2. Adjuvant Hormonal Therapy for Premenopausal Women
Otto Metzger, MD
Dana-Farber Cancer Institute
Harvard Medical School
Boston, USA

3. Chemotherapy-induced amenorrhea
OFR ~10%
Menopausal status should be defined prior to the initiation of adjuvant chemotherapy

4. Plan of the Talk
Tamoxifen versus AI: Is there room for additional discussion in 2017?
What is the real gain with extended endocrine therapy?
Do we need molecular tests to identify patients at risk of recurrence beyond year 5?

5. Plan of the Talk
Tamoxifen versus AI: Is there room for additional discussion in 2017?
What is the real gain with extended endocrine therapy?
Do we need molecular tests to identify patients at risk of recurrence beyond year 5?

6. Aromatase Inhibitor Overview Group
Tamoxifen versus AI
Recurrence
Breast Cancer Mortality
The Lancet  , DOI: ( /S (15) )

7. Aromatase Inhibitor Overview Group
Tamoxifen AI versus AI
Recurrence
Breast Cancer Mortality
The Lancet  , DOI: ( /S (15) )

8. Aromatase Inhibitor Overview Group
Subgroup Analysis
The Lancet  , DOI: ( /S (15) )

9. So Why Bother?
Should we just give upfront AI or sequential strategy to all patients?
My personal consideration:
AI is not tolerated for a significant proportion of patients with discontinuation rates as high as 40% reported in clinical trials
We can safely select a subgroup of patients that can be treated with adjuvant tamoxifen
So, how can we identify a subset of patients that can be treated with upfront tamoxifen?

10. BIG 1-98 Analytic Cohort 12-year update (Lancet Oncol 2011)
2-Arm Option
Tamoxifen
Letrozole 2 5
YEARS A B C D
4-Arm Option
N=1,828
Enrolled
N=3,094
N=4,922
N=911
N=917
N=1548
N=1546
Is letrozole superior than TAM in the subsets of LA and LB disease?
Is there a preferred regimen for patients diagnosed with invasive lobular carcinoma 10

11. Disease-free survival

12. Disease-free survival

13. Multivariate Analysis Cox Model for DFS (IPCW)1
0.5
1.0
1.5
Lobular LB
Lobular LA
Ductal LB
Ductal LA
Hazard Ratio
(95% CI)
0.95 ( )
0.64 ( )
0.49 ( )
0.33 ( )
Favors Letrozole
Favors Tamoxifen
1. Included variables: age, tumor size, nodal status, histological grade, histology, local therapy, subtype (LA/LB) and treatment
Treatment by histology (ductal/lobular), p=0.006
Treatment by subtype (LA/LB), p=0.01
Interactions

14. What be learned from the sequential arms of BIG-198?
What is the impact of tumor cell proliferation on the benefit of AI versus TAM?
What be learned from the sequential arms of BIG-198?
2-Arm Option
Tamoxifen
Letrozole 2 5
YEARS A B C D
4-Arm Option
N=6,182
Enrolled
N=1548
N=1540
N=1548*
N=1546
*612 patients (40%) received letrozole after the tamoxifen arm was unblinded.
This presentation is the intellectual property of the author/presenter. Contact for permission to reprint

15. Invasive Ductal Carcinoma Disease-free survival by LA and LB subtypes
LA-like Ductal LB-like Ductal
This presentation is the intellectual property of the author/presenter. Contact for permission to reprint

16. How can we use this information in our clinical practice?
Points for consideration:
Classic clinico-pathologic features can be used to identify indolent tumors that could be treated with upfront tamoxifen
There might be a potential for the use of genomic tests in the identify “indolent” tumors

17. Very high and very low risk levels are informative
Ultralow
Threshold

18. Stockholm STO 3 phase III postmenopausal N0 <3 cm validates ultralow risk (IDLE, indolent lesions of epithelial origin)
SABCS 2016 PD7-01  

19. TAILORx trial first report: N0, ER+, HER2-negative gene Recurrence Score <11, endocrine therapy alone
Sparano J et al. NEJM 2015

20. 9-Years Risk of Distant Recurrence (%)10 20 30 40 50 60 70 80 90
100
9-Years Risk of Distant Recurrence (%) 5 15 25 35 45
Recurrence Score
Node
Negative
1-3 Positive
Nodes
4+ Positive
95%CI
Mean
TransATAC
Low incidence of distant recurrence at 9 years for those with very low RS levels even in the subset of 1-3 positive nodes

21. Node positivity does not necessarily imply the need for upfront AI
Metzger et al. Unpublished data

22. Plan of the Talk
Tamoxifen versus AI: Is there room for additional discussion in 2017?
What is the real gain with extended endocrine therapy?
Do we need molecular tests to identify patients at risk of recurrence beyond year 5?

23. Extended Endocrine Therapy
1. Goss PE et al, J Natl Cancer Inst 2005;97:1262– Mamounas EP et al., J Clin Oncol 2008;26: Jakesz et al., J Natl Cancer Inst Dec 19;99(24): Davies C et al., Lancet ;381(9869): Gray et al., J Clin Oncol 31, 2013 (suppl; abstr 5). 6. Goss PE et al., N Engl J Med. 2016

24. (1.9% absolute benefit, P=0.03)
New Data From SABCS 2016
Results from 3 extended AI randomized studies presented at SABCS 2016
In all 3 studies, primary analyses demonstrated no statistically significant benefit in DFS from extending AI therapy in post-menopausal patients.
Of note, results from B-42 and DATA were generally similar to previous extended endocrine therapy trials (~3- 4% absolute benefit)
NSABP B-42
DATA
IDEAL
Population
3966 patients who completed 5 years of AI or up to 3 years TAM followed by AI (for a total of 5 years)
1912 patients who completed 2-3 years of Tamoxifen
1824 patients who completed 5 years of Tamoxifen
Treatment
5y AI vs Placebo
3y AI vs 6y AI
2.5y AI vs 5y AI HR
0.85 (0.73 – 0.999)
0.79 ( )
0.96 ( )
DFS
84.7% (5 years AI) vs
81.3% (Placebo)
83.1% (6 years AI) vs 79.4% (3 years AI)
87.9% (5 years AI) vs 88.4% (2.5 years AI)
P value
P= (n.s.)
P=0.07 (n.s.)
P=0.7 (n.s.)
Note, there was a statistically significant benefit in terms of prevention of distant recurrence
(1.9% absolute benefit, P=0.03)
Discontinuation of AIs in all these trials was ~40% in the extended period
1. Mamounas E et al, 2016 SABCS. 2. Tjan-Heijnen VC et al, 2016 SABCS. 3. Block EJ et al, 2016 SABCS

25. NSABP B-42 or Stratification:
Postmenopausal Pts with ER+ or PR+ Breast Cancer
Stage I, II, or IIIa invasive BC at diagnosis
Disease-free After 5 Years of Endocrine Therapy or
AI X 5 yrs
TAM X < 3 yrs
 AI to Complete 5 yrs
Stratification:
Pathological nodal status (Negative, Positive)
Prior adjuvant TAM (Yes, No)
Lowest BMD T score: spine, hip, femur (>-2.0, ≤ -2.0 SD) R
Letrozole X 5 yrs
Placebo X 5 yrs

26. NSABP B-42: Disease-Free Survival
Letrozole
Placebo
100 80 60 40 20
Years After Randomization
Disease-Free Survival
Letrozole
Placebo
HR=0.85 ( ) P = 0.048
84.7%
81.3%
# Events
292
339
*P-value did not reach statistical significance level of

27. NSABP B-42: Cumulative Incidence of Distant Recurrence
Letrozole
Placebo
Cumulative Incidence of DR 12 10 8 6 4 2
5.8%
3.9%
HR=0.72 ( ) P=0.03
Years After Randomization
# Pts # Events 73

28. DATA Study Design 6 years anastrozole 3 years anastrozole
Postmenopausal at randomization
ER+ and/or PR+
No sign of disease recurrence
M0 breast cancer
After 2-3 years adjuvant tamoxifen
6 years anastrozole
1 mg daily
Stratification
Nodal status
ER/PR status
HER2 status
Tamoxifen duration
3 years anastrozole
1 mg daily
80% power to detect an increase in 3-year adapted Disease-Free Survival (aDFS) from 90% to 94%, i.e., a hazard ratio (HR) of and a significance level of 0.05
Accounting for 10% drop-out: 950 patients per group to be included (n=1912 patients actually included)
Minimum follow-up: ≥6 years after randomization, i.e., ≥ 3 years of adapted follow-up (last patient included in August 2009)

29. adapted Disease-Free Survival (aDFS)
San Antonio Breast Cancer Symposium, December 6-10, 2016
adapted Disease-Free Survival (aDFS)
N=1660
6-year Anastrozole
(N=827)
3-year Anastrozole
(N=833)
5-y aDFS (%)
83.1
79.4
HR (95% CI)
0.79 (0.62 – 1.02)
P-value
0.07
3-year aDFS: 90.7% vs. 88.9%

30. aDFS if ER+ and PR+, HER2-, pN+, Chemo+
San Antonio Breast Cancer Symposium, December 6-10, 2016
aDFS if ER+ and PR+, HER2-, pN+, Chemo+
N=597
6-year Anastrozole
(N=293)
3-year Anastrozole
(N=286)
5-y aDFS (%)
86.0
75.9
HR (95% CI)
0.58 (0.39 – 0.89)
P-value
0.01

31. IDEAL Study DFS 5 years HR: 0.96 (0.76-1.20) P-value: 0.70 2.5y: 88.4%

32. Plan of the Talk
Tamoxifen versus AI: Is there room for additional discussion in 2017?
What is the real gain with extended endocrine therapy?
Do we need molecular tests to identify patients at risk of recurrence beyond year 5?

33. NODAL STATUS IS AN IMPORTANT PROGNOSTIC INDICATOR
Saphner et al. JCO 1996

34. What is the risk of distant recurrence for T1 N0 and T2 N0 ?
H.Pan for EBCTCG, ASCO 2106

35. H.Pan for EBCTCG, ASCO 2106

36. H.Pan for EBCTCG, ASCO 2106

37. Limitations of Oxford Overview Data
Old studies
Lack of detailed information on biomarker data
Larger clinico-pathologic variables (?)
Can we do better in identifying those less likely to recur using classic clinico-pathologic variables alone?

38. Preliminary Results from ATAC – Clinical Treatment Score
Node:
0 = Negative
1 = 1 positive
2 = 2-3 positive
3 = 4-9 positive
4 = >9 positive
Size:
Continuous
(if >50 then = 50)
Grade:
0 = Grade 1
1 = Grade 2
2 = Grade 3
Endocrine Rx
0 = Tamoxifen
1 = Anastrozole
Age:
Low risk <1% DR/yr; intermediate risk 1-2% DR/yr; high risk >2%/yr 25 50 75
100
Distant recurrence free (%)
1157
938
853
747
648
318
High
1223
1047
987
893
803
426
Intermediate
1959
1757
1674
1581
1449
777
Low
Number at risk 5 6 7 8 9 10
Follow-up time [years]
2.4%
7.5%
20.6%
Hazard ratio
Reference
3.40 ( )
9.39 ( )
DRs 5-10yr 39 77
181
Validity being assessed with IBCSG BIG 1-98
Courtesy from Mitch Dowsett

39. Can we take advantage of genomic signatures to identify those at risk of disease recurrence beyond year 5?
Can we use genomic tests to identify those more likely to benefit from extended endocrine therapy?

40. Smoothed hazard rates for RS, IHC4 and ROR in TransATAC over 10 years
(Node negative and positive combined)
50% high risk (or above the median) and 50% low risk as defied by each of the score.
Sestak et al 2013, JNCI, 105,

41. What is the additional prognostic value of signatures to clinical variables?
Information included
Clinical Treatment Score (CTS)
Nodal status, grade, tumour size, age, treatment
Immunohistochemical markers (IHC4)
ER, PgR, Ki67, HER2
Oncotype Recurrence Score (RS)
21 genes (oestrogen, proliferation, invasion, HER2 genes)
Breast Cancer Index (BCI)
H/I and 5 proliferation genes (Molecular Grade Index)
Prosigna (ROR)
46 genes, proliferation score, tumour size
(EU cut-offs from transATAC for N- and N+)
EndoPredict (EPclin)
12 genes (proliferation, differentiation, oestrogen);
nodal status and tumour size
Sestak et al SABCS 2016

42. Prognostic value years 5-10 – node-negative (n=591; 34 events)
Likelihood Ratio χ2
EPclin
IHC4
CTS
ROR RS
BCI
Likelihood Ratio ∆χ2
% Improvement
20.0%
67.5%
11.4%
111.0%
62.0% *

43. Prognostic value years 5-10 – node-positive (n=227; 31 events)
Likelihood Ratio χ2
EPclin
IHC4
CTS
ROR RS
BCI
Likelihood Ratio ∆χ2
% Improvement
7.5%
11.3%
6.9%
25.6%
27.5% *

44. Do we have a Genomic Tool able to Predict the benefit of Endocrine Therapy?

45. BCI Predictive (H/I) Results: MA.17 RCT Cohort
In patients with High H/I, extended letrozole reduced recurrence rate significantly from 27% to 10.5% (P=0.007)
No significant reduction in patients with Low H/I (P=0.35)
P=0.007
16.5% absolute benefit
P=0.35
No significant benefit
Recurrences (%)
Sgroi et al, J Natl Cancer Inst. 2013;105:

46. Summary of BCI Predictive (H/I) Validation Data
H/I shown to be a significant predictor of endocrine benefit in 3 randomized trial cohorts
Study Cohort
Treatment
Predictive analysis
Interaction P value
Stockholm (n=600)1
Adjuvant tamoxifen vs untreated
H/I High HR: 0.35 ( ); p=0.0005
H/I Low HR: 0.67 ( ), p=0.2
0.003
TransATAC (n=665)2
Adjuvant anastrozole vs tamoxifen
H/I High HR: ( ); p=0.04
H/I Low HR: 1.33 ( ), p=0.4
0.004
MA.17
(n=249)3
Extended letrozole vs placebo
H/I High OR: 0.33 ( ); p=0.006
H/I Low OR: 0.58 ( ), p=0.21
0.03
Results suggest generalizability as an endocrine response biomarker
1. Zhang Y, et al. Clin Cancer Res. 2013;19(15): Sgroi D, et al. Lancet Oncol Oct;14(11): Sgroi et al, J Natl Cancer Inst. 2013;105:

47. Take Home Messages
Tumor burden (i.e. tumor size and nodal status) reliably identify those more likely to recur between years 0-5 and 5-10
Genomic tools add prognostic value to clinical variables particularly in the node-negative subset
We should be careful when evaluating the additional value of genomic signatures if the “genomic algorithms” include tumor size and nodal status
BCI provides predictive information as an endocrine response biomarker

48. Conclusions
Adjuvant Tamoxifen for low-risk patients may be as good as AI
High-risk patients (defined by tumor burden) are the ones more likely to benefit from 10 years of adjuvant endocrine therapy
BCI predictive value should be explored in a prospective and large phase III clinical trial focused on patients with intermediate to low tumor burden for which the value of extended endocrine therapy is not so clear