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Hormone-Dependent Breast Cancer:
Mechanisms of Resistance and
Treatment Aternatives
Carlos H. Barrios, MD
PUCRS School of Medicine
Porto Alegre, RS, Brazil
VIII Simposio Internacional GEICAM - A Coruña, 2011
Endocrine Receptors and Breast Cancer
• Estrogen receptors (ER) are expressed in 60-70% of
breast cancer cases (incidence increases with age).
• Tamoxifen (5y adjuvant Rx in ER+)
– Reduces:
• Recurrence by 38%
• BC death by 30%
• Contralateral BC by 40%
• 50-60% ER (+) tumors respond to first-line ET.
• But…up to 50% of ER+ tumors are inherently refractory
or acquire resistance during endocrine treatment.
VIII Simposio Internacional GEICAM – A Coruña 2011
Tamoxifen in
ER+ Disease
47% of
patients do
not need Rx !!
Absolute
benefit in 14%
of patients
Recurrence in
33% of
patients in
spite Rx
Primary or
Acquired
Resistance
Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717
Some Proposed Mechanisms of Resistance Development
IGFR
Growth factor
Estrogen
INCREASED EXPRESSION/SIGNALING
EGFR / HER2
THROUGH GF RECEPTORS
P
P
HER2, etc.)
P (IGFR,
P
P
PI3-K
Aromatase
Inhibitors
TamoxifenER
Cell
survival
Akt
P
SOS
RAS
RAF
P
INCREASED SIGNALING THROUGH
MAPK
p90RSK P
THE PI3K PATHWAY
Cytoplasm
P
Nucleus
P
P
P ER
ER
ERE
p160
CBP
Basal
transcription
machinery
MEK
P
P
Cell
growth
CHANGE IN CO-ACTIVATORS
ER target gene transcription
Adapted from Johnston S. Clin Cancer Res. 2005;11:889S
Pathways associated with ET resistance in vitro
Hoskins JM, et al. Nat Rev Cancer 9: 631-43, 2009
Inverse Relationship: ER/PgR and HER2 in Primary Breast Cancers
1200
700
1100
900
900
900
400
100
400
0
0
300
400 1600 3600 6400 10,000
HER2/neu protein (fmol/mg)
200
PgR (fmol/mg)
ER (fmol/mg)
ER (fmol/mg)
500
PgR (fmol/mg)
1000
600
800
700
400
100
600
0
500
0
400 1600 3600 6400 10,000
HER2/neu protein (fmol/mg)
400
300
200
100
100
0
0
0
2000
4000 6000
8000 10,000 12,000
HER2/neu protein (fmol/mg)
0
2000
4000 6000
8000 10,000 12,000
HER2/neu protein (fmol/mg)
Konecny et al. J Natl Cancer Inst. 95:142, 2003.
Cross-Talk Between GF Signal
Transduction and Endocrine Pathways
Growth factor
PHOSPHORYLATION OF ER
Estrogen
HER2-normal MCF-7 cells
EGFR / HER2
Activation of HER2 receptor with heregulin
results in phosphorylation of ER tyrosine
residues, enhances nuclear binding of
ER, and E2-independent growth
Pietras et al, Oncogene 10:2435, 1995
Cell
survival
PI3-K
Akt
ER
P
P
SOS
RAS
RAF
P
MEK
P
P
p90RSK
MAPK
P
Cytoplasm
P
Nucleus
P
P
P ER
ER
ERE
p160
CBP
Basal
transcription
machinery
P
Cell
growth
ER target gene transcription
Adapted from Johnston S. Clin Cancer Res. 2005;11:889S
TAnDEM: Anastrozole ± Trastuzumab in ER+/HER2+
MBC
Post-menopausal
HER2+ (IHC 3+
or FISH+) ER+
and/or PgR+ MBC
R
A
N
D
O
M
I
S
E
Anastrozole 1 mg daily +
Trastuzumab 4 mg/kg loading
dose, then 2 mg/kg qw
(n=103)
Anastrozole 1 mg daily (n=104)
 Crossover to receive trastuzumab offered to all patients who developed tumour
progression on anastrozole alone (70% crossed over)
 Primary end point: PFS
Mackey et al. Breast Cancer Res Treat. 2006;100(suppl 1):S5. Abstract 3.
Kaufman B, et al. J Clin Oncol 27: 5529-5537, 2009
TAnDEM: Efficacy
A+T
(103)
A
(104)
P Value
PFS, mo
4.8
2.4
0.0016
TTP, mo
4.8
2.4
0.0007
ORR, %
20.3
6.8
0.018
CB, %
42.7
27.9
0.026
Kaufman B, et al. J Clin Oncol 27: 5529-5537, 2009
Letrozol + Lapatinib in: ER+/HER2+ MBC
1286 post-menopausal
women with HR+ MBC*
R
A
N
D
O
M
I
S
E
Letrozol 2.5mg/d +
Lapatinib 1500mg/d
(n=642) (HER2+=111)
Lapatinib 1500mg/d
(n=644) (HER2+=108)
 *No prior therapy for metastatic disease; neo-adjuvant/adjuvant ET allowed:
AI/or trastuzumab completed > 1 yr; ECOG 0-1; normal organ function
 Primary end point: PFS
Johnston S, et al. J Clin Oncol. 27:5538, 2009.
Lapatinib + Letrozole in the ITT Population
Johnston S, et al. J Clin Oncol. 27:5538, 2009.
Lapatinib + Letrozole enhances PFS and CBR in pts with HER2+, HR+ MBC
Johnston S, et al. J Clin Oncol. 27:5538, 2009.
No benefit for Lapatinib + Letrozole in HR+/HER2-/ET sensitive MBC.
Possible benefit in ET resistant MBC.
HER2-/ET sensitive population
HER2-/ET resistant population
• A combined targeted strategy with AIs (Letrozole or Anastrozole)
and anti-HER2 therapy (Trastuzumab or Lapatinib) enhances PFS
and CBR in pts with MBC that co-expresses HR and HER2.
• HER2 over-expression is associated with endocrine resistance and
poor DFS. These studies clearly demonstrate that these tumors are
relative insensitive to hormonal therapy (AIs)
– ORR of 6.8-28%
– TTP of 2.4-3.0 months
• The possibility of chemotherapy plus anti-HER2 therapy being a
better alternative needs to be considered. Additional strategies are
urgently needed for these patients.
HER2/HER3
The PI3K pathway
and Breast Cancer
PTEN
TORC2
PI3K
Ras
PIP3
Raf
Akt
PDK1
Tuberin
MEK
Erk
Rheb
Rsk
TORC1
S6K
S6
4EBP1
• Constitutive activation of the PI3K
pathway is frequent.
• PI3K pathway activation conveys
malignant transformation, cell
growth and invasion, tumor neoangiogensis and resistance
towards anti-cancer treatments.
• Known mechanisms of PI3K
pathway activation include
activating mutations of RTKs,
gain-of-function mutation of the
PIK3CA gene, and loss-of-function
mutations of PTEN.
The PI3K/Akt/mTOR pathway is frequently
deregulated in human cancer
Map and frequency distribution of PI3K mutations
Gymnopoulos M,et al. Proc. Natl. Acad. Sci. USA 104, 5569-74, 2007
Frequency of mutations in PIK3CA and PTEN
(n=547 breast cancer cases)
Mutation
Breast Cancer
Subtype
PIK3CA
catalytic
domain*
PIK3CA other
PIK3CA total
PTEN
All breast
tumors
73/547 (13.3%)
44/547 (8.0%)
117/547 (21.4%)
2/88 (2.3%)
HR+
48/232 (20.7%)
32/232 (13.8%)
80/232 (34.5%)
2/58 (3.4%)
HER2+
13/75 (17.3%)
4/75 (5.3%)
17/75 (22.7%)
0/10 (0%)
Triple Negative
12/240 (5.0%)
8/240 (3.3%)
20/240 (8.3%)
0/20 (0%)
Stemke-Hale, K. et al. Cancer Res 68:6084-91, 2008
PI3K/Akt/mTOR pathway inhibitors
McAuliffe P. et al. Clin Breast Cancer
Addressing Resistance in
HR+ Breast Cancer
IGFR-1
HER2-1
Plasma
membrane
P
P
P
P
P
PI3-K
Estrogen
Akt
P
SOS
RAS
RAF
P
MEK
P
ER
mTOR
P
MAPK
Cytoplasm
P
Nucleus
P P
ER
P
ER
ERE
p160
CBP
Basal
transcription
machinery
ER target gene transcription
P
TAMRAD: Phase II trial of Everolimus + Tamoxifen
MBC
HR positive
HER2 negative
Previous AI exposure
Tamoxifen 20 mg daily +
Everolimus 10 mg daily
(n=54)
R
Tamoxifen 20 mg daily (n=57)
 Hypothesis: Previous exposure to AIs may “enrich” the population of patients driven by
activation of the PI3K/Akt/mTOR pathway.
 Stratification: primary or secondary endocrine resistance
 Primary end point: CBR (CR+PR+SDx6m)
Bachelot T, et al. Ca Res 70 (24 Suppl):S1-6. SABCS 2010.
TAMRAD: Phase II Trial of Everolimus + Tamoxifen
TAM
(57)
RAD + TAM
(54)
p Value
CBR*
42%
61%
0.045
TTP
4.5m
8.6m
0.003
Deaths
25
9
0.002
(*) Primary Objective
• Primary Resistance:
• Relapse during adjuvant treatment or progression within first 6 months of AI for MBC
• TTP: TAM 3.9 vs. TAM+RAD 5.0 months, HR 0.74
• Secondary Resistance:
• TTP: TAM 5.0 vs. TAM+RAD 17.4 months, HR 0.38
Bachelot T, et al. Ca Res 70 (24 Suppl):S1-6. SABCS 2010.
Phase II trial of BEZ235 in patients with HR+, HER2-, MBC
with and without activation of the PI3K pathway
BEZ235: Dual PI3K and mTOR inhibitor
MBC
HR positive
HER2 negative
1 prior ET and 2-3 prior CT
Explore PI3K mutation status *
X
PI3K
PTEN
AKT
TSC 1/2
X
mTOR
S6K
Proliferation/Survival
BEZ235 1600mg/day PO
(until disease progression)
Primary objective: 16 weeks PFSR
(*) Group 1: PI3K activation (mutation) + with or without PTEN alterations
Group 2: PI3K activation (wild type) + with PTEN alterations (mutation or PTEN-)
Group 3: No activation of the PI3K pathway (wild type)
www.clinicaltrials.gov, NCT01288092
Addressing Resistance in
HR+ Breast Cancer
IGFR-1
HER2-1
Plasma
membrane
P
P
P
P
P
PI3-K
Estrogen
Akt
P
SOS
RAS
RAF
P
MEK
P
ER
mTOR
P
MAPK
Cytoplasm
P
Nucleus
P P
ER
P
ER
ERE
p160
CBP
Basal
transcription
machinery
ER target gene transcription
P
A Two-Arm Randomized Open Label Phase 2 Study Of CP-751,871 In
Combination With Exemestane Versus Exemestane Alone As First Line
Treatment For Postmenopausal Patients With Hormone Receptor Positive
Advanced Breast Cancer
MBC
HR positive
No previous Rx
N=260
CP-751,871 20 mg/kg IV q21 day
Exemestane 25 mg/day
R
Examestane 25 mg/day
 Primary end point: PFS
Treatment until progression or toxicity
Second line therapy with Faslodex
www.clinicaltrials.gov, NCT00372996
Conclusions
• The molecular/genetic complexity of Breast Cancer is increasingly
recognized.
• Targeting the HER2 pathway or the use of endocrine manipulations
have a positive impact in the natural history of breast cancer.
• Therapeutic strategies simultaneously targeting multiple pathways
have the potential of greater clinical impact.
• Further understanding of the molecular interaction among different
pathways will:
• give us further insights into the heterogeneity of breast cancer
• allow for better patient selection
• provide us with a more rational therapeutic approach
Potential Conflict of Interests
• Research Support
• Honoraria
• Financial Disclosure
VIII Simposio Internacional GEICAM – A Coruña 2011
Long-Term Risk of Breast Cancer Recurrence
ER+ and ER- Patients
Patients received CT, ET, or both (10 ECOG trials)
Recurrence hazard rate
0.3
ER+ (n=2257)
ER– (n=1305)
0.2
0.1
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Years
Annual hazard of recurrence by estrogen receptor status
Saphner et al. J Clin Oncol. 1996;14:2738.
Conclusions
• Understanding breast cancer as a molecular disease
is leading to novel therapies
• Clinical trials will continue to evaluate the efficacy
and safety of biologic therapy in combination or
following standard chemotherapy and endocrine
therapy
• Patient selection will be increasingly important for the
integration of novel agents in the treatment of breast
cancer
• This is an exiting time, but we have to be smart to
avoid waste of time and resources
• A combined targeted strategy with AIs (Letrozole or
Anastrozole) and anti-HER2 therapy (Trastuzumab or
Lapatinib) enhances PFS and CBR in pts with MBC that
co-expresses HR and HER2.
• HER2 over-expression is associated with endocrine
resistance and poor DFS. These studies clearly
demonstrate that these tumors are relative insensitive to
hormonal therapy (AIs)
– ORR of 6.8-28%
– TTP of 2.4-3 months
• Additional strategies are needed for these patients
Estrogen Signaling Pathway
PHOSPHORYLATION OF ER
HER2-normal (HER2–) MCF-7 cells
Activation of HER2 receptor with heregulin
resulted in phosphorylation of ER tyrosine
residues, enhanced nuclear binding of
ER, and E2-independent growth
Pietras et al, Oncogene 10:2435, 1995
INCREASED EXPRESSION OF GF
Osborne CK, et al. Ann Rev Med 62:14.1-15, 2010
Cross-Talk Between Signal
Transduction and Endocrine Pathways
IGFR
Growth factor
Estrogen
P
P
P
P
P
PI3-K
Cell
survival
Akt
ER
Aromatase
Inhibitor
Cytoplasm
P
SOS
RAS
RAF
P
p90RSK
MEK
P
MAPK
Tamoxifen
P
Nucleus
EGFR / HER2
Antibodies
and TKIs
P
P
P ER
ER
ERE
p160
CBP
Basal
transcription
machinery
P
P
Cell
growth
ER target gene transcription
Adapted from Johnston S. Clin Cancer Res. 2005;11:889S
Long-term estrogen deprivation (LTED)
• ER (+) BC cells after LTED become hypersensitive to
low-dose estrogen.
• LTED is NOT due to up-regulation of ER.
• LTED is likely due to activation
of MAPK, PI3K, EGFR, or nongenomic effect of estrogen.
Masamura S, et al. J Clin Endocrinol Metab 2918-25, 1995
Pathways associated
with ET resistance
in vitro
Nat. Rev. Cancer 9: 631-43
Mechanisms of SERM resistance
TAnDEM trial
• First randomized phase III to combine ET and trastuzumab
for HER2/HR + MBC
208 postmenopausal
women with HR/HER2 +
MBC*
(2001-2004)
anastrozole
n=104
(n=73 HR +)
anastrozole 1 mg qd
Trastuzumab 4 mg/kg
IV day 1, followed by
2mg/kg, qwk
*previous ET or anastrozole < 4
months, adequate organ
functions, ECOG 0-1
Randomized
anastrozole +
trastuzumab
n=103
(n=77 HR +)
Primary EP: PFS
2nd EP: CBR, ORR,
TTP, OS, 2-yr SR
double-blinded
187 withdrawals due to PD
73/104 pts received trastuzumab-containing regimen
J Clin Oncol 27: 5529-5537
TAnDEM: Efficacy Summary
A+T
(n=103)
A
(n=104)
P Value
PFS, mo
4.8
2.4
0.0016
– PFS
TTP, mo
4.8
2.4
0.0007
– Secondary end points:
TTP, ORR, CB
ORR, %
20.3
6.8
0.018
CB, %
42.7
27.9
0.026
• Trastuzumab added to anastrozole
(A + T) vs anastrozole alone (A)
significantly improved efficacy
End Point
Update of Mackey et al. Breast Cancer Res Treat. 2006;100(suppl 1):S5. Abstract 3.
TAnDEM trial
• Trastuzumab plus anastrozole improves PFS and TTP,
but not OS for pts with HER2/HR + MBC compared
with anastrozole alone.
• Poor response on both arms is likely due to aggressive
nature of the cancer.
Frequency of mutations in PIK3CA and PTEN
(n=547 breast cancer cases)
Mutation
Breast Cancer
Subtype
PIK3CA
catalytic
domain*
PIK3CA other
PIK3CA total
PTEN
All breast
tumors
73/547 (13.3%) 44/547 (8.0%) 117/547 (21.4%)
2/88 (2.3%)
HR+
48/232 (20.7%) 32/232 (13.8%) 80/232 (34.5%)
2/58 (3.4%)
ER+PR+
39/186 (21%)
22/186 (11.8%)
61/186 (32.8%)
1/48 (2.1%)
ER+PR–
9/41 (22%)
10/41 (24.4%)
19/41 (46.3%)
1/8 (12.5%)
ER–PR+
0/5 (0%)
0/5 (0%)
0/5 (0%)
0/2 (0%)
HER2+
13/75 (17.3%)
4/75 (5.3%)
17/75 (22.7%)
0/10 (0%)
Triple Negative 12/240 (5.0%)
8/240 (3.3%)
20/240 (8.3%)
0/20 (0%)
Stemke-Hale, K. et al. Cancer Res 68:6084-91, 2008
How do we take it to the clinic?
MK-0646
Trastuzumab
MK 0646
AMG 479
AMC A12
AVE 1642
Pertuzumab
IGFR1
HER2
Lapatinib
PI3K/AKT pathway activation
Perifosine
A797
A838450
LY2101831
GSK690693B
KP86328
X
Dasatinib Src-> PI3K -> AKT -> mTOR
Fulvestrant
ER
Tamoxifen
Anastrazole
Letrozole
Exemestane
Fulvestrant
X
Dasatinib
AZD 0530
LY 294002
SF 1126
PX 166
BEZ 235
CCI 779
RAD 001
AP23573
Breast
cancer cell
growth
A phase I-II, randomized clinical trial for
metastatic HR-positive HER2-negative
breast cancer
PET-CT
Biopsy
PET-CT
Biopsy
Pre-Rx
HRpositive
and
HER2negative
Day 14
Fulvestrant
Fulvestrant +
MK-0646
AR
PIK3CA mutations
Fulvestrant +
Dasatinib
Fulvestrant +
MK-0646 + Dasatinib
AR= Adaptive Randomization
(PI: Gonzalez-Angulo & Meric-Bernstam)
www.clinicaltrials.gov
Biopsy
Week 12
Staging
PI3K/PTEN/AKTmutations
PI3K/PTEN/AKT-activation
Src -activation
ER levels
A phase II neoadjuvant trial of BEZ235 in combination
with endocrine therapy in post-menopausal patients with
operable HR-positive breast cancer
Ki-67
TUNEL
P-Akt, etc.
microarrays
RPPA
FDG-PET
1:1 randomization
Arm 2:
Letrozole
Placebo
Biopsy
Breast Cancer
T1-3/N0-1
ER or PR+/HER2–
Post-menopausal
PI3K aberrations
(core biopsy)
Arm 1:
Letrozole
BEZ235
Ki-67
TUNEL
P-Akt, etc
microarrays
RPPA
FDG-PET
Letrozole
BEZ235
Letrozole
Placebo
Surgery
22 weeks
2 weeks
Path CR
Clin Response
(US, Mammo)
Br Cons Surgery
Ki-67
TUNEL
P-Akt, etc
microarrays
RPPA
1286 postmenopausal
women with HR+ MBC*
(2003-2006)
*No prior therapy for metastatic
disease allowed; but
neoadjuvant/adjuvant ET
allowed; AI/or trastuzumab
completed > 1 yr; ECOG 0-1;
normal organ function
Randomized
Letrozole + lapatinib
n=642
(111 HER2 +)
Letrozole + Placebo
N=644
(108 HER2 +)
Letrozole 2.5 mg qd
Lapatinib 1500 mg qd
double-blinded
Median follow-up 1.8 yrs
Primary EP: PFS
2nd EP: ORR, CBR,
OS, safety
UK/USA 1950-2006: BC mortality (ages 35-69)
Breast Cancer Mortality - US
Screening: 50%
Adjuvant Therapy: 50%
Estimated and Actual Rates of Death from Breast Cancer among Women 30 to 79 Years of Age from 1975 to 2000 (Panel A) and under Hypothetical
Assumptions about the Use of Screening Mammography and Adjuvant Treatment (Panel B)
Berry D et al. N Engl J Med 2005;353:1784-1792
Breast Cancer Mortality - US
Screening: 50%
Adjuvant Therapy: 50%
Rates of Death from Breast Cancer among Women 30 to 79 Years of Age from 1975 to 2000 under
Hypothetical Assumptions about the Use of Screening Mammography and Adjuvant Treatment
Berry D et al. N Engl J Med 2005;353:1784-1792
Outline
• Endocrine Receptors and Breast Cancer
• Potential Mechanisms of Resistance to Endocrine Manipulation
• Clinical Trials
• Future Developments
• Ongoing Trials
VIII Simposio Internacional GEICAM – A Coruña 2011
Tamoxifen improves 15-y outcomes in ER+/unknown
60
Recurrence (%)
50
45.0
38.3
40
30
26.5
33.2
24.7
20
15.1
10
Breast cancer mortality (%)
60
10 386 women:
20% ER-unknown,
30% node-positive.
50
40
34.8
30
25.7
25.6
20
11.9
17.8
10
8.3
0
0
0
5
10
Years
0
15
Control
Tamoxifen
5
10
15
Years
Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717
~5 years Tamoxifen vs not,
split by ER status only: RECURRENCE
ER poor
ER+
disease
ER+
Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717
~5 years Tamoxifen vs not,
ER+ split by PgR status: RECURRENCE
ER+ / PR poor
ER+ / PR+
Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717
Distant Mets Comprise the Majority of Early Recurrences During Tam Therapy
Annual recurrence rate
4,245 postmenopausal women with ER+ operable breast cancer, all treated with TAM
0.05
Overall
Locoregional
Distant
Contralateral
0.04
0.03
0.02
0.01
0
0
1
2
3
4
5
Years from diagnosis
Overall
Distant
Locoregional
Contralateral
Cumulative recurrence rate, (% of overall)
2.5 years
5 years
6.2
13.9
4.5 (73 %)
9.8 (71%)
1.0 (16)
2.7 (19)
0.5 (8)
1.3 (9)
Updates of Doughty JC, et al. Breast Cancer Res Treat. 2007;106(suppl 1):S145. Abstract 3057;
Mansell J, et al. Breast Cancer Res Treat. 2006;100(suppl 1):S111. Abstract 2091.
Poster presented at: 29th Annual San Antonio Breast Cancer Symposium. December 14-17, 2006; San Antonio, Texas. Poster 2091.
53
2010 EBCTCG OVERVIEW
TAMOXIFEN
10 yrs vs 5 yrs of adjuvant TAMOXIFEN in
ER+/? Disease
• Absolute reduction in recurrence by 1% (2p=0.03)
• Reduces contralateral BC by 1.3% (2p=0.03)
• Increases endometrial cancer by 0.7% (2p=0.00004)
• Reduces BC mortality by 3% (2p=0.55)
• Increases death without recurrence by 1.5% (2p=0.59)
THE 2010 OVERVIEW
Experience with locally defined predictive biomarkers
used to identify patients who do not benefit
Endocrine therapy
ER+ tumor
not benefiting
from endocrine
therapy ?
ER+ tumor
benefiting from
AI rather than
TAM ?
PgR does not help!
Chemotherapy
Subgroup
without benefit ?
No apparent interaction of ER,
PgR or grade with CT benefit!
The current paradox
Current message
Right or wrong ?
First generation
multigene signatures
« Among ER positive BC
there is no CT benefit
for the low proliferative
tumors »
Too few patients studied
could lead to wrong
conclusions…!
The 2010 Overview
« There is no group
identified without
a benefit! »
Many patients studied with
poor reproducibility in
biomarkers measurement
could lead to wrong
conclusions…
 ER: 15% error ?
 Grade : 40% error ?
PI3K/Akt/mTOR pathway inhibitors
Molecular Targets
Agent
Company
Clinical Trials
PI3K Selective Inhibitors
XL-147
GDC0941
BKM120
PX866
Exelixis
Genentech
Novartis
Oncothyreon
Phase I/II
Phase Ib/II
Phase Ib/II
Phase I
PIK3Cd
CAL-101
Calistoga
Phase I/II
PI3Ka
BYL719
Novartis
Phase I
Dual PI3K/mTOR Inhibitors
GSK1059615
XL-765
BEZ235
BGT226
GlaxoSmithKline
Exelixis
Novartis
Novartis
Phase I
Phase I/II
Phase I/II
Phase I/II
SF1126
Semafore
Phase I
AKT Inhibitors
GSK690693 (AKT 1,2,3)
MK2206 (AKT 1,2,>3)
Perifosine
GlaxoSmithKline
Merck
Keryx
Phase I/II
Phase I/II
Phase II
mTOR kinase inhibitors
AZD8055
OSI027
INK128
AstraZeneca
OSI Oncology
Intellikine
Phase I
Phase I
Phase I
Rapalogs
Sirolimus
Temsirolimus (CCI779)
Everolimus (RAD001)
Wyeth/Pfizer
Wyeth/Pfizer
Novartis
Phase II
Phase III
Phase II
Ridaforolimus (AP23573)
ARIAD/Merck
Phase II
Multimodal Inhibitor
(PI3K, mTOR, DNA-PK, HIF-1α)
McAuliffe P. et al. Clin Breast Cancer (In Press)
PI3K/Akt/mTOR pathway inhibitors
Molecular Targets
Agent
Company
Clinical Trials
PI3K Selective Inhibitors
XL-147
GDC0941
BKM120
PX866
Exelixis
Genentech
Novartis
Oncothyreon
Phase I/II
Phase Ib/II
Phase Ib/II
Phase I
PIK3Cd
CAL-101
Calistoga
Phase I/II
PI3Ka
BYL719
Novartis
Phase I
Dual PI3K/mTOR Inhibitors
GSK1059615
XL-765
BEZ235
BGT226
GlaxoSmithKline
Exelixis
Novartis
Novartis
Phase I
Phase I/II
Phase I/II
Phase I/II
SF1126
Semafore
Phase I
AKT Inhibitors
GSK690693 (AKT 1,2,3)
MK2206 (AKT 1,2,>3)
Perifosine
GlaxoSmithKline
Merck
Keryx
Phase I/II
Phase I/II
Phase II
mTOR kinase inhibitors
AZD8055
OSI027
INK128
AstraZeneca
OSI Oncology
Intellikine
Phase I
Phase I
Phase I
Rapalogs
Sirolimus
Temsirolimus (CCI779)
Everolimus (RAD001)
Wyeth/Pfizer
Wyeth/Pfizer
Novartis
Phase II
Phase III
Phase II
Ridaforolimus (AP23573)
ARIAD/Merck
Phase II
Multimodal Inhibitor
(PI3K, mTOR, DNA-PK, HIF-1α)
2010 EBCTCG OVERVIEW
5y in ER+ disease
TAMOXIFEN
• Reduces:
– Recurrence by 38%
– BC death by 30%
– All deaths by 22%
•
•
•
•
•
Contralateral BC by 40%
Benefits all women with ER+ disease
Unclear benefits in ER-PgR+ disease
Benefits women with ER very rich tumors more
Increases endometrial cancer by 2.3 fold
Cancer Cell Signaling: Complexity
ER and HER-2 (+) Tumors
• Endocrine therapy with AIs has a significantly greater
impact than tamoxifen on response biomarkers such as
Ki67, indicating greater ER inhibition and antiproliferative effects.
• Tumors that express HER2 in conjunction with ER were
considerably more responsive to an AI than to tamoxifen.
• Studies are beginning to investigate the impact of HER2
positivity on anti-proliferative effects of AIs, focusing on
Ki67 as a key biomarker.
Eiermann et al. Ann Oncol. 2001;12:1527.
Ellis et al. J Clin Oncol. 2001;19:3808.
Ellis et al. J Clin Oncol. 2006;24:3019-3025.
Smith et al. J Clin Oncol. 2005;23:5108.
Smith and Dowsett. Breast Cancer Res Treat. 2003;82(suppl 1):S6. Abstract 1.
Young et al. Breast Cancer Res Treat. 2004;88(suppl 1):S38. Abstract 411.
Conclusions
• HER2 overexpression is associated with tamoxifen resistance
and poor DFS
• AIs have a significantly greater impact on response biomarkers than
tamoxifen, indicating greater ER inhibition and antiproliferative effects
• Letrozole is equally effective in HER2+ and HER2– patients in the
neoadjuvant and adjuvant settings
– Letrozole demonstrated a significantly better response than tamoxifen in
patients with ER+, HER2+ disease in the neoadjuvant setting (88% vs 21%,
respectively; P=0.0004)
– The benefit of anastrozole over tamoxifen was seen in HER2+ patients
• HER2 overexpression is a negative predictor of efficacy for both
tamoxifen and AIs
– Additional agents may be required for optimal management