Download 18th Annual Perspectives in Breast Cancer

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18
Annual Perspectives in
Breast Cancer
Growth Factor Pathways in
Hormone Resistant Breast Cancer
Christy A Russell, MD
Fight On!
Tumors Classified as ER+ Have Varied
Receptor Expression Profiles
• ASCO/CAP recommends that a tumor specimen
be considered ER+ if >1% of tumor cells test
positive for ER.
• Breast cancer classified as ER+ is a heterogeneous
disease, based on varying
– ER expression level
– PR status
– HER2 status
• BC with strong ER expression are biologically
distinct from those with weak ER expression
Hormone Receptor Positive
Determination
Any endocrine therapy (n = 777)
Allred Score* for Estrogen Receptor
Score
Straining
Harvey et al. J Clin Oncol 1999;17:1474-1481
Proportion of malignant cells
straining for ER
0
None
1
<0.01
2
0.01-0.1
3
0.1-0.33
4
0.33-0.67
5
>0.67
Intensity
Allred Score of > 3 are
generally considered
hormone-sensitive
Component of Score
Average intensity of positively
stained cells
0
None
1
Weak
2
Intermediate
3
Strong
Compare Survival with Stable Disease (Clinical Benefit) to
Survival with CR or PR with Anastrozole Use in ABC
Clinical Benefit = CR + PR + Stable  24 wks
Survival (%)
100
80
At
Risk Deaths
60
CR or PR
2-Year
Estimate
33
10
85%
40
Stable  24wk 78
23
86%
20
Other
118
35%
0
0
1
2
3
152
4
Years From Randomization
Stable disease on hormone therapy provides
similar benefit as CR or PR
ABC = advanced breast cancer, Clinical benefit = no prognosis for > 24wks
Robertson JF, et al. Breast Cancer Res Treat. 1999;58:157-162.
Patients with Disease Progression on One Hormone
Therapy May Respond to Another Hormone Therapy
40%
30%
25%
15%
1st
Line
2nd
Line
3rd
Line
4th
Line
R
E
S
I
S
T
A
N
C
E
An optimal sequence of hormone therapies has not
been defined
Bavior C, et al. Ann Oncol 2012. Epub Feb 8; Osborne Ck, Schiff R. Ann Res Med 2011;62:233-247
NCCN Guidelines Recommend Serial Endocrine Therapy for Hormone
Receptor Positive, HER2- Advanced Breast Cancer, Not in Visceral Crisis
NCCN Clinical Practice Guidelines in Oncology. Breast Cancer, version 1.2012; Osborne CK, et al. Ann Rev Med 2011;62:233-247
Hormone Receptor Positive, Advanced
Breast Cancer Unmet Need
• With initial hormone therapy of advanced
breast cancer:
– About 30% will have clinical response (PR,
CR)
– About 50% will have clinical benefit (no
progression for 24 weeks)
• However, almost all will develop resistance and
ultimately have disease progression
Endocrine Agents for Postmenopausal
Breast Cancer
• SERMs
• Aromatase Inhibitors

Tamoxifen

Anastrozole

Toremifene

Letrozole

Raloxifene

Exemestane
• Estrogens
• Progestins

Estradiol

Megestrol Acetate

DES, EE2

MPA
• ER-Down Regulator

Fulvestrant
•
Androgens

Fluoxymesterone
Review of Trials of Hormone
Therapy in First-Line Advanced
Breast Cancer
Selected Trials of HT in First-Line ABC
Trial or Lead Author
Nabholtlz
Anastrozole vs tamoxifen
Mouridsen
Letrozole vs tamoxifen
Paridaens
Exemestane vs tamoxifen
Howell
Fulvestrant (250) vs tamoxifen
S02226
Fulvestrant (250, loading) + anastrozole vs anastrozole
N
1021
FACT
Fulvestrant (250, loading) + anastrozole vs anastrozole
514
FIRST
Fulvestrant (500) vs anastrozole
205
916
371
587
694
Mehta SABCS 2011, Abst S1-1; Bergh J Clin Oncol 2012 [Epub ahead of print]; Nabholtz Eur J Cancer 2003;39:1684-1689; Mouridsen
2003;21:2101-2109; Paridaens 2008;26:4883-4890; Howell J Clin Oncol 2004;22:1605-1613.
First-Line Phase III Studies:
AIs and/or Fulvestrant (250) vs Tamoxifen
• AIs have improved efficacy compared with
tamoxifen2-4

TTP (mo): anastrozole (10.7) vs tamoxifen (6.4)2

TTP (mo): letrozole (9.4) vs tamoxifen (6.0)3

PFS (mo): exemestane (9.9) vs tamoxifen (5.8)4
• Fulvestrant (250) has similar efficacy compared with
tamoxifen5
 TTP (mo): fulvestrant (8.2) vs tamoxifen (8.3)
First-Line Phase III Studies Fulvestrant
(250, loading )* + Anastrozole vs
Anastrozole
• In SWOG S0226 (n = 694), fulvestrant addition
improved:
 PFS (mo); fulvestrant + anastrozole (15.0) vs
anastrozole (13.3), P = 0.007

OS (mo): fulvestrant + anastrozole (47.7) vs
anastrozole (41.3), P = 0.049
• In FACT (n=514), fulvestrant addition had: no effect on
PFS or OS seen:
 OS (mo): fulvestrant + anastrozole (37.8) vs
anastrozole (38.2), P = 1.00
Mixed results for fulvestrant 250, loading
Mehta, et al. SABCS 2011, Abst S1-1
Bergh, et al. J Clin Oncol 2012;30(16):1919-25 *Fulvestrant 500 mg d 1 IM, 250 mg d 14 and 28, 250 mg every 28 days thereafter.
FIRST: Fulvestrant (500) vs Anastrozole
(Phase II)
N = 205
PMW with
previously
untreated HR+
advanced breast
cancer
FULVESTRANT 500 mg IM
days 1, 14, 28 and q28days
thereafter
ANASTROZOLE 1 mg QD
orally
Primary
CBR defined
as CR, PR,
and SD for >
24 wks
Secondary
ORR, TTP,
DoR
FUL (500)
n = 102
ANAS
n = 103
HR
P-value
TTP (mo)
23.4
13.1
0.66
0.01
ORR (%)
36.0
35.5
1.02
0.947
CBR (%)
72.5
67.0
1.30
0.386
Robertson JRF, et al. SABCS 2010. Abstract S1-3, Robertson et al. J Clin Oncol 2009;27:4530-35
Proportion of patients alive
and progression-free
FIRST: TTP, Fulvestrant (500) vs Anastrozole
(Phase II)
1.0
Fulvestrant 500 mg
Anastrozole 1 mg
0.8
0.6
0.4
HR = 0.66
95% CI (0.47, 0.92)
p=0.01
0.2
0.0
0
6
12
18
24
30
36
42
48
Time (months)
Percent with progression (%)
Median (months)
Robertson SABCS 2010, Abst S1-3
Fulvestrant 500 mg
Anastrozole 1 mg
n = 102 (%)
n = 103 (%)
63 (61.8)
79 (76.7)
23.4
13.1
Review of Trials of Hormone Therapy
in Advanced Breast Cancer After
Progression on Prior Non-Steroidal
Aromatase Inhibitor
Selected Trials of Fulvestrant Use After
Progression on Prior NSAI*
Trial
EFECT
Fulvestrant vs exemestane
SoFEA
Fulvestrant + anastrozole vs fulvestrant vs
exemestane
CONFIRM
Fulvestrant high vs fulvestrant low
N
693
750
736
Fulvestrant 250, loading
Fulvestrant 500
*Non-steroidal aromatase inhibitor.
EFECT: Fulvestrant (250, loading) vs
Exemestane
N = 693
PMW with
advanced HR+
BC after failure of
NSAI therapy
TTP (mo)
ORR (%)
FULVESTRANT 500 mg IM
day 1, 250 mg day 14, 28,
monthly
EXEMESTANE 25 mg QD
FUL
n = 351
EXE
n = 342
3.7
7.4
3.7
6.7
Primary
TTP
Secondary
ORR, CBR,
DOR, TTR,
OS, tolerability
P-value
0.653
0.736
Fulvestrant (250 loading) similar to exemestane
Chia S, et al. J Clin Oncol 2008;26(10):1664-1670
SoFEA: Fulvestrant (250, loading) With or
Without Anastrozole vs Exemestane
N = 723
Post menopausal
women with
advanced HR+
BC following
progression on
NSAI
FULVESTRANT 500 mg
loading dose on day 1, then
250 mg monthly +
ANASTROZOLE 1 mg/daily
FULVESTRANT 500 mg
loading dose on day 1, then
250 mg monthly +
Placebo daily
Primary
PFS
Secondary
ORR, CBR,
OS, tolerability
EXEMESTANE 25 mg/daily
No significant differences were observed in PFS, ORR, CBR, or OS
PFS (mo)
Johnston S et al. EBCC-8. 2012
FUL 500
n = 231
4.8
FUL + ANA
n = 243
4.4
EXE
3.4
CONFIRM: Fulvestrant 250 vs 500 mg
N = 736
PMW with
advanced HR+
BC after failure of
prior endocrine
therapy
PFS (mo)
ORR (%)
CBR (%)
FULVESTRANT 500 mg
IM on day 1, 14, 28,
monthly
FULVESTRANT 250 mg
IM monthly
FUL 500
n = 362
6.5
9.1
45.6
FUL 250
n = 374
5.5
10.2
39.6
Bachelot T, et al. J Clin Oncol 2012. Epub 1-7; DiLeo et al. J Clin Oncol 2010;28:4594-4600
Primary
PFS
Secondary
ORR, CBR,
DoCB, OS, Qol
P-value
0.004
0.795
0.100
Mechanisms of ER Action in Breast Cancer
Mechanisms of Endocrine 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
ER
T
Increased upstream
signaling through
EGFR and/or IGF-IR
and or VEGFR
Increased signaling
through PI3-K pathway
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 likely similar
From Johnston CCR 2005
Endocrine Resistance and the
PI3K/AKT/mTOR Pathway
• Evidence suggests that the PI3K/AKT/mTOR
pathway becomes activated in hormone resistant
breast cancer
• This pathway allows cells to survive despite
concurrent endocrine therapy
• Targeting the PI3K/AKT/mTOR pathway could
provide benefit in metastatic breast cancer that is
becoming resistant to the current endocrine therapy
Johnston, S. Role of the mTOR Pathway in Endocrine Resistant Breast Cancer — Opportunities
for Novel Combination Strategies. 2009.
PI3K/AKT/mTOR Pathway
http://www.cellsignal.com/reference/pathway/mTor.html
Everolimus as mTOR Kinase Inhibitor
• Mechanisms of Action (MOA): everolimus inhibits
mTOR through allosteric binding to the mTORC1
complex
• Reduces tumor angiogenesis by inhibiting VEGF
and HIF-1 expression
• Targets pathway known to be involved in endocrine
resistance
• Available as oral agent
Villarreal-Garza, et al. Ann Oncol 2012 May 2 Epub ahead of print
Barnett, et al. Pharmacotherapy 2012;32:383-96
Selected Trials of Hormonal Therapy
Including Everolimus After Progression on
Prior AI*
Trial
EFECT
Fulvestrant (250) vs exemestane
CONFIRM
Fulvestrant (500) vs fulvestrant (250)
SoFEA
Fulvestrant + anastrozole vs fulvestrant
(250) vs exemestane
TAMRAD
Tamoxifen + everolimus
BOLERO-2
Exemestane + everolimus
Fulvestrant 250
Fulvestrant 500
N
693
736
750
110
725
Everolimus
Combinations
*Non-steroidal aromatase inhibitor.
TAMRAD: Tamoxifen + Everolimus
(Phase II)
Phase 2 study;
N=111
PMW with
advanced HR+
HER2- BC
Previously treated
with non-steroidal
aromatase
inhibitor therapy in
adjuvant or
metastatic setting
CBR (6 mo)
TTP (mo)
Bachelot T, et al. J Clin Oncol 2012. Epub 1-7.
Tamoxifen 20 mg/day +
Everolimus 10 mg/day
Tamoxifen 20 mg/d +
Placebo
TAM+EVE
n = 54
61%
8.6
TAM
n = 57
42%
4.5
Primary
CBR at 6
months
Secondary
Safety, TTP,
OS, ORR
P-value
0.045
0.002
TAMRAD: Time to Progression
TAM: 4.5 mo.
TAM + EVE: 8.6 mo.
Hazard Ratio (HR) = 0.53; 95% CI (0.35-0.81)
Exploratory log-rank: P = 0.0021
Probability of Survival
1.0
0.9
TAM
TAM + EVE
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
Month
Patients at risk
TAM + RAD: n =
TAM : n =
Everolimus
plus tamoxifen reduced time to
54 45 39 34 28 26 25 19 16 12 9 7 1 1 0
57 44 30 progression
24 22 16 13 11 by
7 47%
6 2 1 0 0 0
Bachelot T, et al. J Clin Oncol 2012.Epub 1-7
TAMRAD: Overall Survival
Everolimus plus tamoxifen increased overall survival
by 55%
Tamoxifen With or Without Everolimus:
TAMRAD: Safety
The addition of everolimus resulted in an increase in the
expected toxicities, including fatigue, stomatitis, rash,
diarrhea, and pneumonitis (predominantly grade 1-2)
Select Grade 3-4 Adverse Events
Stomatitis
Rash
Anorexia
Dose reductions due to AEs
Treatment discontinuation due to
AEs
Bachelot et al. J CLin Oncol 2012. Epub 1-7.
Tamoxifen +
Everolimus
(n = 54)
6 (11%)
3 (6%)
5 (9%)
15 (28%)
3 (6%)
Tamoxife
n (n = 57)
0
1 (2%)
2 (3.5%)
0
4 (7%)
BOLERO-2: Everolimus in Postmenopausal,
Hormone Receptor Positive ABC
N = 724
Postmenopausal
ER+ HER2breast cancer pts
refractory to
letrozole or
anastrozole
Everolimus 10 mg/day +
Exemestane 25 mg/day
(N = 485)
Placebo +
Exemestane 25 mg/day
(N = 239)

Stratification:
1. Sensitivity to prior hormonal therapy
2. Presence of visceral disease

No cross-over
Baselga J, et al. N Engl J Med 2012;366(6):520-9.
Primary
PFS
Secondary
OS
ORR
Bone Markers
Safety
PK
BOLERO-2: Baseline Characteristics
Everolimus +
Exemestane
Placebo +
Exemestane
(N = 485), %
(N = 239), %
62 (34, 93)
61 (28, 90)
Caucasian
74
78
Asian
20
19
Performance status 0
60
59
Liver involvement
33
30
Lung involvement
29
33
Measurable disease*
70
68
Characteristic
Median age (range), years
Race
*All
other patients had ≥ 1 bone lesion.
Baselga J, et al. N Engl J Med 2012;366(6):520-9.
BOLERO-2: Prior Therapy
Everolimus + Placebo +
Exemestane Exemestane
Therapy
(N = 485), %
(N = 239), %
Sensitivity to prior hormonal therapy
84
84
Last treatment: LET/ ANA
74
75
Adjuvant
21
16
Metastatic
79
84
Prior tamoxifen
47
49
Prior fulvestrant
17
16
Prior chemotherapy for metastatic BC
26
24
Number of prior therapies: ≥ 3
54
53
Last treatment
Baselga J, et al. N Engl J Med 2012;366(6):520-9.
BOLERO-2 Primary Endpoint: PFS
Central Assessment
Probability of Event (%)
100
HR = 0.36 (95% CI: 0.27-0.47)
Log rank P value = 3.3 x 10 -15
80
EVE + EXE: 10.6 Months
PBO + EXE: 4.1 Months
60
40
20
Everolimus + Exemestane (E/N=114 / 485)
Placebo + Exemestane (E/N=104 / 239)
0
0
6
12
18
24
30
36
42
48
54
60
66
72
Time (weeks)
Everolimus plus exemestane increased
progression-free survival by 64%
Baselga J, et al. N Engl J Med 2012;366(6):520-9.
78
BOLERO-2: Overall Response Rate and
Clinical Benefit Rate by Local
Assessment
40
Everolimus + Exemestane
35
Placebo + Exemestane
33.4%
30
P < 0.0001
25
18.0%
20
P < 0.0001
15
10
9.5%
5
0.4%
0
Response
Baselga J, et al. N Engl J Med 2012;366(6):520-9.
Clinical Benefit
BOLERO-2: Most Common G3/4 AEs
Everolimus + Exemestane
(N = 482), %
Placebo + Exemestane
(N = 238), %
All
Grades
Grade
3
Grade
4
All
Grades
Grade
3
Grade
4
Stomatitis
56
8
0
11
1
0
Fatigue
33
3
<1
26
1
0
Dyspnea
18
4
0
9
1
<1
Anemia
16
5
<1
4
<1
<1
Hyperglycemia
13
4
<1
2
<1
0
AST
13
3
<1
6
1
0
Pneumonitis
12
3
0
0
0
0
Baselga J, et al. N Engl J Med 2012;366(6):520-9.
BOLERO-2: Overall Survival
•
As of PFS interim analysis: 83 deaths
•
10.6% in everolimus arm
•
13.0% in placebo arm
•
OS interim analysis after 173 events
•
OS final analysis at 392 events
•
80% power to detect 26% reduction in
hazard ratio (0.74)
Baselga J, et al. N Engl J Med 2012;366(6):520-9.
BOLERO-2: Clinical Implications
• The PFS of HR+ MBC patients who took everolimus
+ exemestane had a significantly higher PFS than
those who took exemestane alone
• Everolimus may slow progression of MBC in
patients who initially became resistant to endocrine
therapy alone
Other Mechanisms of Resistance
PI3K Compensatory Pathways
PI3K Compensatory Pathways
Rapalogs Activate Akt
IGFR-1
Phase I Everolimus Study
Tumor pAkt
IRS
PIP3
PDK1
Tuberin
Rheb
TORC1
S6K
S6
on-therapy
Akt
PTEN
pre-therapy
PI3K
10mg/day
50mg/week
4EBP1
Tabernero A, et al. J Clin Oncol. 2008;26(10):1603-1610
PI3K Compensatory Pathways
PI3K Inhibitors Activate ERK Pathway via Enhanced RTK Signaling
IGFR1
HER2
P
P
P
P
PTEN
EGFR
P
P
P
P
P
P
PI3K
Ras
PIP3
Raf
Akt
PDK1
Tuberin
MEK
Erk
Rheb
TORC1
Rsk
P
P
[TITLE]
Conclusions
• The effectiveness of ET is limited by high rates of de
novo and acquired endocrine resistance.
– Resistance to ET is a step-wise progression of BC cells that
renders them estrogen-independent
– Bidirectional crosstalk between the ER and growth factor
receptor signaling pathways, such as the PI3K/AKT/mTOR
pathway, is implicated in resistance to ET
– Under the pressure of ET, dynamic interplay between ER
and growth factor receptor expression exists that can alter
BC cell phenotype
• Overcoming endocrine resistance remains critical to
enhancing further the benefit of existing endocrine
therapies.