2. Start or Switch?: Latest data from ABCSG/ARNO

3. Adjuvant endocrine therapy for early breast cancer
Recent trial data has challenged tamoxifen’s position as the gold standard adjuvant therapy1
The ATAC trial has shown that anastrozole provides a new standard of care for newly-diagnosed postmenopausal women
Anastrozole significantly decreases the risk of recurrence, distant recurrence and contralateral breast cancer and has a significantly better tolerability profile
During recent years, the status of 5 years’ tamoxifen as the standard adjuvant therapy for early breast cancer (EBC) has been questioned. Long-term tamoxifen use is associated with a well-documented increase in the risk of endometrial and thromboembolic complications, and has been shown to confer no extra survival benefit beyond five years’ therapy.
Resistance to tamoxifen is a recognised problem during adjuvant therapy, requiring a change of endocrine treatment. Aromatase inhibitors (AIs) have demonstrated improved efficacy compared with tamoxifen in advanced disease (Bonneterre et al 2000; Mouridsen et al 2003) and anastrozole (‘Arimidex’) has demonstrated superiority over tamoxifen in the adjuvant setting.
1ATAC Trialists’ Group Lancet 2005; 365: 60–62

4. Unanswered questions in adjuvant therapy for early breast cancer
Would postmenopausal patients already receiving tamoxifen benefit from switching to AI therapy?
Are AIs more effective if used as initial treatment or sequential to tamoxifen?
Could premenopausal women with breast cancer also benefit from AI therapy?
However, for those patients currently receiving tamoxifen treatment, the issue of whether to remain on tamoxifen or switch to treatment with an AI still remains. It has been postulated that by changing adjuvant therapy from tamoxifen to an AI before the onset of resistance or disease recurrence, the benefits of adjuvant treatment can be enhanced.
If AIs can be used to improve therapy for postmenopausal women with breast cancer, can anything be done to improve therapy for premenopausal women?

5. Switching trials: evidence from 8,414 postmenopausal women
Italian Tamoxifen Anastrozole (ITA) trial
International Exemestane Study (IES)
ABCSG 8/ARNO 95 combined analysis

6. ITA: study design Tamoxifen (n=225) Surgery ± RT ± Chemo
All women were:
postmenopausal
hormone receptor positive
node positive
Tamoxifen (n=225)
Surgery
± RT
± Chemo
Tamoxifen (n=448)
Therapy blinded at
randomization to A or T
Anastrozole (n=223)
2–3 years
3–2 years
Women were regularly followed until they reached a major trial endpoint that included any of the following:
disease recurrence
second primary tumour (including a second breast tumour)
death (from any cause)
The Italian Tamoxifen Anastrozole (ITA) trial in 2003 was the first study to address whether switching adjuvant treatment to anastrozole benefits women with node-positive EBC already receiving tamoxifen (Boccardo et al 2005).
Boccardo F et al. Breast Cancer Res Treat 2003; 82 (Suppl 1): S6–S7 (abs 3)

7. ITA: disease-free survival
Proportion disease-free
0.0
0.2
0.4
0.6
0.8
1.0 1 2 3 4 5 6
Anastrozole
Tamoxifen
No. of pts
223
225
Obs 17 45
p-value
0.0002
In this smaller study (n=448), the group allocated to switch therapy to anastrozole experienced significantly decreased incidence of events and recurrences (HR=0.35 for both; p≤0.0002) compared with the group continuing on tamoxifen, including patients receiving adjuvant chemotherapy.
Years
Boccardo F et al. Breast Cancer Res Treat 2003; 82 (Suppl 1): S6–S7 (abs 3)

8. Diagnosis of breast cancer and treatment for primary disease
IES: trial design
Diagnosis of breast cancer and
treatment for primary disease
Years from start
of tamoxifen
2–3 years’ tamoxifen 2
Years from
randomisation
RANDOMISED n
=4742 3
2–3 years’
tamoxifen
n=2380
2–3 years’
exemestane
n=2362
The IES is the largest study to date to investigate switching tamoxifen from tamoxifen to an AI compared with completing adjuvant therapy with tamoxifen.
Here, patients were randomised to switch to exemestane after 2-3 years’ tamoxifen.
Patients followed-up
2-3 5
Coombes RC et al. N Engl J Med. 2004; 350: 1081–1092

9. IES: disease-free survival
Proportion
disease-free (%)
100 75
Hazard ratio = 0.68 (95% CI: 0.56–0.82) Log rank test: p-value < 0.001 50 25
Exemestane
Tamoxifen 1 2 3 4
The IES found a DFS benefit of 32% in favour of switching from tamoxifen to an AI.
Years from randomisation
No. of events/at risk:
Exemestane
0/2362
52/2168
60/1696
44/757
20+6†/201
Tamoxifen
0/2380
78/2173
90/1682
76/730
18+4†/185
†events occurring more than 4 years after randomisation
Coombes RC et al. N Engl J Med. 2004; 350: 1081–1092

10. ABCSG 8/ARNO 95 combined analysis
Aim: to prospectively assess whether switching from tamoxifen to anastrozole after 2 years is more effective than continuing on tamoxifen
Pre-planned combined analysis of ABCSG 8 (Austria) and ARNO 95 (Germany)
Patients: postmenopausal women with hormone receptor-positive EBC
Median 28 months’ follow-up
The ABCSG 8 and ARNO 95 trials investigated the efficacy of switching adjuvant therapy from tamoxifen to anastrozole (‘Arimidex’) after 2 years, compared with continuing tamoxifen, in a combined total of 3224 postmenopausal women with hormone receptor-positive EBC.

11. ABCSG 8/ARNO 95: Combined analysis trial structure
Total patients
n=3224
ABCSG 8
n=2262 +
ARNO 95
n=962
TAM 3 years
n=1606
Primary
surgery
+/- RTx
+ TAM
2 years
ANA 3 years
n=1618
The results were generated from a combined analysis of 3,224 patients who received
- either 3 years of tamoxifen
- or 3 years of anastrozole
after primary surgery and exposure to 2 years of tamoxifen.

12. Patient demographics TAM n=1606 % ANA n=1618 % T1 Node negative
Breast conservation
G1,2,x
Age < 60 yrs
ER+/PgR+
ER+/PgR-
ER-/PgR+
69.7
74.0
77.3
93.7
39.9
81.1
18.3
0.6
70.2
74.2
76.4
95.2
38.6
81.3
18.1
0.6
Overall, patients included in the trial had a favorable prognosis with respect to tumor stage and nodal status, leading to a high rate of breast-conserving procedures.
It is also important to point out that only 5% of patients presented with an undifferentiated tumor.
Gx = lobular carcinoma

13. Event-free survival Event-free survival (%) 100 ANA 95 90 TAM 85 80
ANA vs TAM
p= HR 0.60 [95% CI 0.44–0.81] 75
This Kaplan Meier plot of EFS demonstrates the highly significant benefit for our patients switching to anastrozole after 2 years of tamoxifen over those remaining on tamoxifen.
The HR was A truely impressive outcome ! 1 2 3 4 5
EFS time in years*
At risk:
TAM
1606
1217
858
593
343
176
ANA
1618
1243
874
623
375
178
Zero point = 2 years after surgery

14. Localisation of events
Total
n=3224
177 44 28
121
TAM
n=1606
110 24 16 75
ANA
n=1618 67 20 12 46
Events
Locoregional
Contralateral BC
Distant recurrences
We found the most significant effect in the reduction of distant recurrences in the group given sequential endocrine treatment.
This is not what other trials employing endocrine treatment to postmenopausal patients have found.
Remarkably, distant recurrence was the main source of difference, a factor we believe will eventually be reflected in improved OS.
Events occuring simultaneously are included twice

15. Distant recurrence-free survival
100
ANA 96 92
TAM 88
ANA
ANA vs vs
TAM
TAM 84
p=0.0067
HR 0.60 [95% CI 0.42–0.88]
The different rates of distant metastases are graphically shown in a Kaplan Meier plot with a HR of 0.61. 1 2 3 4 5
At risk:
DRFS time in years
TAM
ANA
1606
1224
1247
869
879
600
631
351
181
1618
382
181
Zero point = 2 years after surgery

16. Subgroup analysis of EFS*
3224
2389
833
3044
167
1265
1959
2519
564
All patients
Nodal status -ve
+ve
Grading G1, G2, Gx G3
Age <60 years
>60 years
Receptor (ER / PR) +ve / +ve
+ve / -ve
The Forest plot, based on a subgroup analysis of EFS, shows that sequential treatment is beneficial irrespective of nodal status, age, and receptor status.
There are too few patients with undifferentiated tumors to gain clear information in this respect.
0.25
0.50
0.80
1.00
1.25
1.50
2.00
3.00
*Events: locoregional, metastatic and contralateral recurrences
ANA better
TAM better
Hazard ratio (ANA vs TAM)

17. Tolerability data from ABCSG 8
Both treatments were well tolerated
The incidence of prespecified side effects was low in both groups
As expected, there were significantly more fractures in patients switching to anastrozole: 27 (2.4%) vs 14 (1.2%) for tamoxifen
No significant difference between treatments was seen in gynaecological side effects because – as seen in ATAC – these generally occur soon after starting tamoxifen

18. ABCSG 8/ARNO 95: Summary These data confirm results from ITA and IES
Switching from TAM to ANA at 2 years is superior to continuing on TAM in terms of:
EFS (HR=0.60)
DRFS (HR=0.61)
Data are not yet sufficiently mature to show a significant difference in OS
The benefits of switching to ANA are seen regardless of baseline prognostic factors
Both treatments are well tolerated
In summary, our efficacy analyses have clearly demonstrated that switching treatment to anastrozole, subsequent to 2 years of tamoxifen, is superior to staying on tamoxifen.
Remarkably, the benefits of such sequential treatment are irrespective of our patients‘ nodal status and age.
It seems that anastrozole is more effective in better differentiated tumors.

19. Which of these treatment strategies is more effective?
Conclusions
ATAC: initial adjuvant therapy with anastrozole is superior to tamoxifen
ABCSG/ARNO: switching to anastrozole after 2 years is superior to remaining on tamoxifen
Which of these treatment strategies is more effective?
At the present moment, however, we may safely conclude that postmenopausal breast cancer patients on adjuvant tamoxifen should switch to ANA after 2 years of treatment.

20. Can these benefits of anastrozole in postmenopausal women be translated into the premenopausal setting?

21. What do we know to date? Premenopausal women:
Benefit from adjuvant tamoxifen alone or in combination with goserelin
Combining an LHRHa and tamoxifen confers better efficacy than LHRHa alone in advanced disease
If a patient is rendered postmenopausal, could she also be eligible from the added benefit of anastrozole?
The benefits of adjuvant treatment with AIs in postmenopausal women can potentially be extended to premenopausal women once ovarian oestrogen production has been switched off with a luteinising hormone-releasing hormone agonist such as goserelin (‘Zoladex’).
Goserelin provides a complete ovarian suppression that is reversible in the majority of premenopausal women, resulting in the reduction of endogenous oestrogen levels thus rendering such patients effectively postmenopausal.
Jakesz et al JCO 2002;20:
Klijn et al. JCO 2001; 343–353
Klijn et al. JNCI 2000; 92: 903–911
Bonneterre et al. Cancer 2001; 92: 2247–2258
ATAC Trialists Group. Lancet 2005; 365: 60–62

22. Goserelin plus anastrozole in 2nd line ABC
Patients deriving clinical benefit from goserelin plus tamoxifen received goserelin plus anastrozole on progression 50
100
150
200
250
Baseline
Goserelin +
Tamoxifen
Anastrozole
Mean serum oestradiol (pmol/L)
p<0.0001
Forward DP et al. Br J Cancer 2004; 90: 590–594

23. Clinical benefit N=16 Partial response [PR]
Stable disease [SD] 6 months
Biochemical response [BR]*
Clinical benefit (CB; PR + SD 6 months + BR) rate
n (%)
1 (6)
9 (56)
2 (13)
75%
*no evidence of progression beyond 6 months with decreasing blood tumour markers
Median duration of clinical benefit 17 months (range 6-47)
Forward DP et al. Br J Cancer 2004; 90: 590–594

24. Goserelin plus anastrozole in 1st line ABC
Phase II trial of 22 patients whose E2 was decreased to postmenopausal levels with goserelin and then received anastrozole
Patients (%)
Objective response 28
Complete response 6
Partial response 22
Stable disease 6 months 44
Clinical benefit 72
To date median TTP = ~10 months
Carlson R et al. Breast Cancer Res Treat 2004; 88 (Suppl 1):S237–238, abs 6052

25. ABCSG 12: trial structure
3 years adjuvant endocrine treatment +/- bisphosphonate therapy
premenopausal HR-positive patients
Anastrozole 1 mg/d
Random
1 : 1 : 1 : 1
Anastrozole 1 mg/d
Zoledronic acid 4 mg/d q 6 Mo OP
Goserelin
3.6 mg q 4W
Tamoxifen 20 mg/d
Tamoxifen 20 mg/d
Zoledronic acid 4 mg/d q 6 Mo
Accruals Target: 1800 (450/arm)
Status: 1372 (Jan. 11, 2005)

26. Conclusions
4 trials have reported data suggesting that postmenopausal women receiving adjuvant tamoxifen should switch to an AI after 2–5 years
Postmenopausal women currently receiving tamoxifen are 40% less likely to relapse if switched to anastrozole after 2 years compared with continuing on tamoxifen
For premenopausal women with hormone-sensitive EBC, the combination of goserelin and anastrozole is a promising treatment and warrants further research