Start or Switch?:Latest data from ABCSG/ARNO
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
1ATAC Trialists’ Group Lancet 2005; 365: 60–62
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?
Switching trials: evidence from 8,414 postmenopausal women
Italian Tamoxifen Anastrozole (ITA) trial
International Exemestane Study (IES)
ABCSG 8/ARNO 95 combined analysis
ITA: study design
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)
Tamoxifen (n=448)
Anastrozole (n=223)
Tamoxifen (n=225)
2–3 years
Therapy blinded atrandomization to A or T
Surgery± RT
± Chemo
3–2 years
All women were:
– postmenopausal
– hormone receptor positive
– node positive
Boccardo F et al. Breast Cancer Res Treat 2003; 82 (Suppl 1): S6–S7 (abs 3)
ITA: disease-free survival
0.0
0.2
0.4
0.6
0.8
1.0
0 1 2 3 4 5 6
AnastrozoleTamoxifen
No. of pts223225
Obs1745
p-value0.0002
Years
Boccardo F et al. Breast Cancer Res Treat 2003; 82 (Suppl 1): S6–S7 (abs 3)
Proportion disease-free
IES: trial designDiagnosis of breast cancer andtreatment for primary disease
2–3 years’ tamoxifen
RANDOMISEDn=4742
Patients followed-up
2–3 years’exemestane
n=2362
2–3 years’tamoxifen
n=2380
2
3
0
5
Years from startof tamoxifen
0
2-3
Years fromrandomisation
Coombes RC et al. N Engl J Med. 2004; 350: 1081–1092
Coombes RC et al. N Engl J Med. 2004; 350: 1081–1092
IES: disease-free survival
0
Exemestane Tamoxifen
Hazard ratio = 0.68 (95% CI: 0.56–0.82)Log rank test: p-value < 0.001
1 2 3 40
25
50
75
100Proportiondisease-free (%)
52/216878/2173
60/169690/1682
44/75776/730
20+6†/2010/23620/2380
ExemestaneTamoxifen
No. of events/at risk:
18+4†/185
Years from randomisation
†events occurring more than 4 years after randomisation
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
Primarysurgery+/- RTx
TAM 3 yearsn=1606
Total patientsn=3224
ABCSG 8n=2262
+ARNO 95
n=962
ANA 3 yearsn=1618
ABCSG 8/ARNO 95:Combined analysis trial structure
+ TAM
2 years
T1
Node negative
Breast conservation
G1,2,x
Age < 60 yrs
ER+/PgR+
ER+/PgR-
ER-/PgR+
Patient demographics
Gx = lobular carcinoma
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
TAMn=1606
%
ANAn=1618
%
Event-free survival
Zero point = 2 years after surgery
0
75
80
85
90
95
100
0 1 2 3 4 5
Event-free survival (%)
ANA vs TAM p=0.0009 HR 0.60 [95% CI 0.44–0.81]
EFS time in years*
ANA
TAM
At risk:1606 343 176TAM
ANA 161812171243
858874
593623 375 178
EventsLocoregionalContralateral BCDistant recurrences
Localisation of events
Events occuring simultaneously are included twice
Totaln=3224
1774428121
ANAn=1618
67201246
TAMn=1606
110 241675
Distant recurrence-free survival
Zero point = 2 years after surgery
ANADistant recurrence-free survival (%)
TAM
ANA vs TAMp=0.0067 HR 0.60 [95% CI 0.42–0.88]
DRFS time in years
84
88
92
96
100
0 1 2 3 4 5
0
ANA vs TAM
At risk:1606 351 181TAM
ANA 161812241247
869879
600631 382 181
Subgroup analysis of EFS*All patients
Receptor (ER / PR) +ve / +ve
+ve / -ve
Nodal status -ve+ve
Grading G1, G2, GxG3
Age <60 years>60 years
0.25
0.50
0.80
1.00
1.25
1.50
2.00
3.00
Hazard ratio (ANA vs TAM)
n
3224
2389
833
3044
167
1265
1959
2519
564
ANA better TAM better*Events: locoregional, metastatic and contralateral recurrences
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
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
ABCSG 8/ARNO 95: Summary
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?
Can these benefits of anastrozole in postmenopausal women be translated into the premenopausal setting?
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?
Jakesz et al JCO 2002;20:4621-4627Klijn et al. JCO 2001; 343–353
Klijn et al. JNCI 2000; 92: 903–911Bonneterre et al. Cancer 2001; 92: 2247–2258
ATAC Trialists Group. Lancet 2005; 365: 60–62
Forward DP et al. Br J Cancer 2004; 90: 590–594
0
50
100
150
200
250
Baseline Goserelin +Tamoxifen
Goserelin +Anastrozole
Me
an
se
rum
oe
stra
dio
l (p
mo
l/L)
p<0.0001
p<0.0001
• Patients deriving clinical benefit from goserelin plus tamoxifen received goserelin plus anastrozole on progression
Goserelin plus anastrozole in 2nd line ABC
Clinical benefit
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%
N=16
*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
To date median TTP = ~10 months
Patients (%)Objective response 28
Complete response 6Partial response 22
Stable disease 6 months 44Clinical benefit 72
Goserelin plus anastrozole in 1st line ABC
Carlson R et al. Breast Cancer Res Treat 2004; 88 (Suppl 1):S237–238, abs 6052
Phase II trial of 22 patients whose E2 was decreased to postmenopausal levels with goserelin and then received anastrozole
• 3 years adjuvant endocrine treatment +/- bisphosphonate therapy• premenopausal HR-positive patients
Anastrozole 1 mg/dZoledronic acid 4 mg/d q 6 Mo
Random1 : 1 : 1 : 1
Goserelin3.6 mg q 4W
Accruals Target: 1800 (450/arm)Status: 1372 (Jan. 11, 2005)
Tamoxifen 20 mg/dOP
ABCSG 12: trial structure
Anastrozole 1 mg/d
Tamoxifen 20 mg/dZoledronic acid 4 mg/d q 6 Mo
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