1. Verdringen de Aromatase-I de SERM’s?
Prof. dr. Rudy Van den Broecke Coördinator Multidisciplinair Borstcentrum UZ Gent
VVOG
Postuniversitaire Studiedag
15 november 2007

2. Anastrozole Letrozole Exemestane Tamoxifen NMe2 O CH3 H3C NC CN N NC

3. Introduction Evidence-based Medicine Aromatase-I in adjuvant setting
Special issues

4. Evidence-based Medicine
"Evidence-based medicine is the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients.“
Full paper in peer review journal
Long-term follow-up
Patients numbers
Double blind controlled trial(s)
…..
? Subgroup analyses !!!
? Indirect comparison !!!

5. All postmenopausal women with receptor positive disease should receive an AI during the course of their treatment
WHEN?

6. Trial strategies in adjuvant setting with AI’s
1. Treatment strategies:
Upfront
Prospective sequential
2. Treatment opportunities:
Switch
Extended

7. Trial strategies in adjuvant setting with AI’s0y 2y 5y
ATAC
BIG 1-98
Upfront
ABCSG 8
BIG 1-98
Sequential
Third-generation AIs are currently being tested in the adjuvant setting.
The main adjuvant trials include
Two trials with the nonsteroidal AI anastrozole.
Two trials with the nonsteroidal AI letrozole.
Four trials with the steroidal AI exemestane.
The shortest trial is EXEM 027, which will take 2 years to complete. It is also the only trial that will compare AI treatment with placebo in treatment naïve patients.
The trial of the longest adjuvant therapy is MA-17, which addresses 10 years of treatment. This trial will compare letrozole to placebo in the second phase of the trial, after 5 years of tamoxifen.
All the other trials will examine 5 to 7 years of adjuvant treatment.
The ATAC trial has already reported intermediate data at 33 months and at 47 months of follow-up.1,2 In this trial, patients in combination arm did not fare any better than those in the tamoxifen alone arm. As a result, the combination arm was discontinued.
1. The ATAC Trialists’ Group. Lancet. 2002;359:2131.
2. Buzdar. Breast Cancer Res Treat. 2003;77:295 [Abstract 28].
Randomisation
TAMOXIFEN
ANASTROZOLE
LETROZOLE
EXEMESTANE
Placebo/Control

8. Treatment opportunities in adjuvant setting with AI’s0y 2y 5y
IES
ITA
ARNO 95
Switch
Third-generation AIs are currently being tested in the adjuvant setting.
The main adjuvant trials include
Two trials with the nonsteroidal AI anastrozole.
Two trials with the nonsteroidal AI letrozole.
Four trials with the steroidal AI exemestane.
The shortest trial is EXEM 027, which will take 2 years to complete. It is also the only trial that will compare AI treatment with placebo in treatment naïve patients.
The trial of the longest adjuvant therapy is MA-17, which addresses 10 years of treatment. This trial will compare letrozole to placebo in the second phase of the trial, after 5 years of tamoxifen.
All the other trials will examine 5 to 7 years of adjuvant treatment.
The ATAC trial has already reported intermediate data at 33 months and at 47 months of follow-up.1,2 In this trial, patients in combination arm did not fare any better than those in the tamoxifen alone arm. As a result, the combination arm was discontinued.
1. The ATAC Trialists’ Group. Lancet. 2002;359:2131.
2. Buzdar. Breast Cancer Res Treat. 2003;77:295 [Abstract 28].
MA-17
ABCSG 6a
Ext
Randomisation
TAMOXIFEN
ANASTROZOLE
LETROZOLE
EXEMESTANE
Placebo/Control

9. Aromatase Inhibitors: UpfrontFU
DFS
(HR+ patients)
TTR
TTDR
(ITT population) OS
ATAC
Anastrozole vs Tamoxifen
68 mths
HR=0.83 SS
HR=0.74
HR=0.80
CI:
P=0.04 SS
HR=0.97 NS
BIG 1-98
Letrozole vs Tamoxifen
51 mths
HR=0.82
HR=0.78
HR=0.81
CI:
P=0.03 SS
HR=0.91
ATAC: Lancet 2005; 365: 60-62
BIG 1-98: Coates AS et al. J Clin Oncol 2007; 25(5)

10. Aromatase Inhibitors after 2-3 y Tamoxifen: SwitchFU
DFS OS
ARNO
Anastrozole vs
Tamoxifen
30.1 mths
HR=0.66 SS
HR=0.53
ARNO/ABCSG8/ ITA
30 mths
HR=0.59
HR=0.71
Meta-analyse?
IES
Exemestane vs
55.7 mths
HR=0.76
HR=0.85 for ITT pts NS
HR=0.83 for ER+/unknown pts
ARNO: Kaufmann M et al. J Clin Oncol 2007; 25(19) - ARNO/ABCSG 8:Jakesz R et al. Lancet Oncology 2005; 366: ARNO/ABCSG 8/ITA: Jonat W et al. Lancet Oncology 2006; 7: IES: Coombes RC et al. Lancet Feb 2007

11. Aromatase Inhibitors: Prospective SequentialFU
DFS
ABCSG 8
2y Tamoxifen + 3y Anastrozole vs
5y Tamoxifen
54.6 mths
HR=0.76 NS
BIG 1-98
2y Tamoxifen + 3y Letrozole vs
5y Tamoxifen or 5y Letrozole vs
2y Letrozole + 3 y tamoxifen
Currently no available data
TEAM
2y Tamoxifen + 3y Exemestane vs
5y Exemestane
ABCSG 8: Jakesz R SABCS 2005 presentation BIG 1-98: Coates AS ESMO 2006 presentation TEAM: van de Velde CJ et al. SABCS 2005 Abstr 3057

12. AI’s after 5y Tam: ExtendedFU
DFS OS
MA 17*
Letrozole vs placebo
30 mths
HR=0.58 SS
HR=0.82 NS
HR=0.61 for Node +
ABCSG 6a
Anastrozole vs
no treatment
60.4 mths
HR=0.64 ND
NSABP 33**
Exemestane vs
placebo
HR=0.68
MA 17: Goss PE SABCS 2005 presentation ABCSG 6a: Jakesz R ASCO 2005 Poster 526 NSABP 33: Mamounas E SABCS 2006 Abstr 48
*Early unblinded trial
**Trial closed prematurely

13. Conclusions (1)
For each adjuvant strategy of treatment, Aromatase inhibitors are more efficient than former standard treatments
In upfront 5 y, Anastrozole or Letrozole are more efficient than 5 y Tamoxifen
After 2-3 y of Tamoxifen, Anastrozole or Exemestane are more efficient than continuing on Tamoxifen
After 5 y of Tamoxifen, Anastrozole or Letrozole are more efficient than placebo/no treatment
In all these trials, the use of Aromatase Inhibitors is beneficial for the whole populations

14. Conclusions (2)
The best treatment available should be offered at the earliest opportunity in order to reduce the risk of recurrence and minimise life-threatening side effects
Patients currently receiving adjuvant Tamoxifen should consider switching to an Aromatase Inhibitor at the earliest opportunity

15. All postmenopausal women with receptor positive disease should receive an AI during the course of their treatment
who ?

16. Early peak of recurrences in presence or absence of adjuvant therapy5 10 15 20 25
0.5
1.5
2.5
3.5
4.5
5.5
6.5
7.5
8.5
9.5
10.5
Time (years)
Hazard of recurrence by yearly interval
Total
Node 0
Node 1-3
Node (4+)
Tumour size (<1 cm)
Tumour size (1.1-3 cm)
Tumour size (>3 cm)
ER +ve
ER -ve
Premenopausal
Postmenopausal
ER, oestrogen receptor
Saphner T et al. J Clin Oncol 1996
Baum M. ASCO 2005, poster 612

17. Follow-up time (years)
ATAC smoothed hazard-rates for recurrence HR+ve population, 68 months’ median follow-up
Annual hazard rates (%)
3.0
2.5
2.0
1.5
1.0
Tamoxifen
0.5
Anastrozole
0.0 1 2 3 4 5 6
Follow-up time (years)
HR+ve, hormone receptor-positive
Houghton J et al. ESMO 2006, poster 243

18. ATAC: time to recurrence by subgroup* (68 months’ follow-up)
All patients
Nodal status
+ve
Tumour size
≤2 cm
>2 cm
HR (A:T) and 95% CI
Anastrozole (A) better
Tamoxifen (T) better
0.40
1.50
1.75
0.60
0.80
1.00
1.25
Previous chemotherapy
yes no
-ve
* ITT population
Howell T. SABCS 2005 presentation
Coates AS et al. J Clin Oncol 2007; 25(5)

19. BIG 1-98: disease-free survival by subgroup (51 months’ follow-up)
HR (L:T) and 95% CI
0.40
1.50
1.75
0.60
0.80
1.00
1.25
All patients
Nodal status
Tumour size
≤2 cm
>2 cm
Previous chemotherapy
yes no
Letrozole (L) better
+ve
-ve
Tamoxifen (T) better
Coates AS et al. J Clin Oncol 2007; 25(5)

20. ATAC vs. BIG 1-98 by subgroup
Nodal status
+ve
-ve
Previous chemotherapy
yes no
Tumour size
≤2 cm
>2 cm
All patients
0.40
0.60
0.80
1.00
1.25
1.50
1.75
HR (L:T) and 95% CI
Letrozole (L) better
Tamoxifen (T) better
Anastrozole (A) better
ATAC Trialists’ Group. Lancet 2005; 365: 60-62
Coates AS et al. J Clin Oncol 2007; 25(5)

21. Predictors of early relapse in postmenopausal women: BIG 1-98 trial
Mauriac L. et al: Ann of Oncology 14 Feb 2007

22. Forest plots: Interpretation of subgroups
It is inappropriate to evaluate the effects of treatment on a single subgroup by examination of the 95% CI for that subgroup. This can lead to 2 types of error
Attributing an effect to a subgroup when there is no overall effect and no evidence of heterogeneity
Claiming a lack of effect in a subgroup when the overall effect is significant
Cuzick J. Lancet 2005; 365:1308

23. Definition of risk categories
LOW RISK: NODE NEGATIVE
pT </= 2cm, AND
Grade AND
Absence of extensive peritumoral vascular invasion (pvi) AND
HER2/neu gene neither overexpressed nor amplified AND
Age >/= 35 years
INTERMEDIATE RISK: NODE NEGATIVE AND AT LEAST ONE
pT > 2cm OR
Grade 2 – OR
Presence of extensive pvi OR
ER and PgR absent OR
HER2/neu gene overexpressed or amplified OR
Age <35 years
Sankt Gallen 2007
Definition of risk categories
NODE POSITIVE ( 1 – 3 involved nodes)
AND
ER and /or PgR expressed AND
HER2/neu gene neither overexpressed nor
amplified
HIGH RISK: NODE POSITIVE (1- 3 involved nodes) AND
ER and PgR absent OR
HER2/neu gene overexpressed or amplified
NODE POSITIVE ( 4 or more involved nodes)

24. Treatment allocation by therapeutic target and risk categories: Sankt Gallen 2007
Treatment options in each cell of the table are listed in the order of preference
HER2 neg
HER2 pos
Endocrine responsiveness
highly
incompletely
non
highly
incompletely
non E
Low * E
C→E C
C→E
+Tr
C+Tr N-
Intermediate E
C→E
1-3 N+
High
1-3 N+
>4 N+
C→E C
+Tr
C+Tr *
*Look for risk definitions
° Pre en Postmenopausal
Annals of Oncology: Vol 18 No.7 July 2007

25. Endocrine therapy in postmenopausal patients Sankt Gallen Guidelines 2007
5 years of tamoxifen alone is still a viable option for certain patient categories
Patients now on Tamoxifen should be switched to an AI after 2-3 years
Initial AI is more acceptable in patients at higher risk or with HER2-positive disease
After 5 years of Tamoxifen a further period of time on an AI in node+ disease
Optimal duration of therapy between 5-10 years
Annals of Oncology: Vol 18 No.7 July 2007

30. © 2006 Adjuvant! Inc.

31. Special Issues Contra-indications for Tamoxifen
Inoperable ER+ breast carcinoma
Neo-adjuvant hormonal treatment
Selective Serotonine Re-uptake Inhibitors: ISSR
CYP2 D6
Prevention: IBIS II –trial?

32. Take home messages (1)
Subgroup analyses, especially when retrospective, must be interpreted with caution, and should not be used as a basis for making clinical decisions
The best treatment available should be offered at the earliest opportunity in order to reduce the risk of recurrence and minimise life-threatening side effects
Patients currently receiving adjuvant Tamoxifen should consider switching to an Aromatase Inhibitor at the earliest opportunity

33. Take home messages (2)
Inderect comparisons do not seem to demonstrate reasons for prefer one or other of the available agents
There are more life-threatening side effects with Tam
QOL between both classes is comparable
Reimbursement criteria in Belgium for AI’s are based on the risk profile of the patient
For each adjuvant strategy of treatment, Aromatase inhibitors are more efficient than former standard treatments

34. Are AI’s replacing SERM’s as the most effective adjuvant hormonal treatment in postmenopausal women with receptor-positive disease?
YES!

35. In which patients?
IN ALL!

36. When?
All patients schould start with an AI upfront (at least we schould be offered the possibility to choose)
Patients on tamoxifen schould be switched as soon as possible