Transcript Challenges in the Treatment of Breast Cancer: Overcoming

Clinical Updates
Optimizing Endocrine Therapy for Early Breast Cancer
Recent Advances in Adjuvant Endocrine
Therapy for Early Breast Cancer
Ruth M. O’Regan, MD
Associate Professor, Hematology and Medical Oncology
Emory University School of Medicine
Director, Translational Breast Cancer Research Program
Emory Winship Cancer Institute
Chair, The Louisa and Rand Glenn Family Chair in Breast Cancer Research
Director, Hematology and Medical Oncology Fellowship Program
Emory University School of Medicine
Atlanta, Georgia
Adjuvant Hormonal Therapy Options for
Postmenopausal Patients
AI
ATAC, BIG-1-98 (upfront AI vs TAM)
TAM
AI
AI
TAM
TAM
IES, ABCSG, BIG-1-98 (TAM to AI)
BIG-1-98, TEAM (AI to TAM)
AI
MA.17
Extended
AI
All superior to 5 years of TAM but which approach is best?
ATAC Trialists Lancet Onc 2008, Mouridsen NEJM 2009, Goss JCO 2008,
Coombes R Lancet 2007, Jakesz R JNCI 2007
ATAC
• Recruitment July 1996 – March 2000
• Median follow-up 100 months
Tamoxifen (n = 3,116)
Surgery
+/- RT
+/- Chemo (20%)
• 84% HR positive
• 61% Node negative
Anastrozole (n = 3,125)
Discontinued following
initial analysis as no
efficacy or tolerability
benefit compared with
tamoxifen arm
5 years
ATAC Trialists Lancet Onc 2009
Efficacy of Anastrozole vs Tamoxifen in HR+
Patient Population of ATAC Study
9-Year Follow-up
Recurrence
Distant Recurrence
Contralateral Breast Cancer
Disease-Free Survival
Death After Recurrence
Anastrozole
Tamoxifen
17.0%
21.8%
HR = 0.76; P = .0001
13.2%
15.6%
HR = 0.84; P = .022
2.5%
4.2%
HR = 0.60; P = .004
HR = 0.85; P = .003
HR = 0.90; P = .2
• Significant long-term carryover effect for anastrozole:
- Absolute difference in recurrence increased from 2.8% after 5 years to
4.8% after 9 years
- Hazard ratio anastrozole vs tamoxifen for years 5-9 = 0.75; P = .01
ATAC Trialists Lancet Onc 2009
Death: All Causes
HR+ Patients
Patients
(%)
30
HR
95% CI
HR+ 0.97 (0.86, 1.11)
25
20
30
P-value
0.70
25
20
Tamoxifen (T)
Anastrozole (A)
15
15
10
10
5
5
0
0
0
1
2
3
4
5
6
Follow-up time (years)
7
8
At risk:
A 2618 2567 2511 2445 2389 2274 2102 1911 1586
T 2598 2549 2504 2432 2339 2227 2068 1888 1551
9
659
620
ATAC Trialists Lancet Onc 2009
BIG 1-98 Design
R
A
N
D
O
M
I
Z
E
A
Tamoxifen
B
Letrozole
C
Tamoxifen
Letrozole
D
Letrozole
Tamoxifen
0
2
2-Arm Option
3/98 to 3/00
1,835 pts
4-Arm Option
9/99-5/03
6,193 pts
5
YEARS
Mouridsen NEJM 2009
Letrozole vs Tamoxifen
Disease-free Survival
97.7
97.6
Percent Alive and Disease-Free
Yearly
DFS %
100
95.1
93.4
90.5
89.0
84.0
81.4
86.8
84.6
L
80
T
60
40
N
20
8010
HR (95% CI)
0.81 (.70-.93)
P
0.003
0
0
No. at
Risk
4003
4007
1
3892
3896
2
3
Years from Randomization
2964
1261
2926
1238
4
5
892
866
567
544
Mouridsen NEJM 2009
Cumulative Incidence
Breast Cancer Relapse
20
5-year diff (L-T) = -3.4%
(S.E. 1.2) cuminc P=0.0002
Proportion Failure (%)
15
10
13.6%
T
L
8.1%
10.2%
5
6.2%
0
0
1
2
3
Years from Randomization
4
5
Mouridsen NEJM 2009
IES: Trial Design
Tamoxifen
R
A
N
D
O
M
I
Z
E
5,162*
Post Treatment
Follow-up
Tamoxifen
10,335*
5,294*
2-3 years study
treatment
2-3 years
Diagnosis
Exemestane
Start of
study
Total 5 years
endocrine therapy
* Total women years
Coombes R Lancet 2007
Exemestane After Tamoxifen
Disease Free Survival
ITT
ER+/Unknown
E = 339 / 2296
% surviving disease free
T = 454 / 2372
HR=0.76 (95% CI: 0.66-0.88)
Log-rank test: P=0.0001
0
1
2
3
4
5
Time since randomization (years)
100
90
80
70
60
50
40
30
20
10
0
End of
treatment
100
90
80
70
60
50
40
30
20
10
0
End of
treatment
% surviving disease free
E = 354 / 2352
T = 438 / 2306
HR=0.75 (95% CI: 0.65-0.87)
Log-rank test: P=0.0001
0
1
2
3
4
5
Time since randomization (years)
Year
2.5
5
2.5
5
% abs. diff.
3.2
3.4
3.4
3.5
(95% CI)
(1.6 – 4.9)
(0.1 – 6.8)
(1.8 – 5.1)
(0.1 – 6.9)
Coombes Lancet 2007
Exemestane After Tamoxifen
Overall Survival
ER+/Unknown
E=222 / 2352
Women alive (%)
T=261 / 2372
HR=0.85 (95% CI: 0.71-1.02)
Log-rank test: P=0.08
0
1
2
3
4
5
Time since randomization (years)
E=210 / 2296
100
90
80
70
60
50
40
30
20
10
0
T=251 / 2306
End of
treatment
100
90
80
70
60
50
40
30
20
10
0
End of
treatment
Women alive (%)
ITT
HR=0.83 (95% CI: 0.69-1.00)
Log-rank test: P=0.05
0
1
2
3
4
5
Time since randomization (years)
year
2.5
5
2.5
5
% abs. diff.
(95% CI)
0.8
1.2
0.7
1.6
(-0.4 – 1.9)
(-1.5 – 3.9)
(-0.4 – 1.9)
(-1.2 – 4.3)
Coombes Lancet 2007
BIG 1-98 Design
R
A
N
D
O
M
I
Z
E
A
Tamoxifen
B
Letrozole
C
Tamoxifen
Letrozole
D
Letrozole
Tamoxifen
0
2
2-Arm Option
3/98 to 3/00
1,835 pts
4-Arm Option
9/99-5/03
6,193 pts
5
YEARS
Mouridsen NEJM 2009
BIG 1-98 Sequential Therapy
Two Pairwise Comparisons
• 3 blinded arms
• Sequential vs letrozole
monotherapy
• Evaluated from randomization
• Median Follow-up 71 mos.
• 99% confidence intervals to
account for multiple comparisons
Letrozole
Letrozole
Tamoxifen
0
2
N = 3,094
5
Letrozole
Letrozole
Tamoxifen
0
2
N = 3,086
5
YEARS
Mouridsen NEJM 2009
BIG 1-98 Sequential Treatment
Disease-Free Survival
Mouridsen NEJM 2009
Breast Cancer Events
TamLet vs Let
Overall
By Nodal Status*
*42% of the population is node positive; 58% node negative
Mouridsen NEJM 2009
Breast Cancer Events
TamLet vs Let
Overall
By Nodal Status*
*42% of the population is node positive; 58% node negative
Mouridsen NEJM 2009
TEAM Trial
Upfront AI vs Switching
• Postmenopausal
• ER+ and/or PgR+
invasive breast
cancer
Primary
Surgery
Current analysis
(2.75 year follow-up)
R
A
N
D
O
M
I
Z
E
Tamoxifen
20 mg/day
(2-3 years)
Exemestane
25 mg/day
(2-3 years)
Exemestane 25 mg/day
(5 years)
Primary endpoint: DFS for tamoxifen vs exemestane (2.75 years)
Following IES: protocol modified - DFS for exemestane vs tamoxifen→exemestane (5 years)
Jones et al. SABCS 2008. Abstract 15.
TEAM Trial
Efficacy of Tamoxifen vs Exemestane
(n = 9,766)
HR (95% CI)
P Value
Disease-Free Survival*
0.89 (0.77-1.03)
.12
Disease-Free Survival (on Study Drug)
0.83 (0.71-0.97)
.02
Recurrence-Free Survival
0.85 (0.72-1.00)
.05
Time to Distant Metastases
0.81 (0.67-0.98)
< .03
* Events: Exemestane 7% vs tamoxifen 8%
Jones et al. SABCS 2008. Abstract 15.
Extended Adjuvant Therapy
MA.17: Trial Design
Randomization
(Disease-free)
Letrozole 2.5 mg daily
n = 2,575
Tamoxifen
5 years early adjuvant
Node(–) 2,581
Node(+) 2,370
Placebo
n = 2,582
5 years extended adjuvant
Follow-up 30 months
Goss JCO 2008
Extended Adjuvant Therapy
Letrozole After 5 Years of TAM
Node+
pts
Node–
pts
HR=0.53*
(0.36-0.78)
HR=0.61*
(0.38-0.98)
DFS*
Distant*
DFS
OS
HR=0.45*
(0.27-0.75)
HR=0.63
(0.31-1.27)
HR=0.61*
(0.45-0.84)
HR=1.52
(0.76-3.06)
*Statistically significant benefit of LET.
 A similar reduction in local recurrences, new primaries, and distant
recurrences occurred in node-positive and node-negative patients
Goss et al JNCI 2005
Ongoing First Generation AI Adjuvant Trials
Tamoxifen
Anastrozole
ITA
Letrozole
Exemestane
IES Trial
Placebo
NSABP B33
MA.17
BIG 1-98
(BIG FEMTA)
ATAC Trialists Lancet Onc 2008, Mouridsen NEJM 2009, Goss JCO 2008,
Coombes R Lancet 2007, Jakesz R JNCI 2007
Upfront vs Sequencing Approach?
• BIG-1-98 suggests that an upfront AI may be superior
to a TAM-AI sequencing approach
• But patients seem to do just as well with an AI followed
by TAM (unclear what clinical relevance this has)
• Major issue is the fact that ER-positive cancers are not
all the same and therefore one size may not fit all
Key Questions
Can we use biomarkers/molecular profiling to decide how
to treat patients with ER+ cancers?
– Do all or just a subset of ER+ cancers require more than 5 years
of endocrine treatment?
– Can we use biomarkers/molecular profiling/pharmacogenomics
to individualize endocrine therapy (AI vs TAM)?
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
Paik et al NEJM 2004
Poor Outcome for Patients with HER2+ MBC
Treated with Endocrine Agents Alone
Agent
Clinical Benefit
PFS
Anastrozole
28%
2.4 months
Letrozole
29%
3.0 months
*PFS in first-line aromatase inhibitor trials ranges from 9 to 11 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
Luminal B Cancers Most Likely to Relapse
in First 5 Years
Copyright ©2003 by the National Academy of Sciences
Sorlie et al PNAS 2003
Extended Adjuvant Therapy is Beneficial in Luminal A
But Not B Cancers (using PR as a surrogate)?
ER+PR-
LUMINAL B
ER+PR+
LUMINAL A
Disease free survival
Copyright © American Society of Clinical Oncology
Distant disease free survival
Goss et al. J Clin Oncol; 2007
ATAC Trial: Disease-free Survival
HR+ patients
Patients
(%)
30
HR
95% CI
HR+ 0.85 (0.76, 0.94)
25
30
0.003
25
25.8%
Tamoxifen (T)
Anastrozole (A)
20
29.9%
P-value
20
16.4%
15
15
13.9%
10
10
5
5
Absolute difference
0
0
At risk:
A
T
1
2
3
4
2.5%
5
4.1%
6
7
8
0
9
Follow-up time (years)
2618 2541 2453 2361 2278 2159 1995 1801 1492
2598 2516 2400 2306 2196 2075 1896 1711 1396
HR, hazard ratio; CI, confidence interval
608
547
ATAC Trialists Lancet Onc 2008
Aromatase Inhibitor vs Tamoxifen?
 TransATAC is a subset of patients from the ATAC trial in
whom tumor blocks are available for molecular profiling
 21-gene recurrence score performed (n = 1,308)
 None of these patients received chemotherapy
 Will 21-gene recurrence score be prognostic for postmenopausal patients treated with anastrozole?
 Can the recurrence score define a group of patients who
would do just as well with tamoxifen?
Dowsett, SABCS 2008, Abstract 53
21-gene Recurrence Score To
Predict Risk of Distant Recurrence In Patients
Treated With Anastrozole or Tamoxifen
Results
Node- (N=872)
Node+ (N=306)
% pts
9-year DR rate
% pts
9-year DR rate
Low RS <18
59%
4%
52%
17%
Int RS 18-30
26%
12%
31%
28%
High RS ≥ 30
15%
25%
17%
49%
High vs. Low RS: HR 5.2
High vs. Low RS: HR 2.7
Int vs. Low RS: HR 2.5
Int vs. Low RS: HR 1.8
P<.001 for RS in predicting time to distant recurrence (DR) in N+ and N- patients
Dowsett, SABCS 2008, Abstract 53
Percent with Distant Recurrence at 9 Years
Node Negative
# of events
All Patients, Int. RS (n=229)
20
24
All Patients, High RS (n=130)
28
All Patients (n = 872)
72
All Patients, Low RS (n=513)
Tamoxifen, Low RS (n=245)
8
Tamoxifen, Int. RS (n=117)
Tamoxifen, High RS (n=70)
All Tamoxifen (n = 432)
12
21
41
Anastrozole, Low RS (n=268)
12
Anastrozole, Int. RS (n=112)
12
7
Anastrozole, High RS (n=60)
31
All Anastrozole (n = 440)
Dowsett, SABCS 2008,
Abstract 53
0
10
20
30
40
50
60
70
Percent with Distant Recurrence at 9 Years
Percent with Distant Recurrence at 9 Years
Node Positive
# of events
All Patients, Int. RS (n=94)
25
25
All Patients, High RS (n=52)
24
All Patients (n = 306)
74
Tamoxifen, Low RS (n=79)
11
Tamoxifen, Int. RS (n=47)
Tamoxifen, High RS (n=26)
All Tamoxifen (n = 152)
13
11
35
Anastrozole, Low RS (n=81)
14
Anastrozole, Int. RS (n=47)
12
Anastrozole, High RS (n=26)
13
All Anastrozole (n = 154)
39
All Patients, Low RS (n=160)
Dowsett, SABCS 2008,
Abstract 53
0
10
20
30
40
50
60
70
Percent with Distant Recurrence at 9 Years
Summary
Postmenopausal Patients
 Available data suggests that upfront AI approach is
optimal for unselected ER+ breast cancers
 But luminal A and B are clearly different and may need
different therapeutic approaches
 Luminal A (low RS):
 May do fine with tamoxifen or sequencing approach
 Require extended adjuvant therapy?
 Luminal B (high RS):

Five years of treatment probably sufficient
 AIs may be better in some patients (or they could be hormonerefractory)
Premenopausal Patients
• Tamoxifen for 5 years is standard of care
• SOFT trial is evaluating ovarian suppression plus
tamoxifen vs exemestane
• Should we evaluate CYP2D6 in premenopausal patients
and what should we do if they are poor metabolizers?
Randomized Trial in Premenopausal
Patients With HR+ Breast Cancer
• 1,803 premenopausal breast cancer patients
• Endocrine-responsive (ER and/or PR positive)
• No chemotherapy except neoadjuvant
• Treatment duration: 3 years
Surgery
(+ RT)
Goserelin
3.6 mg
q28d
R
A
N
D
O
M
I
Z
A
T
I
O
N
Tamoxifen 20 mg daily
Tamoxifen 20 mg daily
Zoledronic acid 4 mg q6mo
Anastrozole 1 mg daily
Anastrozole mg daily
Zoledronic acid 4 mg q6mo
Gnant et al NEJM 2009
Primary Endpoint: Disease-free Survival
Zoledronic Acid vs No Zoledronic Acid
100
Disease-free survival, %
90
80
70
60
50
40
No. of
events
30
20
ZOL
No ZOL
10
54
83
Hazard ratio (95% CI)
vs No ZOL
P value
0.643 (0.46 to 0.91)
.011
0
0
12
24
36
48
60
Time since randomization, months
72
84
42
Gnant et al NEJM 2009
Primary Endpoint: Disease-free Survival
Anastrozole vs Tamoxifen
Follow-up 60 months
100
Disease-free survival, %
90
80
70
60
50
40
30
ANA
TAM
20
10
0
0
12
72
65
1.096 (0.78 to 1.53)
24
36
48
.593
60
72
84
Time since randomization, months
SOFT study continues to accrue
Gnant et al NEJM 2009
43
Metabolism of Tamoxifen
Jin et al JNCI 97: 30-39, 2005
CYP2D6 Genetic Variations
• Caucasians and Western Europeans:
– 1-2% have multiple copies (Ultra-rapids = UM)
– 70% have two wild type alleles (Extensive = EM)
– 20% have one variant (CYP2D6*4) allele (Intermediate = IM)
– ~8% have two variant alleles (Poor = PM)
• CYP2D6 is responsible for the conversion of tamoxifen to its most
abundant active metabolite: endoxifen
Kaplan Meier Plots For Patient By
CYP2D6*4 Genotype
Hot flashes
0/13
Disease Free
Hot flashes
36/177
Overall Survival
Goetz J Clin Oncol 23: 9312-9318, 2005
CYP2D6 as Predictive Marker as
Prognostic Marker in the ABCSG-8 Trial
ABCSG-8 : TAM vs TAM followed by anastrozole
CYP2D6 and risk of breast event relative to extensive metabolizers (EM)
N
CYP2D6: PM
CYP2D6: IM
Tamoxifen (5 years)
67
3.83, P= .017
0.87, P = .689
Tam to Ana (5 years)
55
1.02, P = .985
0.81, P = .538
Tamoxifen (years 3-5)
55
2.81, P = .081
0.75, P = .431
Anastrozole (years 3-5)
31
0.71, P = .782
0.57, P = .269
Goetz, SABCS 2008, Abstract 57
Risk of Breast Cancer Recurrence in Women
Initiating Tamoxifen With CYP2D6 Inhibitors
Eligibility:
• Continuous eligibility 6
mos. prior to tamoxifen
initiation
• Tamoxifen naïve (6 mos.
negative history)
• Tamoxifen duration ≥ 24
mos.
• Medication possession
ratio of ≥ 0.7
No CYP2D6 inhibitor therapy
(n = 945)
Weak CYP2D6 inhibitor therapy use or
without overlap with tamoxifen
(n = 355)
Moderate-severe CYP2D6 inhibitor
use with tamoxifen
(n = 359)
(n = 1,659)
• Retrospective cohort analysis of medical and pharmacy claims from the Medco
Health Solutions integrated database
• Primary endpoint: hospitalization for breast cancer (event-free survival)
• Median duration of overlap between CYP2D6 inhibitors and tamoxifen: 287 days
Aubert et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA508).
Risk of Breast Cancer Recurrence in Women
Initiating Tamoxifen With CYP2D6 Inhibitors
N
Breast cancer
recurrence
HR*
P value
No CYP2D6 inhibitors
945
7.5%
reference
reference
Moderate/severe CYP2D6
inhibitors
407
14%
1.92 (1.36-2.73)
.0002
Weak
137
9%
1.07 (0.79-1.45)
.677
Moderate/potent
213
16%
2.20 (1.46-3.31)
.0002
SSRIs
* HR relative to no CYP2D6 inhibitor group
• Concomitant use of tamoxifen with moderate-severe CYP2D6 inhibitors
significantly increases the risk of breast cancer recurrence
• Moderate-potent SSRIs double the risk of recurrence, while weak SSRIs were
not associated with increased risk
Aubert et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA508).
Summary
Premenopausal Patients
 Available data do not support a role for ovarian ablation
with an AI
 However, trials have not taken into account the luminal
subtypes
 CYP2D6 data is compelling and should be looked at in
patients on the SOFT trial
 Until then the role of CYP2D6 testing remains unclear
since we do not have data on how to treat poor
metabolizers
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