1. CONTROVERSIES IN ADJUVANT ENDOCRINE THERAPY AROMATASE INHIBITORS
JAMES F BISHOP MD
PROFESSOR OF CANCER MEDICINE, UNIVERSITY OF SYDNEY
DIRECTOR, SYDNEY CANCER CENTRE
ROYAL PRINCE ALFRED HOSPITAL, SYDNEY

2. 3RD GENERATION AROMATASE INHIBITORS
Aromatase convert androgens to low level estrogen in PM women
AI suppress estrogen levels to 1-10% pre-treatment levels with Letrozole > Anastrozole*
Inadequate data in pre-menstrual women with hormone combination with LHRH analogue
* J Clin Oncol 20:751, 2002

3. AROMATASE INHIBITORS IN MBC
All AI superior or equivalent to megestrol acetate as second line for efficacy and toxicity
Anastrozole and Letrozole superior or equivalent to TAM for efficacy (TTP) and toxicity (fewer TE events)
Exemestane vs TAM ongoing phase III trial

4. LESSONS FROM THE OVERVIEW IMPACT OF TAMOXIFEN (5 YEARS) VS NONE
Reduction In Annual Odds
Age (Years)
Recurrence
Death
< 50
45 + 8% %
50 – 59
37 + 6%
11 + 8%
60 – 69
54 + 5%
33 + 6%
Lancet 351:1451, 1998

5. NSABP B-24: TAMOXIFEN RISK REDUCTION
No of Patients
RR*
95% CI P
DCIS
1804
All breast ca
0.63
(0.47 – 0.83)
0.0009
Non-invasive
0.69
(0.46 – 1.04)
0.08
Invasive
0.57
(0.38 – 0.85)
0.004
* At 74 mos median follow up
Fisher et al Lancet 353:1993, 1999

6. LESSONS FROM THE OVERVIEW OVARIAN ABLATION < 50 YEARS
Reduction In Annual Odds
Recurrence
Mortality
15 Year Survival
Ovarian ablation
vs none
18.5 (+ 5.5)%
18.4 (+ 5.7) %
6.3 (+ 2.3)%
Effect less in the presence of chemotherapy
Lancet 348:1189, 1998

7. ATAC TRIAL DESIGN â å æ +
Postmenopausal women with invasive breast cancer
Completion of primary therapy*
Randomization 1:1:1 for 5 years
Anastrozole 1mg od + Tamoxifen placebo
Anastrozole placebo + Tamoxifen 20mg od
Anastrozole 1mg od + Tamoxifen 20mg od
Regular follow-up monitoring adverse events
Trial endpoints
* Surgery + radiotherapy + chemotherapy
(Patients may start trial therapy while still receiving radiotherapy)

8. ATAC TRIAL – STUDY ENDPOINTS
Primary Endpoints
Disease-free survival
 Loco regional or distant recurrence, new primary breast cancer, or death from any cause
Safety/Tolerability
Secondary Endpoints
Incidence of new breast (contralateral) primaries
Time to distant recurrence
Survival (data will be mature in ~ 2 years)
Hormone receptor-positive population (protocol-defined sub-group)

9. PATIENT CHARACTERISTICS
Anastrozole (n=3125)
Tamoxifen (n=3116)
Combination (n=3125)
Mean age (years)
Mean weight (kg)
Receptor status (%)
Positive
Negative
Other
Primary treatment (%)
Mastectomy
Axillary surgery
Radiotherapy
Chemotherapy
Prior tamoxifen

10. Proportion event free (%) Proportion event free (%)
KAPLAN–MEIER CURVES OF DISEASE-FREE SURVIVAL IN ITT POPULATION
100 95
Anastrozole
Tamoxifen 90
Combination
Proportion event free (%)
Proportion event free (%) 85
HR 95.2% CI p-value
AN vs TAM –
Comb vs TAM – 80 6 12 18 24 30 36 42
Time to event (months)
Time to event (months)
Curves truncated at 42 months

11. Proportion event free (%)
KAPLAN–MEIER CURVES OF DISEASE-FREE SURVIVAL IN RECEPTOR-POSITIVE POPULATION
HR 95.2% CI p-value
AN vs TAM –
Comb vs TAM –
Time to event (months)
Proportion event free (%)
Anastrozole
Tamoxifen
Combination 80 85 90 95
100 6 12 18 24 30 36 42
Curves truncated at 42 months

12. ANALYSIS OF THE INCIDENCE OF NEW (CONTRALATERAL) BREAST PRIMARIES
100
Anastrozole
Tamoxifen 99
Combination
Proportion without CL BCa (%)
OR 95% CI p-value
AN vs TAM –
Comb vs TAM – 98 6 12 18 24 30 36 42
Time to first contralateral new primary (months)

13. SIGNIFICANT DIFFERENCE IN PRE-DEFINED ADVERSE EVENTS
In favour of anastrozole
In favour of tamoxifen
Hot flushes
(-5.4%)
(6.6%)
MSK disorders
Weight gain*
(-1.8%)
(2.1%)
Fractures
(0.8%)
Fractures of hip, spine, wrist
Vag. bleeding
(-3.6%)
Vag. discharge
(-8.6%)
Endo Ca
(-0.4%)
ICVA
(-1.1%)
VTE
(-1.4%)
DVT
(-0.7%)
-10 -5 5 10
Difference between anastrozole and tamoxifen AEs (%)
* proportion with ³10% gain in body weight from baseline to year 2

14. ASCO TECHNOLOGICAL REPORT 2002
AIM:
To define whether adjuvant AI should have broad based use in conventional practice
METHODOLOGY:
Panel of experts
Computerised searches of Medline/ASCO Jan 2002
3 companies invited to provide unpublished data

15. ASCO TECHNOLOGICAL REPORT 2002 IMPLICATIONS OF THE ATAC TRIAL
EVIDENCE:
Long term adverse effects of TAM but not AI are known. Some concern about adverse bone effects
Absolute differences in DFS are small, currently 2.02%
5 years of TAM need to see full benefit but reported at 33 mos FU
No reported differences in survival
Optimal duration of AI not addressed in this trial
Possible optimal sequence of TAM and AI not addressed
ATAC trial data not yet peer reviewed

16. ASCO TECHNOLOGICAL REPORT 2002 IMPLICATIONS OF THE ATAC TRIAL
PANEL CONSENSUS:
ATAC trial is preliminary
5 years of TAM remains standard of care
Need for longer FU and other trial results

17. ASCO TECHNOLOGICAL REPORT 2002
ARE ALL AROMATASE INHIBITORS EQUIVALENT?
EVIDENCE:
Confined discussion to third generation anastrozole, Letrozole and Exemestane which may be equivalent in MBC
Quoted RCT in 713 MBC Anastrozole vs Letrozole showing equivalence in TTP, response duration *
Ongoing trials which will compare AI
PANEL CONSENSUS:
Only adjuvant data is with Anastrozole
If AI to be used in an adjuvant setting should be Anastrozole
* Rose et al ASCO 2002

18. ASCO TECHNOLOGICAL REPORT 2002 WOMEN ALREADY ON ADJUVANT TAM
EVIDENCE:
Study of TAM vs TAM -> aminoglutethimide * with superiority for sequential arm
PANEL CONSENSUS:
No data supporting substitution of TAM for AI
Intolerable SE from TAM, AI could be considered but unproven
* Boccardo et al J Clin Oncol 19:4201, 2001.

19. ASCO TECHNOLOGICAL REPORT 2002 SHOULD AI BE GIVEN AFTER 5 YEARS OF TAM
EVIDENCE:
No data
PANEL CONSENSUS:
After TAM for 5 years should not receive AI unless in a trial

20. ASCO TECHNOLOGICAL REPORT 2002 DURATION OF ADJUVANT AI
EVIDENCE:
No trials
ATAC trial current report with FU 33 mos
PANEL CONSENSUS:
Patients receiving adjuvant AI should receive 2-3 years
Review as more data is available

21. ASCO TECHNOLOGICAL REPORT 2002 AROMATASE INHIBITORS IN PRE-MENOPAUSAL
EVIDENCE:
AI no established role in pre-menopausal women
MBC trials with LHRH + AI show activity
PANEL CONSENSUS:
AI alone is contra-indicated in pre-menopausal women
Adjuvant Zoladex or oophorectomy plus AI not been reported

22. ASCO TECHNOLOGICAL REPORT 2002
AROMATASE INHIBITORS AFTER CT INDUCED AMENORRHEA
EVIDENCE:
Resumption of ovarian function frequently occurs especially in younger women
Such resumption would render AI ineffective
PANEL CONSENSUS:
Cautioned against use of AI in this setting because of the substantial probability of resumption of ovarian function

23. ASCO TECHNOLOGICAL REPORT 2002 AROMATASE INHIBITORS IN DCIS
EVIDENCE:
Reduction in contralateral cancers in Anastrozole arm of ATAC
No data on DCIS
PANEL CONSENSUS:
Women with DCIS should not receive AI outside a clinical trial

24. ASCO TECHNOLOGICAL REPORT 2002
AROMATASE INHIBITORS IN CHEMO-PREVENTION
EVIDENCE:
TAM remains the only agent tested and approved by the FDA
Reduction in contralateral breast cancer in Anastrozole arm of ATAC is insufficient evidence
PANEL CONSENSUS:
Women with increased risk of breast cancer should not receive AI to reduce risk outside a clinical trial

25. ASCO TECHNOLOGICAL REPORT 2002
AROMATASE INHIBITORS IN ER NEGATIVE CANCERS
EVIDENCE:
Overwhelming evidence that adjuvant hormone therapy is effective only in ER positive patients
No contradictory data with AI
PANEL CONSENSUS:
Women with ER negative cancers should not receive AI as adjuvant therapy

26. ASCO TECHNOLOGICAL REPORT 2002
AROMATASE INHIBITORS IN HER-2 POSITIVE CANCERS
EVIDENCE:
Conflicting studies some suggest TAM is less beneficial in HER-2 positive cancers
Many studies have methodological flaws
NIH consensus conference recommended all ER positive patients receive TAM regardless of HER-2 status

27. ASCO TECHNOLOGICAL REPORT 2002
AROMATASE INHIBITORS IN HER-2 POSITIVE CANCERS
OPR ErbB-1 +/or Breast
Erb-2 Positive Sparing Surgery
TAM
4mos 41% 21% 21%
Letrozole
4mos 60% 86% 41%
ER +/OR
PR Positive R
Ellis et al: J Clin Oncol 19:3808, 2001.

28. IRESSA RESTORES TAM SENSITIVITY IN HER-2 OVEREXPRESSING TUMOURS
MCF-7/HER2 overexpressing cells
Given estrogen, TAM estrogren deprivation + Iressa
Iressa restored TAM sensitivity
Massarweh: ASCO #130:2002.

29. ASCO TECHNOLOGICAL REPORT 2002
AROMATASE INHIBITORS IN HER-2 POSITIVE CASES
PANEL CONSENSUS:
Recommendation against use of HER-2 studies to make decisions about adjuvant hormone therapy
Clinical data to support use of HER-2 status are inadequate

30. ASCO TECHNOLOGICAL REPORT 2002
AROMATASE INHIBITORS WHEN TAM IS CONTRAINDICATED
EVIDENCE:
TAM is associated with increased risk of thrombo-embolic and cerebrovascular disease
PANEL CONSENSUS:
Reasonable to use adjuvant AI with a relative or absolute contraindication to TAM
Recommend careful consideration of the significance of the contraindication given the proven benefits with TAM

31. ASCO TECHNOLOGICAL REPORT 2002
AROMATASE INHIBITORS FOR INVASIVE BREAST CANCER WHILE ON TAM OR RALOXIFEN
EVIDENCE:
In MBC AI are effective following progression on TAM
Role of AI following Raloxifen unknown
Evidence of cross resistance between Raloxifen and TAM suggesting TAM may be ineffective after Raloxifen
PANEL CONSENSUS:
Reasonable to use adjuvant AI although data are poor

32. ADJUVANT ANASTROZOLE TRIALS
Group
Special Eligibility
Study
Target
Status
ATAC
ER/PR
Unknown
TAM AI
TAM + AI
9336
Completed
Austrian ABCSG
Post-TAM (5y)
AI Control
1700
800
Austrian AU08
Post-TAM
(2 y)
2500
2600
Austrian AU 12
Pre-M
TAM + Zoladex
AI + Zoladex
1250
600
German GR001
Post-TAM (2y)
1000
N/A
ItalianIT 02
525
Total targets
16,311

33. ADJUVANT LETROZOLE TRIALS
Group
Special Eligibility
Study
Target
Status
NCIC
MA-17
Post-TAM (5y) AI
Placebo
4800
4100
IBCSG-1-18
BIG-FEMTA
Post CT
TAM (5y)
AI (5y)
TAM (2y) -> AI
AI (2y) -> TAM
7900
5004
Total Target
12,700

34. ADJUVANT EXEMESTANE TRIALS
Group
Special Eligibility
Study
Target
NSABP B-33
Post-TAM (5y) AI
Placebo
3000
BIG-9702
Post-TAM (2y)
TAM
4400
CRC-TU-TEAM
Prior CT
Total Target
11,800
Total target accrual for all adjuvant AI trials 40,811 women

35. ASCO TECHNOLOGICAL REPORT 2002 SUMMARY OF ROLE OF ADJUVANT AI
ATAC Trial – not yet
Are all AI the same – Anastrozole now
If now on TAM – no
After 5 years of TAM – no
Duration of AI – don’t know
In pre-menopausal – no
After CT amenorrhoea – watch out!

36. ASCO TECHNOLOGICAL REPORT 2002 SUMMARY OF ROLE OF ADJUVANT AI
8. DCIS – no
9. Chemo-prevention – no
10. ER/PR negative cancers – definitely no!
HER-2 positive cancers – no, but who knows
Women where TAM contraindicated – maybe
New invasive cancers after chemo-prevention - OK