Study Design
Treatment§
Letrozole
Letrozole + Trastuzumab
N
ORR
CBR
PFS
OS
(%)
(%)
(mo)
31
13
39**
3.3*
NR
26
27
65**
14.1*
NR
*hazard ratio 0.67; p = 0.23
** odds ratio 2.99, 95% CI 1.01-8.84
Huober Breast 2012
HER Family Inhibitors
Trastuzumab
EGF
TGFα
Pertuzumab
Heregulin
HER2
EGFR
HER2
HER3
HER4
Lapatinib
?
Gefitinib
X
Tumor growth and survival
Effect of HER Family Inhibitors on TamStimulated Growth
Tumor Volumes (mm3)
800
E2
Complete Responses
Tam
600
Tam+P
400
Tam+P+T
Tam+P
12/18
Tam+P+T+G 18/20
Tam+P+T
200
5/18
Tam+P+T+G
0
1
21
42
63
84
105
126
147
168
189
209
Days
Arpino, JNCI 2007
MCF7/HER2-18
Effect of HER Family Inhibitors on Estrogen
Deprivation
Tumor Volume (mm3)
1000
Complete Regression
ED+T 4/13
800
ED
ED+L 5/13
ED+L+T 11/13
600
400
ED+L
200
ED+T
ED+L+T
0
50
100
150
200
250
Treatment Days
Rimawi Cancer res in press
TBCRC 006: Neoadjuvant Lapatinib &
Trastuzumab Without Chemotherapy
S
u
r
g
e
r
y
Lapatinib (1000 mg/day)
Trastuzumab (4 mg/kg load, 2 mg/kg q-weekly)
Bx
0
8
2
12
Weeks
Lap (L) + Tras (T) + Endocrine Rx if ER+
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%)
PERTAIN
Investigational arm [Arm A]
Pertuzumab + trastuzumab
Until disease progression, unacceptable toxicity, withdrawal of consent, or
death
+
Patients with HER2and hormone receptorpositive advanced
breast cancer not
previously treated with
systemic non-hormonal
anticancer therapy in
the metastatic setting
(n ~250)
AI
or
Patients receiving induction chemotherapy (investigator’s discretion)
Docetaxel or paclitaxel AI (starting after induction chemotherapy phase)
Up to 18 weeks
R
Control arm [Arm B]
Trastuzumab
Until disease progression, unacceptable toxicity, withdrawal of consent, or
death
+
AI
or
Patients receiving induction chemotherapy (investigator’s discretion)
Docetaxel or paclitaxel AI (starting after induction chemotherapy phase)
Up to 18 weeks
In Vivo Model of Tamoxifen Resistance
Tumor 1200
volume
(mm3)
1000
De Novo Tam-R
Tam-S
Acquired Tam-R
800
600
Tam
400
MCF7
MCF7 / HER2
200
0
0
21
49
77
105
Days
Osborne et al. JNCI 1994
Acquired Endocrine Resistance
● ER signaling survivers:
• ER expressed, although function may change
• Enhance ER activation
• Reversible silencing of ER can also occur
● Enhanced growth factor signaling (EGFR, HER2)
occurs:
• Cross-talk between GFR and ER:
− activation of genomic ER via AkT/MAPK induced
phosphorylation
− non-genomic association of ER with HER2 / EGFR / IGFR
● mTOR pathway activation disregulating ER genomic
function
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 tumors
•Indications:
- MBC progressing after other antiestrogen therapy in
postmenopausal women
Figure 1. Comparison of the differing modes of action of (A) oestradiol, (B) tamoxifen and (C)
fulvestrant.
Piccart M et al. Ann Oncol 2003;14:1017-1025
©2003 by Oxford University Press
FIRST: Fulvestrant 500 mg vs Anastrazole-TTP
SWOG 0226: Progression-Free Survival
All eligible patients (n=694)
1.00
Anastrozole + Fulvestrant (268 events)
Anastrozole (297 events)
Stratified log-rank p = 0.0070
0.75
Median PFS
Anastrozole 13.5 mos (95% CI 12.1-15.1)
Combination 15.0 mos (95% CI 13.2-18.4)
0.50
0.25
0.00
HR = 0.80 (95% CI 0.68-0.94)
0
12
24
36
48
60
72
8
3
2
0
Months since registration
N at risk
AN 349
AN + FV 345
199
193
114
92
53
39
21
11
SWOG 0226: Progression-Free Survival
Prior adjuvant tamoxifen (n=280)
1.00
Anastrozole + Fulvestrant (114 events)
Anastrozole (119 events)
Log-rank p = 0.037
0.75
Median PFS
Anastrozole 14.1 mos (95% CI 12.0-16.8)
Combination 13.5 mos (95% CI 11.0-19.3)
0.50
0.25
0.00
HR = 0.89 (95% CI 0.69-1.15)
0
12
24
36
48
60
72
2
1
1
0
Months since registration
N at risk
AN 141
AN + FV 139
74
80
43
32
17
17
5
3
SWOG 0226: Progression-Free Survival
No prior adjuvant tamoxifen (n=414)
1.00
Anastrozole + Fulvestrant (154 events)
Anastrozole (178 events)
Log-rank p = 0.0055
0.75
Median PFS
Anastrozole 12.6 mos (95% CI 11.2-15.6)
Combination 17.0 mos (95% CI 13.8-19.9)
0.50
0.25
0.00
HR = 0.74 (95% CI 0.59-0.92)
0
12
24
36
48
60
72
6
2
1
0
Months since registration
N at risk
AN 208
AN + FV 206
125
113
71
60
36
22
16
8
SWOG 0226: Overall Survival
All eligible patients (n=694)
1.00
Median OS
Anastrozole 41.3 mos (95% CI 37.2-45.0)
Combination 47.7 mos (95% CI 43.0-55.7)
0.75
0.50
HR = 0.81 (95% CI 0.65-1.00)
0.25
Anastrozole + Fulvestrant (154 deaths)
Anastrozole (176 deaths)
Stratified log-rank p = 0.049
0.00
0
12
24
36
48
60
72
26
22
4
4
Months since registration
N at risk
AN 349
AN + FV 345
315
306
259
239
145
136
62
54
SWOG 0226: Overall Survival
Prior adjuvant tamoxifen (n=280)
1.00
Median OS
Anastrozole 44.5 mos (95% CI 38.0-54.8)
Combination 49.6 mos (95% CI 37.9-71.2)
0.75
0.50
HR = 0.91 (95% CI 0.65-1.28)
0.25
Anastrozole + Fulvestrant (63 deaths)
Anastrozole (68 deaths)
Log-rank p = 0.59
0.00
0
12
24
36
48
60
72
13
10
3
2
Months since registration
N at risk
AN 141
AN + FV 139
125
125
101
100
54
59
28
24
SWOG 0226: Overall Survival
No prior adjuvant tamoxifen (n=414)
1.00
Median OS
Anastrozole 39.7 mos (95% CI 33.1-43.9)
Combination 47.7 mos (95% CI 43.4-58.3)
0.75
0.50
HR = 0.74 (95% CI 0.56-0.98)
0.25
Anastrozole + Fulvestrant (91 deaths)
Anastrozole (108 deaths)
Log-rank p = 0.0362
0.00
0
12
24
36
48
60
72
13
12
1
2
Months since registration
N at risk
AN 208
AN + FV 206
190
181
158
139
91
77
34
30
Acquired Endocrine Resistance
● ER signaling survivers:
• ER expressed, although function may change
• Enhance ER activation
• Reversible silencing of ER can also occur
● Enhanced growth factor signaling (EGFR, HER2)
occurs:
• Cross-talk between GFR and ER:
− activation of genomic ER via AkT/MAPK induced
phosphorylation
− non-genomic association of ER with HER2 / EGFR / IGFR
● mTOR pathway activation disregulating ER genomic
function
Changes of ER and PgR Expression in
Primary vs. Subsequent Metestatic Disease
Curigliano et al.
Ann. Onc. 2011
The discordance rates for ER, PgR, and
HER2 status between primary tumor and liver
metastases were 14.5%, 48.6%, and
13.9%, respectively, which led to change in
therapy for 31 of 255 patients (12.1%).
Curigliano et al. Ann. Onc. 2011
Changes in Molecular Profile Subtype at the
Development of Endocrine Resistance
Creighton et al Cancer Res. 2009
ER+ve Tamoxifen Resistance Cells (TAM-R)
show Increased EGFR Signaling
WT
TAM-R
p-EGFR
p-HER2
p-ERK 1/2
Total-ERK 1/2
p-ERK 1/2
Knowlden et al. Endocrinology 2003
Changes in Growth Factor Receptor Expression and
ER Activation in Acquired TamR vs WT cell lines
Type I growth factor receptors
(EGFR, ERBB2, ERBB3, ERBB4)
WT
TamR
WT
p EGFR
TamR
p ERK 1/2
Ras SoS
EGFR
ERK 1/2
p ERBB2
Raf
PI3K
pAKT (ser173)
ERBB2
MEK
AKT
ERBB3
ERBB4
MAPK
Akt
pERa (ser118)
p90RSK
Actin
P
P P
ER
Basal
ER p160
ERE
CBP
transcription
machinery
pERa (ser167)
total ERa
Target gene
Pancholi et al. Endocr Relat Cancer 2008
1839IL/0225 – A randomised phase II study of Tamoxifen ±
Gefitinib in patients with ER+ve metastatic breast cancer
STRATUM 1: (Endocrine
Naive or > 12 m post
adjuvant tamoxifen)
Time to Progression
Proportion progression-free
1.0
Tamoxifen +
Gefitinib
(n = 105)
Tamoxifen +
Placebo
(n = 101)
10.9
8.8
Median PFS (months)
HR of gefitinib to placebo = 0.84 (0.59, 1.18)
0.8
HER2+ subset (n=37)
Median PFS (months)
0.6
6.7
5.8
HR of gefitinib to placebo = 0.54 (0.25, 1.15)
0.4
0.2
0.0
0 100
Treatment Group
200
300
400
500 600 700
800
900
1000
1100
time (days)
tamoxifen + gefitinib
tamoxifen + placebo
Osborne et al. CCR 2010
Randomised phase II study of Anastrozole ± Gefitinib in
patients with ER+ve metastatic breast cancer
Anastrozole + Anastrozole +
Gefitinib
Placebo
(n = 43)
(n = 50)
Probability of PFS
1.0
0.8
Events
22
32
Median PFS (months)
14.5
8.2
HR (95% CI) = 0.55 (0.32, 0.94)
0.6
0.4
0.2
0.0
0
3
6
9
12
15
18
21
24
Placebo
50
35
23
13
9
6
5
3
1
Gefitinib
43
40
28
22
13
10
6
3
2
25
At risk
1
Cristofanilli et al. CCR2012
28
Months
EGF30008 Progression-Free Survival: ITT
and HER2-ve Populations
HER2-ve *
ITT
Letrozole
Progressed or died
Median PFS, mo
Hazard ratio (95% CI)
p-value
(N = 644)
Letrozole +
Lapatinib
(N = 642)
476 (74%)
413 (64%)
10.8
11.9
0.86 (0.76, 0.98)
0.026
Letrozole
Progressed or died
Median PFS, mo
Hazard ratio (95% CI)
p-value
(N=474)
Letrozole +
Lapatinib
(N=478)
342 (72%)
294 (62%)
13.4
13.7
0.90 (0.77, 1.05)
0.188
*Centrally confirmed
EGF30008 PFS: HER2-ve Patients (N=952)
≥ 6 Mo Since D/C of Tam (33%) or
No Tam (67%)
< 6 Mo Since D/C
of Tam
• Median tam duration 5 y
• Median tam duration 2.8 y
• Median time since d/c 3.5 y
• Median time since d/c 1 mo
Median PFS, mo
Hazard ratio
(95% CI), p-value
Let
(N=370)
Let + Lap
(N=382)
15.0
14.7
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
Over Trial Design
2x2 Factorial Design
Fulvestrant
+
Placebo
Fulvestrant
+
Lapatinib
Fulvestrant
+
Aromatase In.
+
Placebo
Fulvestrant
+
Aromatase In.
+
Lapatinib
Over Trial Design
Fulvestrant
+
Placebo
Fulvestrant
+
Lapatinib
Fulvestrant
+
Aromatase In.
+
Lapatinib
Fulvestrant
+
Aromatase In.
+
Lapatinib
Evaluation of Retaining the AI
Over Trial Design
Fulvestrant
+
Placebo
Fulvestrant
+
Lapatinib
Fulvestrant
+
Aromatase In.
+
Placebo
Fulvestrant
+
Aromatase In.
+
Lapatinib
Evaluation of Adding Lapatinib
Acquired Endocrine Resistance
● ER signaling survivers:
• ER expressed, although function may change
• Enhance ER activation
• Reversible silencing of ER can also occur
● Enhanced growth factor signaling (EGFR, HER2)
occurs:
• Cross-talk between GFR and ER:
− activation of genomic ER via AkT/MAPK induced
phosphorylation
− non-genomic association of ER with HER2 / EGFR / IGFR
● mTOR pathway activation disregulating ER genomic
function
Targeting mTOR & cell growth inhibition
IGF1R
IRS1
PDK1
PI3K
PIP2 PIP3
Akt
PTEN
TSC1
TSC2
Rheb
GTP
Rheb
GDP
mTOR
ki67
Everolimus
Temsirolimus
S6K
4EBP1
S6
elF4E-F-G
Proliferation
Atzori et al, ASCO 2008
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 pathway
1. 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):35773584. 3. deGraffenried LA, et al. Ann Oncol. 2004;15(10):1510-1516. 4. Bachman KE, et al. Cancer Biol Ther. 2004;3(8):772-775. 5.
Campbell IG, et al. Cancer Res. 2004;64(21):7678-7681. 6. Stemke-Hale K, et 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.
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.
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):
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
TAMRAD: Overall Survival
Bourgier C, et al. Eur J Cancer Suppl. 2011
BOLERO-2: Trial Design
Stratification:
1. Sensitivity to prior hormonal therapy
2. Presence of visceral disease
No crossover
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
Baselga J, et al. Eur J Cancer Suppl. 2011;47(Suppl 2): Abstract: 9LBA.
18-Months Update BOLERO-2
Primary Endpoint: PFS
BOLERO-2: Most Common G3/4
AEs
Inhibitors of PI3K-AKT-mTOR
Signaling in Clinical Development
Engelman JA. Nat Rev Cancer. 2009;9(8):550-562.
Modulation of Resistance to Endocrine
Therapies: A Look Into the Future
ABC-1 Congress 2011
Endocrine Rx and STIs - Conclusions
● Endocrine resistance:
• ER still expressed, although function may change
• Complex “cross-talk” exists between GFR and ER
• Non-genomic association of ER with HER2
● Targeted growth factor receptor therapies:
• Proof of concept on inhibiting growth/ER signaling/restoring
endocrine sensitivity
• Targeting of EGFR/HER2 to treat/delay emergence of resistance
● Clinical trials combining STI’s + endocrine therapies:
• Appropriate selection of patients that may benefit is crucial
• Correct clinical endpoints (ORR vs PFS) are important
• Neo-adjuvant setting – some advantages for early development