Download Targeting the PI3K pathway in breast cancer

Role of the PI3K/AKT/mTOR
Pathway in Endocrine TherapyResistant Breast Cancer
Ana M. Gonzalez-Angulo, MD
Associate Professor
Breast Medical Oncology
Systems Biology
Chicago, IL, ASCO 6/2012
PI3K Pathway
Meric-Bernstam F, Gonzalez-Angulo AM, J Clin Oncol. 2009;27(13):2278-2287.
PI3K Pathway: Genetic Target in
Breast Cancer
Growth
Factors
HER2
RAS
PI3K
PTEN
INPP4B
AKT
AMPK
TSC
1/2
mTOR
S6K
Tumor suppressor gene
Oncogene
LKB1
Gene
% Mutation
% Amp/Del
HER2
2
25
PIK3CA
25
16
KRAS
4
PTEN
4
INPP4B
AKT1
8
55 (TN)
3
Modified from Sellers W. SABCS. 2009.
Onc*Base and Beroukhim R, et al Nature.
2010;463(7283):899-905.
PI3K Pathway: Distinct Cancer States
Are There Distinctive Dependences?
Modified from Sellers W. AACR. 2011.
Resistance to Endocrine Therapy in ER+ Breast
Cancer Is Dependent Upon PI3K Signaling
LTED cells exhibit
increased PI3K/mTOR
pathway activation
PI3K pathway inhibition suppresses
LTED cell growth, and prevents
the emergence of hormoneindependent cells
LTED, long-term estrogen-deprived
Miller TW, et al. J Clin Invest. 2010;120(7):2406-2413.
Resistance to Endocrine Therapy in ER+ Breast
Cancer Is Dependent Upon PI3K Signaling
Miller TW, et al. J Clin Invest. 2010;120(7):2406-2413.
PI3K Pathway Activation
mTOR
Courtesy of S. Johnston
Temsirolimus Reverses TAM Resistance in AktExpressing Breast Cancer by Restoration of
Apoptotic Response
Control
Temsirolimus
TAM
TAM + Temsirolimus
WT
MCF-7
MyrAkt1
MCF7
TAM, tamoxifen
De Graffenried LA, et al, Clin Cancer Res. 2004;10(23):8059-8067.
Temsirolimus Reverses TAM Resistance in AktExpressing Breast Cancer by Restoration of
Apoptotic Response
Control
Temsirolimus
Tam
Tam + Temsirolimus
WT
MCF-7
MyrAkt1
MCF7
De Graffenried LA, et al, Clin Cancer Res. 2004;10(23):8059-8067.
Phase II Neoadjuvant Everolimus
(RAD001) Breast Cancer Study
• Newly diagnosed, untreated patients with ER+ localized breast
cancer likely to benefit from hormonal therapy
• Palpable tumor: >2 cm diameter
S
C
R
E
E
N
R
A
N
D
O
M
I
Z
E
N = 138
Letrozole 2.5 mg/d
RAD001 10 mg/d
Surgery
N = 132
Letrozole 2.5 mg/d
Placebo
16 weeks
Tumor biopsies
(Pretreatment)
Tumor biopsies
(Day 15)
Baselga J, et al. J Clin Oncol. 2009;27(16):2630-2637.
Tumor samples
(Surgery)
Results: Efficacy Summary
Overall Response (CR + PR), %
Palpation
(primary endpoint)
Ultrasound
Everolimus +
Letrozole
n = 138
Placebo +
Letrozole
n = 132
P
68.1
59.1
.062*
58.0
47.0
.035*
*1-sided chi-square level of significance is 10%.
CR, complete response; PR, partial response
Baselga J, et al. J Clin Oncol. 2009;27(16):2630-2637.
Results:
Major Pharmacodynamic Changes at Day 15
Reduction in pS6240 and pS6235 reveals everolimus-treated patients
CyclinD1
ER
PR
Ki67
pS6235
pAkt
Baselga J, et al. J Clin Oncol. 2009;27(16):2630-2637.
pS6240
Cell Cycle Response (Ki67) Correlates With Clinical
Response: Role of PIK3CA Mutations
Reduction in Ki67 at Day 15
Day 15 Ki67 score correlated
with clinical response
Patients with PIK3CA exon 9 mut
less responsive to letrozole as
sensitive to everolimus + letrozole
PIK3CA e9 PIK3CA e20 PIK3CA
mutant only mutant only wt only
80
60
Ki67d15
40
20
0
CR
PR
NC
PD
Everolimus + letrozole
Letrozole
Baselga J, et al. J Clin Oncol. 2009;27(16):2630-2637.
TAMRAD Schema
Randomized phase II
Metastatic patients with prior exposure to aromatase
inhibitor (AI)
A : Tamoxifen, 20 mg/d (TAM)
B : Tamoxifen 20 mg/d + RAD001 10 mg/d (TAM + RAD)
• 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 M, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-6
Time to Progression
TAM: 4.5 months
TAM + RAD: 8.6 months Hazard Ratio (HR) = 0.53; 95% CI (0.35-0.81)
Probability of Survival
Exploratory log-rank: P = .0026
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Patients at risk
TAM + RAD: n =
TAM : n =
TAM
TAM + RAD
0
2
4
6
8
10 12 14 16 18 20 22 24 26 28
Month
54 45 39 34 28 26 25 19 16 12 9
57 44 30 24 22 16 13 11 7 6 2
7
1
1
0
1
0
Bachelot M, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-6
0
0
Time to Progression as a Function
of Intrinsic Hormone Resistance
• Primary hormone resistance
(n = 54)
– TAM: 3.9 months
– TAM + RAD: 5.4 months
– HR = 0.74 (0.42-1.3)
Probability of Survival
TAM
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
TAM + RAD
6
12
18
24
30
24
30
• Secondary hormone resistance
(n = 56)
– TAM: 5.0 months
– TAM + RAD: 17.4 months
– HR = 0.38 (0.21-0.71)
Probability of Survival
Months
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
6
12
18
Months
Bachelot M, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-6
Adverse Events
TAM
n = 57
Incidence, n (%)
Grade
Most Common Adverse Events (AE)
Fatigue
Stomatitis
Rash
Anorexia
Diarrhea
Nausea
Vomiting
Pneumonitis
Thromboembolic
Pain
Dose reduction due to AE
Treatment discontinuation due to AE
TAM + RAD
n = 54
Any
3/4
Any
3/4
30 (52.6)
4 (7.0)
3 (5.3)
10 (17.5)
5 (8.8)
19 (33.3)
7 (12.3)
2 (3.5)
4 (7.0)
48 (84.2)
6 (10.5)
0
1 (1.8)
2 (3.5)
0
0
2 (3.5)
2 (3.5)
4 (7.0)
11 (19.3)
40 (74.1)
28 (51.9)
21 (38.9)
24 (44.4)
21 (38.9)
18 (33.3)
9 (16.7)
9 (16.7)
7 (13.0)
42 (77.8)
3 (5.6)
6 (11.1)
3 (5.6)
5 (9.3)
1 (1.9)
2 (3.7)
0
1 (1.9)
3 (5.6)
5 (9.3)
0 (0)
15 (28)
4 (7.0)
3 (5.6)
Bachelot M, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-6
BOLERO-2 Schema
N = 724
Postmenopausal 2
ER+ HER2- ABC
refractory to
1
letrozole or
anastrozole
Everolimus 10 mg/day +
Exemestane 25 mg/day
(N = 485)
Placebo +
Exemestane 25 mg/day
(N = 239)
PFS
OS
ORR
Bone Markers
Safety
PK
 Stratification:
1. Sensitivity to prior hormonal therapy
2. Presence of visceral disease
 No cross-over
ABC, advanced breast cancer; ORR, overall response rate;
OS, overall survival; PK, pharmacokinetics
Baselga J, et al. N Engl J Med. 2012;366(6):520-529.
BOLERO-2 Primary Endpoint: PFS
Local Assessment
HR = 0.43 (95% CI: 0.35–0.54)
Probability of Event, %
100
Log rank P value = 1.4 x 10-15
EVE + EXE: 6.9 months
80
PBO + EXE: 2.8 months
60
40
20
Everolimus + Exemestane (E/N=202/485)
Placebo + Exemestane (E/N=157/239)
0
0
6
12
18
24
30
485
239
398
177
294
109
212
70
144
36
108
26
36
42
48
54
60
66
72
78
51
14
34
9
18
4
8
3
3
1
3
0
0
0
Time, weeks
Everolimus
Placebo
75
16
Baselga J, et al. N Engl J Med. 2012;366(6):520-529
BOLERO-2 Primary Endpoint: PFS
Central Assessment
HR = 0.36 (95% CI: 0.27–0.47)
Probability of Event, %
100
Log rank P value = 3.3 x 10
-15
EVE + EXE: 10.6 Months
80
PBO + EXE: 4.1 Months
60
40
20
Everolimus + Exemestane (E/N=114/485)
Placebo + Exemestane (E/N=104/239)
0
Everolimus
Placebo
0
6
12
18
24
485
239
385
168
281
94
201
55
132
33
30
36
42
Time, weeks
102
20
67
11
43
11
48
54
60
66
72
78
28
6
18
3
9
3
3
1
2
0
0
0
Baselga J, et al. N Engl J Med. 2012;366(6):520-529
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):520-529
BOLERO-2 PFS in Subgroups
Favors Everolimus
+ Exemestane
Favors Placebo +
Exemestane
Subgroups (N)
All (724)
Age
<65 (449)
≥65 (275)
Hormonal sensitivity
YES (610)
NO (114)
Visceral metastasis
YES (406)
NO (318)
Baseline ECOG PS
0 (435)
1, 2 (274)
Prior chemotherapy
YES (493)
NO (231)
No. of prior therapies
1 (118)
2 (217)
≥3 (389)
Non-NSAI hormonal therapy
YES (398)
NO (326)
PgR status positive
YES (523)
NO (184)
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Hazard Ratio
Baselga J, et al. N Engl J Med. 2012;366(6):520-529
BOLERO-2: Response & Clinical Benefit
Baselga J, et al. N Engl J Med. 2012;366(6):520-529
PI3K Pathway: Markers vs Targets
INPP4B
LKB1
Modified from McAuliffe P, et al. Clin Breast Cancer. 2010;10 Suppl 3:S59-S65.
Fulvestrant in ER-Positive Breast Cancer
With GDC-0941 and GDC-0980 Inhibitors
PIK3CA/PTEN
Results
PIK3CA/PTEN
analysis
Randomization
Stratification
Arm A - GDC-0941 (Daily)
Registration
Arm C – Placebo (Daily)
Arm B - GDC-0980 (Daily)
Fulvestrant
500 mg
screening
D-28
Fulvestrant
500 mg
Fulvestrant
500 mg/Q4w
“run-in”
C1D1
Fulvestrant
500 mg/Q4w
D1-D28
D1-D28
C1D15
C2D1
C3D1
Phase III Randomized, Placebo-controlled Clinical Trial Evaluating the Use of
Adjuvant Endocrine Therapy +/- Everolimus in Patients with High-Risk, NodePositive, Hormone Receptor–Positive and HER2-neu Normal Breast Cancer
Node-positive HR-positive and HER2-negative breast cancer
Number of positive nodes ?
1-3 positive
Patients consent to study-sponsored RS
testing if not already done
RECURRENCE
SCORE evaluated
RS > 25
RS ≤ 25
Low risk
1-3 positive nodes
and RS ≤ 25
RANDOMIZATION
Chemotherapy vs.
No Chemotherapy
4+ positive
1-3 positive nodes and
RS > 25 or 4+ positive
nodes
Adjuvant or
neoadjuvant
chemotherapy
Chemotherapy;
endocrine therapy
RANDOMIZATION
Post-chemotherapy
(stratification by number of
lymph nodes and timing of
chemotherapy)
Everolimus +
Endocrine Therapy
No Chemotherapy;
endocrine therapy
Everolimus vs.
Placebo
Placebo +
Endocrine Therapy
Current RxPONDER trial
New adjuvant trial
A Phase II Neoadjuvant Trial of BEZ-235 in
Combination With Endocrine Therapy in
Postmenopausal Patients With Operable Hormone
Receptor-Positive Breast Cancer
22 weeks
2 weeks
Ki67
TUNEL
P-Akt, etc.
microarrays
RPPA
FDG-PET
2:1 randomization
Surgery
Letrozole
BEZ235
Biopsy
Postmenpausal
Breast Cancer
T1-3/N0-1
ER or PR+/HER2–
Postmenopausal
PI3K pathway aberration
(core biopsy)
Arm 1:
Letrozole
BEZ235
Arm 2:
Letrozole
Placebo
Letrozole
Placebo
Ki67
TUNEL
P-Akt, etc
microarrays
RPPA
FDG-PET
Path CR
Clin Response
(US, Mammo)
Breast Cons Surgery
Ki67
TUNEL
P-Akt, etc
microarrays
RPPA
Conclusions
•
The PI3K pathway is one of the most important active signaling pathways in
cancer growth through various mechanisms
•
Modulation of signal transduction pathway may modulate activity of
endocrine therapy and influence outcome… Assuming of course that the
tumor is “addicted” to the intended target!!
•
PI3K pathway activation is an important component in all subtypes of breast
cancer, both in cancer growth and in therapy resistance
•
The PI3K pathway is a common mechanism of endocrine therapy resistance
Benefit is impressive
Will be studied in the adjuvant setting
Toxicities?
Patient selection (awaiting correlatives)
•
Clinical trials to evaluate the role PI3K pathway inhibitors at different
levels of the pathway are ongoing and should have extensive correlative
components to be able to decipher the best use of these drugs according to
the molecular aberrations of the tumors
What Would You Recommend to
This Patient at This Time?
1. Fulvestrant alone
2. Fulvestrant + PI3K/AKT/mTOR inhibitor in a
clinical trial
3. pan-ErbB receptor inhibitor in a clinical trial
4. Chemotherapy
5. Other
Acknowledgements
Collaborators MDACC
Mentorship
• G.N. Hortobagyi
• G.B. Mills
• F. Meric-Bernstam
Gonzalez-Angulo’s Lab
• S. Liu
• X. Meng
• C. Phan
• H. Chen
• E. Tarco
Meric-Berstam’s Lab
• A. Akcakanat
• G. Singh
•
•
•
•
•
•
•
•
•
Systems Biology
•
K. Hale
•
J. Mendelsohn
Transcriptional Profiling
•
L. Pusztai
•
W.F. Symmans
Tumor Bank
•
A. Sahin
BMO
•
L. Hsu
Surgical Oncology
•
E. Mittendorf
Funding By
NIH
MDACC Physician-Scientist Start up Funds
Komen for the Cure
BCRF
Texas Fed of Business and Professional Women
Commonwealth Foundation for Cancer Research
AACR SU2C Dream Team
ACS
Clayton Foundation
• PI of Investigator Initiative Trials with Novartis, BMS, GSK,
Abraxis, Roche Dx, Genomic Health Inc, Merck.
• Lab MTAs with NIH, Merck, Exelixis, Novartis, Xcovery,
EMD Serono, Genentech, Bayer
Bioinformatics
• K. Coombes
• Y. Ji
• Z. Ju
• W. Liu
Biostatistics
• D. Berry
• K. Do
• X. Lei
T and H&N
• G. Blumenschein
Phase I
•
Razelle Kurzrock
Collaborators Outside MDA
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
C. Perou, L. Carey
I. Krop
R. Bernards, H. Horlings
A. Lluch, J. Ferrer
C. Arteaga
J. Baselga
J. Tabernero, J. Rodon
J. Gray
M. Ellis
C. Hudis, N. Rosen
C. Sotiriou
P. Lorusso
AL. Borresen-Dale
F. Andre
M. Pollak