1. Recent Advances in Adjuvant Endocrine Therapy for Early Breast Cancer
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
Atlanta, Georgia

2. Adjuvant Hormonal Therapy Options for Postmenopausal PatientsAI
ATAC, BIG-1-98 (upfront AI vs TAM)
IES, ABCSG, BIG-1-98 (TAM to AI)
TAM AI
BIG-1-98, TEAM (AI to TAM) AI
TAM
MA.17
Extended AI
TAM 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

3. ATAC Recruitment July 1996 – March 2000 Median follow-up 100 months
Tamoxifen (n = 3,116)
Surgery
+/- RT
+/- Chemo (20%)
Anastrozole (n = 3,125)
Discontinued following initial analysis as no efficacy or tolerability benefit compared with tamoxifen arm
84% HR positive
61% Node negative
5 years
ATAC Trialists Lancet Onc 2009

4. Efficacy of Anastrozole vs Tamoxifen in HR+ Patient Population of ATAC Study
9-Year Follow-up
Anastrozole
Tamoxifen
Recurrence
17.0%
21.8%
HR = 0.76; P = .0001
Distant Recurrence
13.2%
15.6%
HR = 0.84; P = .022
Contralateral Breast Cancer
2.5%
4.2%
HR = 0.60; P = .004
Disease-Free Survival
HR = 0.85; P = .003
Death After Recurrence
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

5. Death: All Causes HR+ Patients30 30 25 20 15 10 5 HR
0.97
95% CI
(0.86, 1.11)
P-value
0.70
HR+ 25 20
Tamoxifen (T) Anastrozole (A) 15 10 5 1 2 3 4 5 6 7 8 9
Follow-up time (years)
At risk: A T
ATAC Trialists Lancet Onc 2009

6. BIG 1-98 Design R A N D O M I Z E A Tamoxifen B Letrozole C Tamoxifen
2-Arm Option
3/98 to 3/00
1,835 pts B
Letrozole
4-Arm Option
9/99-5/03
6,193 pts C
Tamoxifen
Letrozole D
Letrozole
Tamoxifen 2 5
YEARS
Mouridsen NEJM 2009

7. Letrozole vs Tamoxifen
Disease-free Survival
Yearly
DFS %
97.7
97.6
95.1
93.4
90.5
89.0
86.8
84.6
84.0
81.4 T 20 40 60 80
100 1 2 3 4 5
Percent Alive and Disease-Free
Years from Randomization L N
HR (95% CI) P
8010
0.81 ( )
0.003
No. at
Risk
4003
4007
3892
3896
2964
2926
1261
1238
892
866
567
544
Mouridsen NEJM 2009

8. Cumulative Incidence Breast Cancer Relapse20
5-year diff (L-T) = -3.4%
(S.E. 1.2) cuminc P=0.0002
13.6% 15 T L 10
8.1%
Proportion Failure (%)
10.2% 5
6.2% 1 2 3 4 5
Years from Randomization
Mouridsen NEJM 2009

9. IES: Trial Design RANDOMI ZE Exemestane 5,162*
Post Treatment Follow-up
10,335*
Tamoxifen
Tamoxifen
5,294*
2-3 years study treatment
2-3 years
Start of study
Diagnosis
Total 5 years endocrine therapy
* Total women years
Coombes R Lancet 2007

10. Exemestane After Tamoxifen Disease Free Survival
ITT
ER+/Unknown
E = 354 / 2352
E = 339 / 2296
treatment
End of
treatment
End of
T = 454 / 2372
T = 438 / 2306
HR=0.76 (95% CI: )
Log-rank test: P=0.0001
HR=0.75 (95% CI: )
Log-rank test: P=0.0001
Year
% abs. diff.
(95% CI)
2.5 5
3.2
3.4
(1.6 – 4.9)
(0.1 – 6.8)
2.5 5
3.4
3.5
(1.8 – 5.1)
(0.1 – 6.9)
Coombes Lancet 2007

11. Exemestane After Tamoxifen Overall Survival
ITT
ER+/Unknown
E=222 / 2352
treatment
End of
treatment
End of
E=210 / 2296
T=261 / 2372
T=251 / 2306
HR=0.85 (95% CI: )
Log-rank test: P=0.08
HR=0.83 (95% CI: )
Log-rank test: P=0.05
year
% abs. diff. (95% CI)
2.5 5
0.8
1.2
(-0.4 – 1.9)
(-1.5 – 3.9)
2.5 5
0.7
1.6
(-0.4 – 1.9)
(-1.2 – 4.3)
Coombes Lancet 2007

12. BIG 1-98 Design A B C D R A N D O M I Z E Tamoxifen 2-Arm Option
3/98 to 3/00
1,835 pts B
Letrozole C
Tamoxifen
Letrozole
4-Arm Option
9/99-5/03
6,193 pts D
Letrozole
Tamoxifen 2 5
YEARS
Mouridsen NEJM 2009

13. BIG 1-98 Sequential Therapy Two Pairwise Comparisons
Letrozole
3 blinded arms
Sequential vs letrozole monotherapy
Evaluated from randomization
Median Follow-up 71 mos.
99% confidence intervals to account for multiple comparisons
N = 3,094
Tamoxifen
Letrozole 2 5
Letrozole
N = 3,086
Letrozole
Tamoxifen 2 5
YEARS
Mouridsen NEJM 2009 13

14. BIG 1-98 Sequential Treatment Disease-Free Survival
Mouridsen NEJM 2009 14

15. Breast Cancer Events TamLet vs Let
Overall
By Nodal Status*
*42% of the population is node positive; 58% node negative
Mouridsen NEJM 2009 15

16. Breast Cancer Events TamLet vs Let
Overall
By Nodal Status*
*42% of the population is node positive; 58% node negative
Mouridsen NEJM 2009

17. TEAM Trial Upfront AI vs Switching
Postmenopausal
ER+ and/or PgR+ invasive breast cancer
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)
Primary Surgery
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 Abstract 15. 17 17

18. TEAM Trial Efficacy of Tamoxifen vs Exemestane
HR (95% CI)
P Value
Disease-Free Survival*
0.89 ( )
.12
Disease-Free Survival (on Study Drug)
0.83 ( )
.02
Recurrence-Free Survival
0.85 ( )
.05
Time to Distant Metastases
0.81 ( )
< .03
* Events: Exemestane 7% vs tamoxifen 8%
Jones et al. SABCS Abstract 15.

19. Extended Adjuvant Therapy MA.17: Trial Design
Randomization
(Disease-free)
Letrozole 2.5 mg daily
n = 2,575
Tamoxifen
Placebo
n = 2,582
5 years early adjuvant
5 years extended adjuvant
Node(–) 2,581
Node(+) 2,370
Follow-up 30 months
Goss JCO 2008

20. Extended Adjuvant Therapy Letrozole After 5 Years of TAM
DFS*
Distant* DFS OS
Node–
pts
Node+
HR=0.61*
( )
HR=0.45*
( )
HR=0.63
( )
HR=0.53*
( )
HR=1.52
( )
( )
*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

21. Ongoing First Generation AI Adjuvant Trials
BIG 1-98 (BIG FEMTA)
NSABP B33
IES Trial
ITA
Tamoxifen
Anastrozole
Placebo
Letrozole
Exemestane
MA.17
ATAC Trialists Lancet Onc 2008, Mouridsen NEJM 2009, Goss JCO 2008,
Coombes R Lancet 2007, Jakesz R JNCI 2007

22. 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

23. 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)?

24. Are Heterogenous in Outcome
ER+ Cancers
Are Heterogenous in Outcome
ER+
ER+
Copyright ©2003 by the National Academy of Sciences
Sorlie et al PNAS 2003

25. Efficacy of Tamoxifen Varies in ER+ Cancers2 4 6 8 14 16
Years
0.0
0.2
0.4
0.6
0.8
1.0
DRFS
Placebo
Tamoxifen 12 10 2 4 6 8 14 16
Years
0.0
0.2
0.4
0.6
0.8
1.0
DRFS
Placebo
Tamoxifen 12 10
Low Risk (RS<18)
Int Risk (RS 18-30) N
171
142 N 85 69
High Risk (RS≥31) N 99 79 2 4 6 8 14 16
Years
0.0
0.2
0.4
0.6
0.8
1.0
DRFS
Placebo
Tamoxifen 12 10
TAM-resistant
Interaction P = 0.06
Paik et al SABCS 2004

26. Correlation Between Recurrence Score and Intrinsic Subtype
Luminal A
(n = 123)
Luminal B
(n = 55)
Low 62 1
Intermediate 25 4
High 36 50
Fan et al NEJM 2006

27. 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
ESTROGEN ER PR
Bcl2
SCUBE2
GSTM1
BAG1
INVASION
Stromolysin 3
Cathepsin L2
CD68
Category
RS (0 – 100)
Low risk
RS < 18
Int risk
RS ≥ 18 and < 31
High risk
RS ≥ 31
Reference
Beta-actin
GAPDH
RPLPO
GUS
TFRC
HER2
GRB7
Paik et al NEJM 2004

28. Poor Outcome for Patients with HER2+ MBC Treated with Endocrine Agents Alone
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

29. PR is prognostic or predictive for patients treated with tamoxifen
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:

30. 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.

31. Possible Surrogate Markers for Hormone Resistance
LUM A LUM B ER PR
HER2 RS
Low Ki High Ki-67
Hormone-sensitive Hormone-resistant

32. Luminal B Cancers Most Likely to Relapse
in First 5 Years
Copyright ©2003 by the National Academy of Sciences
Sorlie et al PNAS 2003

33. 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
Distant disease free survival
Goss et al. J Clin Oncol; 2007

34. ATAC Trial: Disease-free Survival HR+ patients30
29.9% 30 25 20 15 10 5 HR
0.85
95% CI
(0.76, 0.94)
P-value
0.003
HR+ 25
25.8% 20
Tamoxifen (T) Anastrozole (A)
16.4% 15 10
13.9% 5
Absolute difference
2.5%
4.1% 1 2 3 4 5 6 7 8 9
Follow-up time (years)
At risk: A T
HR, hazard ratio; CI, confidence interval
ATAC Trialists Lancet Onc 2008

35. 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 post-menopausal 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

36. 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
Low RS <18
59% 4%
52%
17%
Int RS 18-30
26%
12%
31%
28%
High RS ≥ 30
15%
25%
49%
High vs. Low RS: HR 5.2
Int vs. Low RS: HR 2.5
High vs. Low RS: HR 2.7
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 36 36

37. Percent with Distant Recurrence at 9 Years
Node Negative
# of events
All Patients, Low RS (n=513) 20
All Patients, Int. RS (n=229) 24
All Patients, High RS (n=130) 28
All Patients (n = 872) 72
Tamoxifen, Low RS (n=245) 8
Tamoxifen, Int. RS (n=117) 12
Tamoxifen, High RS (n=70) 21
All Tamoxifen (n = 432) 41
Anastrozole, Low RS (n=268) 12
Anastrozole, Int. RS (n=112) 12
Anastrozole, High RS (n=60) 7
All Anastrozole (n = 440) 31
Dowsett, SABCS 2008,
Abstract 53 10 20 30 40 50 60 70
Percent with Distant Recurrence at 9 Years 37

38. Percent with Distant Recurrence at 9 Years
Node Positive
# of events
All Patients, Low RS (n=160) 25
All Patients, Int. RS (n=94) 25
All Patients, High RS (n=52) 24
All Patients (n = 306) 74
Tamoxifen, Low RS (n=79) 11
Tamoxifen, Int. RS (n=47) 13
Tamoxifen, High RS (n=26) 11
All Tamoxifen (n = 152) 35
Anastrozole, Low RS (n=81) 14
Anastrozole, Int. RS (n=47) 12
Anastrozole, High RS (n=26) 13
All Anastrozole (n = 154) 39
Dowsett, SABCS 2008,
Abstract 53 10 20 30 40 50 60 70
Percent with Distant Recurrence at 9 Years 38

39. 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 hormone-refractory)

40. 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?

41. 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
Tamoxifen 20 mg daily
Zoledronic acid 4 mg q6mo
Anastrozole 1 mg daily
Anastrozole mg daily
Surgery
(+ RT)
Goserelin
3.6 mg q28d
RANDOMI
ZAT I ON
Gnant et al NEJM 2009

42. Zoledronic Acid (ZOMETA®) Preclinical Profile
Primary Endpoint: Disease-free Survival Zoledronic Acid vs No Zoledronic Acid
100 90 80 70 60 50 40 30 20 10 12 24 36 48 72 84
Time since randomization, months
Disease-free survival, %
No. of Hazard ratio (95% CI) events vs No ZOL P value
ZOL (0.46 to 0.91) .011
No ZOL 83
Gnant et al NEJM 2009 42 42

43. Primary Endpoint: Disease-free Survival Anastrozole vs Tamoxifen
Zoledronic Acid (ZOMETA®) Preclinical Profile
Primary Endpoint: Disease-free Survival Anastrozole vs Tamoxifen
Follow-up 60 months
100 90 80 70 60 50
Disease-free survival, % 40 30
No. of Hazard ratio (95% CI) events vs TAM P value
ANA (0.78 to 1.53) .593
TAM 65 20 10 12 24 36 48 60 72 84
Time since randomization, months
SOFT study continues to accrue
Gnant et al NEJM 2009 43 43

44. Metabolism of Tamoxifen
Jin et al JNCI 97: 30-39, 2005

45. 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

46. Kaplan Meier Plots For Patient By CYP2D6*4 Genotype
Disease Free
Overall Survival
Hot flashes
36/177
0/13
Goetz J Clin Oncol 23: , 2005

47. 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)
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 47 47

48. 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).

49. Risk of Breast Cancer Recurrence in Women Initiating Tamoxifen With CYP2D6 Inhibitors
HR*
P value
No CYP2D6 inhibitors
945
7.5%
reference
Moderate/severe CYP2D6 inhibitors
407
14%
1.92 ( )
.0002
SSRIs
Weak
137 9%
1.07 ( )
.677
Moderate/potent
213
16%
2.20 ( )
* 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).

50. 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

51. 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