Trial design and patient recruitment
description
Transcript of Trial design and patient recruitment
Trial Comparison: ‘Arimidex’, Tamoxifen, Alone or
in Combination (ATAC) and
Breast International Group (BIG) 1-98
Trial design and patient recruitment
9366 patients recruited from 381 centres in 21 countries
ATAC trial:
2222
30160
201
Belgium 192Czech Republic 84France 366Germany 121Hungary 243Ireland 41Italy 654
Netherlands 195Poland 107Portugal 74Slovakia 33Spain 417Sweden 291Turkey 53UK 3228
14
640
Combinationn=3125
Discontinued following initial analysis as no efficacy or
tolerability benefit compared with tamoxifen arm
Regular follow-up
9366 postmenopausal women with invasive breast cancer: mean age 64 years; 84% hormone receptor-positive;
61% node negative; 64% with tumour 2 cm in diameter
Surgery radiotherapy chemotherapy
Randomisation 1:1:1 for 5 years
Anastrozole n=3125
Tamoxifen n=3116
Primary trial endpoints:• Disease-free survival• Safety / tolerability
Secondary trial endpoints:• Incidence of contralateral breast cancer• Time to distant recurrence• Overall survival • Time to breast cancer death
ATAC trial design
ATAC Completed Treatment Analysis
Data cut-off 31 March 2004, based on at least 704 deaths in the two monotherapy arms combined
68 months’ median follow-up – beyond completion of treatment
59 months’ median treatment duration
Only 8% of patients remain on treatment – the great majority of these nearing completion
ATAC Trialists’ Group. Lancet 2005; 365: 60-62
8028 postmenopausal women with ER+ diseaseMedian age 61 years52% node negative63% tumour 2 cm in diameter
Tamoxifen
BIG 1-98 trial designR
A
N
D
O
M
I
S
E
Letrozole
Tamoxifen
Letrozole Tamoxifen
Letrozole
0 2 5
A
B
C
D
Arm
A vs B: March 1998 – March 2000; (n=1835)
A vs B vs C vs D; September 1999 – May 2003; (n = 6193)
BIG = Breast International GroupER+ = estrogen receptor-positive
Time (years)1 3 4
Adapted from Thürlimann B. St Gallen presentation 2005
0
10
20
30
40
50
60
70
80
Total number of DFS events (monotherapy arms) 1226
<1 1–<2 2–<3 3–<4 4–<5 >5
Duration of follow-up (years)
Patients (%)
ATAC: 73% of patients have been followed-up for 5 years or more
Updated analysis (median follow-up 47 months)Treatment completion analysis (median follow-up 68 months)
DFS = disease-free survival
BIG 1-98: only 15% of patients have been followed-up for 5 years 99
77
46
28
15
99
76
33
24
15
0
20
40
60
80
100 Overall (median follow-up 35.5 months)
Primary core (median follow-up 25.8 months)
1 2 3 4 5
Follow-up (years)
Patients (%)
Thürlimann B. St Gallen presentation 2005
Demographics
Patient characteristics BIG 1-98(n=8010)
ATAC(n=6291)
Age (years)
Primary treatment (%)
mastectomy
radiotherapy
chemotherapy
Mean 64.1
47.6
62.9
21.6
Median 61.0
43.0
71.6
25.3
ATAC Trialists’ Group. Lancet 2002; 359: 2131-39 Adapted from Thürlimann B. St Gallen presentation 2005
Baseline disease characteristics
Tumour size 2 cm (%)
Nodal status (%)
node-positive
node-negative
unknown
HR status (%)
ER+/PgR+
ER+/PgR-
ER+/PgR unknown
ER-/PgR+
63.4
34.2
60.7
5.0
61.5
14.1
5.5
2.2
62.9
41.3
52.2
6.5
63.1
20.4
14.4
1.8
BIG 1-98(n=8010)
ATAC(n=6291)
ATAC Trialists’ Group. Lancet 2002; 359: 2131-39 Adapted from Thürlimann B. St Gallen presentation 2005
Efficacy analyses
Definition of disease-free survival differs
ATAC
– loco-regional recurrence or new contralateral breast cancer (invasive or DCIS)
– distant recurrence or death (for any reason)
BIG 1-98
– breast cancer recurrence (local, regional and distant) or invasive contralateral breast cancer
– non-breast cancer deaths (deaths without recurrence)
– non-breast cancer second primaries
Time to recurrence is similar for both trials
DCIS = ductal carcinoma in situATAC Trialists’ Group. Lancet 2002; 359: 2131-39
Thürlimann B et al. The Breast 2005;14; S3. Abstract S4
Definition of time to distantrecurrence appears to differ
ATAC - time to distant recurrence (TTDR)
– distant recurrence or any death following a loco-regional recurrence (including ipsilateral new breast cancer) or breast cancer death
– ~45% of first events were distant events
– ~18% of first events were locoregional
BIG 1-98 - time to distant metastasis (TTM) – breast cancer recurrence (excluding local or regional
recurrences, and contralateral breast cancer)
– censoring for non-breast cancer deaths
– ~65% of first events* were distant events
– ~12% of first events* were local or regional
ATAC Trialists’ Group. Lancet 2005; 365: 60-62Thürlimann B et al. The Breast 2005;14; S3. Abstract S4 *excluding second primary events
A 2618 2540 2448 2355 2268 2014 830T 2598 2516 2398 2304 2189 1932 774
ATAC: disease-free survival (HR-positive population)
0 1 2 3 4 5 6
p value
0.005
HR
0.83A vs T
95% CI
(0.73, 0.94)
At risk:Follow-up time (years)
Anastrozole (A)
Tamoxifen (T)
0
5
10
15
20
25
Absolute difference: 1.6% 2.6% 2.5% 3.3%
Patients(%)
CI, confidence interval Howell A. SABCS presentation 2004
4003 3892 2964 1261 892 567
4007 3896 2926 1238 866 544
L
T
At risk: Follow-up time (years)
N=8010
Letrozole
Tamoxifen
p value
0.003
HR
0.81L vs T
95% CI
(0.70, 0.93)
0 1 2 3 4 50
20
15
10
5
25
BIG 1-98: disease-free survival97.7 95.1 90.5 86.8 84.0Yearly
97.6 93.4 89.0 84.6 81.4DFS %
L
T
Adapted from Thürlimann B. St Gallen presentation 2005
ATAC: recurrence (HR-positive population)
A 2618 2540 2448 2355 2268 2014 830T 2598 2516 2398 2304 2189 1932 774
0 1 2 3 4 5 6
Anastrozole (A)
Tamoxifen (T)
p value
0.0002
HR
0.74A vs T
95% CI
(0.64, 0.87)
Follow-up time (years)At risk:
0
5
10
15
20
25
Absolute difference: 1.7% 2.4% 2.8% 3.7%
Patients(%)
ATAC Trialists’ Group. Lancet 2005;365:60-62
BIG 1-98: breast cancer relapse(Time to recurrence) Cumulative incidence
0 1 2 3 4 5
Proportion failure (%)
20
15
10
5
0
5-year difference (L-T) = -3.41.2%p=0.0002 (based on CI)
6.2%
10.2%
8.1%
13.6%
Letrozole (L)
Tamoxifen (T)
Years from randomisation
Thürlimann B. St Gallen presentation 2005
A 2618 2550 2464 2386 2309 2051 845T 2598 2533 2438 2361 2251 2005 816
ATAC: time to distant recurrence (HR-positive population)
0 1 2 3 4 5 6
p value
0.06
HR
0.84A vs T
95% CI
(0.70, 1.00)
Anastrozole (A)
Tamoxifen (T)
Follow-up time (years)At risk:
0
5
10
15
20
25Patients(%)
Howell A. SABCS presentation 2004
A 2618 2566 2505 2437 2377 2117 867T 2598 2549 2502 2430 2333 2080 855
ATAC: overall survival (HR-positive population)
0 1 2 3 4 5 6
p value
0.7
HR
0.97A vs T
95% CI
(0.83, 1.14)
Anastrozole (A)
Tamoxifen (T)
Follow-up time (years)At risk:
0
5
10
15
20
25Patients(%)
Howell A. SABCS presentation 2004
Hazard ratio (A:T) and 95% CI
Disease-free survival
Time to recurrence
Time to distant recurrence
Overall survival
Time to breast cancer death
Contralateral breast cancer
0.2 0.4 0.6 0.8 1.0 1.2 1.5 2.0
ATAC: efficacy summary(HR-positive population)
Anastrozole (A) better Tamoxifen (T) better
0.83
0.74
0.84
0.97
0.87
0.47
Hazardratio
ATAC Trialists’ Group. Lancet 2005;365:60-62
ATAC: efficacy analysis (ITT and HR +ve)
HR (A:T) and 95% CI
Disease-free survival
Time to recurrence
Time to distant recurrence
Overall survival
Time to breast cancer death
Contralateral breast cancer
0.2 0.4 0.6 0.8 1.0 1.2 1.5 2.0
ITT population
HR +ve populationAnastrozole (A) better Tamoxifen (T) better
ATAC Trialists’ Group. Lancet 2005;365:60-62
0.87
0.79
0.86
0.97
0.88
0.58
ITT HR+
0.83
0.74
0.84
0.97
0.87
0.47
Time to distant recurrence
Time to recurrence
BIG 1-98: efficacy summary
Disease-free survival
Systemic disease-free survival
Disease-free survival (without 2nd primary)
Hazard ratio (L:T) and 95% CI 0.2 0.4 0.6 0.8 1.0 1.2 1.5 2.0
Letrozole (L) better Tamoxifen (T) better
Overall survival
0.81
0.72
0.73
0.86
0.83
0.79
Hazard ratio
Adapted from Thürlimann B. St Gallen presentation 2005
0.83
0.74
0.84
0.97
BIG 1-98 ATAC
BIG 1-98: sites of first failure
Failures (DFS events)
local
contralateral breast
regional*
distant
second (non-breast) malignancy
death without recurrence
Deaths
Systemic failures**
8.8
0.5
0.4
0.3
4.4
1.7
1.4
4.1
8.1
10.7
0.9
0.7
0.3
5.8
2.0
0.9
4.8
9.6
0.004
0.047
0.125
0.845
0.006
0.324
0.077
0.176
0.020
Letrozole (%) Tamoxifen (%) p value
*Regional includes axilla or internal mammary**SDFS ignores local and contralateral events
Thürlimann B. St Gallen presentation 2005
ATAC vs BIG 1-98 efficacy summary
Anastrozole is more effective than tamoxifen in reducing the risk of recurrence, distant recurrence and contralateral breast cancer
– absolute difference between anastrozole and tamoxifen continues to increase over time, and extends beyond completion of treatment
Letrozole demonstrates DFS benefits and early benefits in distant recurrence
– BIG 1-98 has a comparatively higher number of patients per arm, resulting in a higher number of events per unit time
– patient population in BIG 1-98 has a slightly worse prognosis
– Absolute differences at 5 years for BIG 1-98 data are projected out to 5 years and are calculated from immature data hence liable to change
Sub-group analysis
ATAC: time-to-recurrence by subgroup
Intent-to-treat populationHazard ratio (A:T) and 95% CI
Nodal status +ve
-ve
All patients
Tumour size ≤ 2 cm
>2 cm
Receptor status +ve
-ve
Previous chemotherapy
yes
no
0.40 1.50 1.750.60 0.80 1.00 1.25
Anastrozole (A) better Tamoxifen (T) better
Howell A. SABCS presentation 2004
Intent-to-treat populationHazard ratio (L:T) and 95% CI
Nodal status +ve
-ve
All patients
Previous chemotherapy
yes
no
0.40 1.50 1.750.60 0.80 1.00 1.25
Letrozole (L) better Tamoxifen (T) better
Previous radiotherapy
yes
no
BIG 1-98: disease-free survivalby subgroup
Adapted from Thürlimann B. St Gallen presentation 2005
ATAC vs BIG 1-98 subgroup summary (1) Anastrozole demonstrated advantages over
tamoxifen for all subgroups examined
– no heterogeneity of subgroups
– no significant interaction with any baseline prognostic factor, including prior chemotherapy or nodal status
– more effective than tamoxifen in overall HR+ve group
even greater improvement in ER+PgR- subgroup
Subgroup analyses must be interpreted with caution
– should not be used as a basis for making clinical decisions
ATAC vs BIG 1-98 subgroup summary (2) Letrozole demonstrated benefits over tamoxifen
– node positive patients
no apparent benefit in node negative patients
– prior chemotherapy patients
slightly worse prognosis, more patients received prior chemotherapy (25% vs 20%)
No apparent difference between ER+/PgR+ and ER+/PgR- subgroups for letrozole and tamoxifen
– tamoxifen does not appear to be performing in line with expectations
previous studies demonstrate that ER+/PgR- patients on tamoxifen have a higher rate of recurrence than ER+/PgR+
Subgroup analyses must be interpreted with caution
– should not be used as a basis for making clinical decisions
Tolerability analysis
BIG 1-98: safety analysis
Included all patients that had received at least 1 treatment dose
Protocol-specified only ‘targeted’ adverse event data was collected every 6 months
Number of patients experiencing at least 1 serious adverse event:
– 587 vs 643 (letrozole vs tamoxifen)
ATAC: overview of adverse events*
All adverse events
Adverse events leading to withdrawal
Drug-related adverse events leading to withdrawal
All serious adverse events
Serious adverse events leading to withdrawal
Serious adverse events leading to death
Drug-related serious adverse events leading to death
p value
0.2
0.0002
0.0005
0.03
0.04
0.6
0.5
Tamoxifen (%)(n=3094)
94.6
14.3
8.9
36.0
5.9
3.6
0.3
Anastrozole (%)(n=3092)
93.9
11.1
6.5
33.3
4.7
3.3
0.2
*Adverse events on treatment or within 14 days of discontinuation Howell A. SABCS presentation 2004
T40.910.213.20.82.8
4.5
2.4
29.47.7
A35.75.43.50.22.0
2.8
1.6
35.611.0
Completion analysis (%)
p value
<0.0001<0.0001<0.0001
0.020.03
0.0004
0.02
<0.0001<0.0001
Hot flushesVaginal bleedingVaginal dischargeEndometrial cancer**Ischaemic cerebrovascular
eventVenous thromboembolic
eventsDeep venous
thromboembolic eventsJoint symptomsTotal fractures***
*Adverse events on treatment or within 14 days of discontinuation; **Excludes patients with prior hysterectomy and includes on- and off-therapy AEs; ***Fractures occurring at anytime prior to recurrence (includes patients no longer receiving treatment)
ATAC: pre-defined adverse events*
ATAC Trialists’ Group. Lancet 2005;365:60-62
T38.16.6
16.2 9.5 2.42.61.18.34.1
19.2
L33.63.3148.8 1.02.71.2 8.75.8
43.6
Primary core analysis (%)
Hot flushesVaginal bleedingNight sweatsNausea Thromboembolic eventsVomitingCVA/TIAOther cardiovascularBone fractureHypercholesterolemia
BIG 1-98: targeted adverse events
Adapted from Thürlimann B. St Gallen presentation 2005
No arthralgia/joint symptoms or osteoporosis data are available from BIG 1-98Endometrial cancer shows no significant difference between L and T
ATAC vs BIG 1-98: bone fractures
Patients with bone fracture 340 vs 237 (11.0% vs 7.7%)
1.49, p<0.0001
ATAC
(A vs T)
BIG 1-98
(L vs T )Patients
228 vs 162 (5.8% vs 4.1%)
1.44, p=0.0006Odds ratio, p value
2.2 vs 1.5
(per 100 patient years)
2.3 vs 1.6
(per 100 patient years)
Bone fracture rate
Adapted from ATAC Trialists’ Group. Lancet 2005;365:60-62 ;Thürlimann B. St Gallen presentation 2005
ATAC: fracture risk is predictable and manageable
YearsArimidexTamoxifen
030923094
129232932
227242741
325532579
423932401
520702100
6845846
Number at risk
0
0.5
1
1.5
2
2.5
3
1 2 3 4 5 6
Years since randomisation
*Calculated using Kaplan-Meier estimates
Annual rates, %*
Anastrozole 1 mg odTamoxifen 20 mg od
0
Howell A. SABCS presentation 2004
ATAC vs BIG 1-98: endometrial cancer
Patients with endometrial cancer
5 vs 17
(0.2% vs 0.8%)
0.29, p=0.02
ATAC
(A vs T)
BIG 1-98
(L vs T )Patients
6 vs 15
(0.2% vs 0.4%)
0.40, p=0.078Odds ratio, p value
Adapted from ATAC Trialists’ Group. Lancet 2005;365:60-62 ;Thürlimann B. St Gallen presentation 2005
BIG 1-98: Grade 3-5 cardiovascular events
CVA/TIA
Thromboembolic
Other cardiovascular
46 (1.2%)
30 (0.8%)
143 (3.6%)
Letrozole(n=3965)
Tamoxifen(n=3984)Patients
42 (1.1%)
79 (2.0%)
101 (2.5%)
Thürlimann B. St Gallen presentation 2005
There is a significantly higher number of other cardiovascular events on letrozole compared with tamoxifen (p=0.006)
BIG 1-98: death without recurrence Cumulative incidence
1 2 3 4 5
20
15
10
5
0
Years from randomisation
5-year difference (L-T) = 1.30.6% p=0.08 (based on CI)
1.4%
1.8%0.8%
3.1%
Proportion failure (%)
0
Letrozole (L)
Tamoxifen (T)
Thürlimann B. St Gallen presentation 2005
BIG 1-98: deaths without recurrence(non-breast cancer deaths)
Total
CVA
thromboembolic
cardiac
other
Overall p value based on cumulative incidence
55
7
3
26
19
Letrozole(n=4003)
Tamoxifen(n=4007)
38
1
2
13
22
0.08
Patients
Adapted from Thürlimann B. St Gallen presentation 2005
In ATAC, the numbers of cardiovascular deaths are comparable
between anastrozole and tamoxifen (49 vs. 46, respectively)
ATAC: deathsMedian follow-up 68 months
All deaths
non-breast cancer deaths
cerebrovascular
cardiac
411
176
14
49
Anastrozole(n=3125)
Tamoxifen(n=3116)
420
155
21
46
Patients
A detailed review found that the non-breast cancer deaths in
the anastrozole arm were due to a variety of apparently unrelated
causes, with no link to anastrozole
ATAC Trialists’ Group. Lancet 2005 ;365:60-62ATAC Trialists’ Group. Lancet 2005 In Press
Comparison of safety between ATAC and BIG 1-98
LNS ???
A
NS
Endometrial cancerRisk of strokeVenous thromboembolic eventsCardiovascular deathsJoint symptomsFracturesHot flushesVaginal bleedingVaginal dischargeHysterectomy
Compared with tamoxifen
? – not reported
ATAC: tolerability and safety summary vs tamoxifen
Compared with tamoxifen, anastrozole is associated with significantly fewer:
– SAEs, treatment-related AEs and withdrawals due to SAEs or AEs
– potentially life-threatening AEs such as endometrial cancer, thromboembolic and cerebrovascular events
No new safety concerns have emerged with long-term follow-up. There is no issue with cardiovascular safety
Anastrozole now has a known, predictable and manageable safety profile
The ATAC Trialists’ Group. Lancet 2005; 365: 60-62; Howell A. Breast Cancer Res Treat 2004; 88 (Suppl 1): S7, abs 1
AEs = adverse events;SAEs = serious AEs
Only anastrozole has a tolerability profile of this robustness and maturity, as it covers more than
5-years’ follow-up
BIG 1-98: tolerability and safety summary vs tamoxifen
Serious safety concerns about letrozole have emerged in this first analysis
– increased incidence of stroke and cardiovascular events
– increase in number of cerebrovascular and cardiovascular deaths
No significant reduction in the incidence of endometrial cancer was observed
The long-term safety profile of letrozole is unknown at this stage
– cardiovascular effects of letrozole require further evaluation
BIG 1-98 has raised serious safety concerns for letrozoleat this early stage
Summary
Conclusions (1)
The ATAC completed treatment analysis extends and strengthens the evidence that 5 years of anastrozole is significantly more effective and better tolerated than 5 years of tamoxifen
The efficacy benefit continues to increase with time and extends beyond the completion of therapy
These data support using anastrozole as initial adjuvant therapy
The higher rates of recurrence, adverse events, and withdrawals from treatment with tamoxifen and the substantial benefit of
anastrozole over the first3 years justify the approach of offering the most effective
therapy at the earliest opportunity
Conclusions (2)
BIG 1-98 provides further evidence that tamoxifen should no longer be the standard of care for EBC
No overall efficacy benefits have emerged for letrozole in BIG 1-98 that have not already been demonstrated for anastrozole in the ATAC trial
There appear to be marked differences emerging in the safety of the aromatase inhibitors in the adjuvant setting
– women treated with letrozole have a greater risk of stroke and cardiac events
The ATAC completed treatment analysis demonstrates that the overall benefit:risk profile remains clearly and consistently in favour of anastrozole
Only anastrozole has established efficacy and safety with>5 years’ long-term follow-up data
Back-up slides
ATAC: patient characteristics Tamoxifen(n=3116)
Anastrozole(n=3125)
Mean age (years)
Receptor status (%)
positive
negative
unknown
Primary treatment (%)
mastectomy
radiotherapy
chemotherapy
64.1
83.7
8.3
8.0
47.8
63.3
22.3
64.1
83.4
8.7
7.9
47.3
62.5
20.8
ATAC Trialists’ Group. Lancet 2002; 359: 2131-39
BIG 1-98: patient characteristics
Tamoxifen(n=4007)
Letrozole(n=4003)
Median age (years)
Primary treatment (%)
chemotherapy
Surgery/RT group (%)
BC with RT
BC without RT
mastectomy with RT
mastectomy without RT
61.0
25.3
53.3
2.8
18.3
25.4
61.0
25.3
54.0
3.3
17.6
24.8
BC = breast conservation; RT = radiotherapy Adapted from Thürlimann B. St Gallen presentation 2005
ATAC: baseline disease characteristics
Primary tumour size (%)
T1 (2 cm)
Nodal status (%)
node-positive
node-negative
node-unknown
HR status (%)
ER+/PgR+
ER+/PgR-
ER+/PgR unknown
ER-/PgR+
63.9
34.9
60.0
5.0
61.8
14.4
5.3
2.0
62.9
33.6
61.5
4.9
61.1
13.8
5.8
2.4
Tamoxifen(n=3116)
Anastrozole(n=3125)
HR = hormone receptor; ER = oestrogen receptor; PgR = progesterone receptorATAC Trialists’ Group. Lancet 2002; 359: 2131-39
BIG 1-98: baseline disease characteristics
Tumour size 2 cm (%)
Nodal status (%)
node-positive
node-negative
unknown
HR status (%)
ER+/PgR+
ER+/PgR-
ER+/PgR unknown
ER-/PgR+
63.5
41.5
52.0
6.5
63.5
20.2
14.5
1.5
62.3
41.2
52.3
6.5
62.7
20.5
14.3
2.1
Tamoxifen(n=4007)
Letrozole(n=4003)
Adapted from Thürlimann B. St Gallen presentation 2005
ATAC vs BIG 1-98 demographics
Patients in the ATAC trial had an improved prognosis compared with patients in BIG 1-98
– fewer patients in ATAC had node positive disease
– fewer patients in ATAC had received prior radiotherapy
– fewer patients in ATAC had received prior chemotherapy
Definition of further ATAC endpoints
Time to recurrence (TTR)
– loco-regional recurrence (including ipsilateral new breast cancer) or new contralateral breast cancer
– distant recurrence or death due to breast cancer
Overall survival (OS)
– death (for any reason)
Time to breast cancer death (TTBCD)
– any death following a loco-regional (including ipsilateral new breast cancer) or distant recurrence
– breast cancer death
Definition of further BIG 1-98 endpoints Time to recurrence (TTR)
– breast cancer recurrence or new contralateral breast cancer (excluding non-breast cancer second primaries*)
– censoring for non-breast cancer deaths
Overall survival (OS)– death (for any reason)
DFS without second primary events– as DFS (excluding non-breast second primaries*)
Systemic disease-free survival (SDFS)†
– regional or distant recurrence (not including local and contralateral)
– non-breast second primaries
– non-breast cancer death
Thürlimann B et al. The Breast 2005;14; S3. Abstract S4
*allows comparison with ATAC†no ATAC equivalent
ATAC: efficacy analysis (ITT and HR +ve)
HR (A:T) and 95% CI
Disease-free survival
Time to recurrence
Time to distant recurrence
Overall survival
Time to breast cancer death
Contralateral breast cancer
0.2 0.4 0.6 0.8 1.0 1.2 1.5 2.0
ITT population
HR +ve populationAnastrozole (A) better Tamoxifen (T) better
ATAC Trialists’ Group. Lancet 2005;365:60-62
0.87
0.79
0.86
0.97
0.88
0.58
ITT HR+
0.83
0.74
0.84
0.97
0.87
0.47
ATAC: recurrence in ER+/PgR- patients
At risk:
A 451 435 417 400 390 347 124
T 429 412 375 353 327 276 96
Follow-up time (years)
0
5
10
15
20
25
0 1 2 3 4 5 6
Anastrozole (A)
Tamoxifen (T)
Patients (%)
ATAC: recurrence in ER+/PgR+ patients
Follow-up time (years)
0
5
10
15
20
25
0 1 2 3 4 5 6
Anastrozole (A)
Tamoxifen (T)
Patients (%)
At risk:
A 1930 1880 18201820 1755 1690 1505 641
T 1904 1849 1779 1716 1639 1459 597
ATAC: retrospective analysis ofHR subgroups
Anastrozole was more effective than tamoxifen in the overall HR+ group
The improvement with anastrozole in the ER+PgR+ subgroup was comparable to that for the HR+ group
There was even greater improvement with anastrozole in the ER+PgR- subgroup
The relative benefit for anastrozole over tamoxifen appears to be larger in patients with ER+PgR- tumours than in those with ER+PgR+ tumours, but prospective studies are needed to confirm this
Patient group HR+ ER+/PgR+ ER+/PgR-
Hazard ratio 0.79 0.84 0.43
BIG 1-98: DFS in ER/PgR* subgroups
Hazard Ratio (A:T) and 95% CI
ER+ PgR+ (n=5055)
ER+ PgR- (n=1631)
ER+ PgR unknown (n=1154)
0.5 0.75 1.0 1.33 2.0
Letrozole better Tamoxifen (T) better
*Based on local assessment Thürlimann B. St Gallen presentation 2005
Introduction to ‘best first’
The risk of recurrence is highest in the first five years after surgery, with a peak at 2 years
Patients deserve to receive the best treatment first in order to reduce the risk of breast cancer recurrence
When to treat?
Recurrence rates in early breast cancer are highest in the first 5 years after surgery, with a peak at 2 years, regardless of baseline prognostic factors
Tamoxifen is associated with higher rates of recurrence, AEs and withdrawals than anastrozole
Substantial benefit with anastrozole in the first 3 years justifies offering the most effective therapy at the earliest opportunity
Recurrence rate/year(%)
Year
0
2
4
6
8
10
12
14
16
0 1 2 3 4 5 6 7 8 9 10
Node (–)
Node (+)
Saphner et al JCO 1996; 14: 2738-2746
Most recurrences occur within the first 5 years of primary therapy
Need to give most effective treatment first
to reduce risk of recurrence
Annual risk of recurrence: ECOG data
0
5
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
Hazard of recurrence by yearly interval (%)
Time (years)
Total
Positive nodes (0)
Positive nodes (>4)
Postmenopausal
Premenopausal
ER +ve
ER -ve
Tumour size (>3 cm)
Tumour size (<1 cm)
ECOG = Eastern Cooperative Oncology Group Saphner T et al. J Clin Oncol 1996;14:2738-2746
Timing of recurrence in the first10 years post-diagnosis
Adapted from EBCTCG meta–analysis
EBCTCG, Lancet 1998; 351; 1451-1467
80
62% 61%Node +ve
Node -ve
38%
0-5 years 5-10 years
39%
60
40
20
0
Proportion of recurrence (%)
ATAC: smoothed hazard rates for recurrence (HR-positive population)
0 1 2 3 4 5 6Follow-up time (years)
Annualhazardrates(%)
Anastrozole
Tamoxifen 0.5
1.0
1.5
2.0
2.5
3.0
0
Patients deserve the best treatment first
Recurrence rates in early breast cancer are highest in the first 5 years after surgery, with a peak at2 years, for all patients (irrespective of risk)
Anastrozole demonstrated substantial benefits over tamoxifen throughout the entire 5-year follow-up period in the ATAC trial, regardless of baseline prognostic factors
– the peak of recurrences at years’ 1-3 is suppressed by anastrozole
All patients deserve the best treatment available at the earliest opportunity in order to reduce the risk of recurrence