Trial Comparison: ‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) and Breast International Group (BIG) 1-98

Trial design and patient recruitment

640 2222 Belgium 192 Czech Republic 84 France 366 Germany 121 Hungary 243 Ireland 41 Italy 654 Netherlands 195 Poland 107 Portugal 74 Slovakia 33 Spain 417 Sweden 291 Turkey 53 UK 3228 30

ATAC trial:

160 201 14

9366 patients recruited from 381 centres in 21 countries

ATAC trial design

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

• •

Primary trial endpoints: Disease-free survival Safety / tolerability Tamoxifen n=3116 Combination n=3125 tolerability benefit compared with tamoxifen arm Regular follow-up

• • • •

Secondary trial endpoints: Incidence of contralateral breast cancer Time to distant recurrence Overall survival Time to breast cancer death

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

BIG 1-98 trial design

8028 postmenopausal women with ER+ disease Median age 61 years 52% node negative 63% tumour



2 cm in diameter O M I S R A N D Letrozole Tamoxifen Tamoxifen Letrozole Letrozole Tamoxifen Arm A B C D E 0 1 2 3 Time (years) 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 Group ER+ = estrogen receptor-positive 4 5

Adapted from Thürlimann B. St Gallen presentation 2005

ATAC: 73% of patients have been followed-up for 5 years or more

Patients (%) 80 70 Updated analysis (median follow-up 47 months) Treatment completion analysis (median follow-up 68 months) 60 50 40 30 20 10 0 <1 1 –<2 2 –<3 3 –<4 4 –<5 Duration of follow-up (years) Total number of DFS events (monotherapy arms) 1226 >5 DFS = disease-free survival

BIG 1-98: only 15% of patients have been followed-up for 5 years

99 99 Patients (%) 100 Overall (median follow-up 35.5 months) Primary core (median follow-up 25.8 months) 77 76 80 60 40 20 46 33 28 24 15 15 0



1



2



3



4



5 Follow-up (years)

Thürlimann B. St Gallen presentation 2005

Demographics

Age (years)

Patient characteristics

ATAC (n=6291) Mean 64.1

BIG 1-98 (n=8010) Median 61.0 Primary treatment (%) mastectomy radiotherapy chemotherapy 47.6

62.9

21.6

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+ ATAC (n=6291) 63.4

34.2

60.7

5.0

61.5

14.1

5.5

2.2

BIG 1-98 (n=8010) 62.9

41.3

52.2

6.5

63.1

20.4

14.4

1.8

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 situ

ATAC Trialists’ Group. Lancet 2002; 359: 2131-39 Th ürlimann B et al. The Breast 2005;14; S3. Abstract S4

Definition of time to distant recurrence 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 *excluding second primary events

ATAC Trialists’ Group. Lancet 2005; 365: 60-62 Th ürlimann B et al. The Breast 2005;14; S3. Abstract S4

Patients (%) 25 20 ATAC: disease-free survival (HR-positive population) A vs T HR 0.83

95% CI (0.73, 0.94) p value 0.005

15 Anastrozole (A) Tamoxifen (T) 10 5 0 0 At risk: A T 2618 2598 CI, confidence interval 1 Absolute difference: 1.6% 2540 2516 2.6% 2 3 4 Follow-up time (years) 2448 2398 2355 2304 2268 2189 2.5% 5 2014 1932 3.3% 6 830 774

Howell A. SABCS presentation 2004

Yearly DFS %

BIG 1-98: disease-free survival

L 97.7

95.1

90.5

86.8

84.0

T 97.6

93.4

89.0

84.6

81.4

25 20 15 10 5 0 0 HR L vs T 0.81

N=8010 1 95% CI (0.70, 0.93) 2 3 p value 0.003

4 Letrozole Tamoxifen 5 At risk: L 4003 T 4007 3892 3896 Follow-up time (years) 2964 1261 892 567 2926 1238 866 544

Adapted from Thürlimann B. St Gallen presentation 2005

Patients (%) 25 20 15 10 5 0 0 At risk: A T 2618 2598 ATAC: recurrence (HR-positive population) HR 95% CI p value A vs T 0.74

(0.64, 0.87) 0.0002

Anastrozole (A) Tamoxifen (T) 1 Absolute difference: 1.7% 2540 2516 2.4% 2 3 4 Follow-up time (years) 2448 2398 2355 2304 2268 2189 2.8% 5 2014 1932 3.7% 6 830 774

ATAC Trialists’ Group. Lancet 2005;365:60-62

BIG 1-98: breast cancer relapse

(Time to recurrence) Cumulative incidence Proportion failure (%) 20 15 5-year difference (L-T) = -3.4



1.2% p=0.0002 (based on CI) 13.6% 10 Letrozole (L) Tamoxifen (T) 8.1% 10.2% 5 6.2% 0 0 1 2 3 Years from randomisation 4 5

Thürlimann B. St Gallen presentation 2005

Patients 25 (%) ATAC: time to distant recurrence (HR-positive population) HR 95% CI p value A vs T 0.84

(0.70, 1.00) 0.06

20 15 Anastrozole (A) Tamoxifen (T) 10 5 0 0 At risk: A T 2618 2598 1 2550 2533 2 3 4 Follow-up time (years) 2464 2438 2386 2361 2309 2251 5 2051 2005 6 845 816

Howell A. SABCS presentation 2004

Patients 25 (%) 20 15 10 5 0 0 At risk: A T 2618 2598 ATAC: overall survival (HR-positive population) HR 95% CI p value A vs T 0.97

(0.83, 1.14) 0.7

Anastrozole (A) Tamoxifen (T) 1 2566 2549 2 3 4 Follow-up time (years) 2505 2502 2437 2430 2377 2333 5 2117 2080 6 867 855

Howell A. SABCS presentation 2004

ATAC: efficacy summary

(HR-positive population) Disease-free survival Hazard ratio 0.83

Time to recurrence Time to distant recurrence Overall survival Time to breast cancer death 0.74

0.84

0.97

0.87

Contralateral breast cancer 0.2

0.47

0.4

0.6

0.8 1.0 1.2 1.5

Hazard ratio (A:T) and 95% CI 2.0

Anastrozole (A) better Tamoxifen (T) better

ATAC Trialists’ Group. Lancet 2005;365:60-62

ATAC: efficacy analysis (ITT and HR +ve)

ITT HR+ Disease-free survival 0.87

0.83

Time to recurrence 0.79

0.74

Time to distant recurrence 0.86

0.84

Overall survival 0.97

0.97

Time to breast cancer death 0.88

0.87

Contralateral breast cancer 0.58 0.47

ITT population HR +ve population 0.2

0.4

0.6

0.8 1.0 1.2 1.5

HR (A:T) and 95% CI 2.0

Anastrozole (A) better Tamoxifen (T) better

ATAC Trialists’ Group. Lancet 2005;365:60-62

BIG 1-98: efficacy summary

Hazard ratio BIG 1-98 ATAC Disease-free survival 0.81

Time to recurrence 0.72

0.74

Time to distant recurrence Overall survival 0.73

0.86

0.84

0.97

Systemic disease-free survival 0.83

Disease-free survival (without 2nd primary) 0.2

0.79

0.83

0.4

0.6

0.8 1.0 1.2 1.5

Hazard ratio (L:T) and 95% CI 2.0

Letrozole (L) better Tamoxifen (T) better

Adapted from Thürlimann B. St Gallen presentation 2005

BIG 1-98: sites of first failure

Letrozole (%) Tamoxifen (%) p value 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

*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

Nodal status +ve -ve Tumour size ≤ 2 cm >2 cm Receptor status +ve -ve Previous chemotherapy All patients yes no Intent-to-treat population Hazard ratio (A:T) and 95% CI 0.40

0.60

0.80

1.00

1.25

1.50 1.75

Anastrozole (A) better Tamoxifen (T) better

Howell A. SABCS presentation 2004

BIG 1-98: disease-free survival by subgroup Nodal status +ve -ve Previous chemotherapy yes no Previous radiotherapy yes no All patients Intent-to-treat population Hazard ratio (L:T) and 95% CI 0.40

0.60

0.80

1.00

1.25

1.50 1.75

Letrozole (L) better Tamoxifen (T) better

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*

Anastrozole (%) (n=3092) Tamoxifen (%) (n=3094) p value 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 93.9

11.1

6.5

33.3

4.7

3.3

0.2

94.6

14.3

8.9

36.0

5.9

3.6

0.3

0.2

0.0002

0.0005

0.03

0.04

0.6

0.5

*Adverse events on treatment or within 14 days of discontinuation

Howell A. SABCS presentation 2004

ATAC: pre-defined adverse events*

Hot flushes Vaginal bleeding Vaginal discharge Endometrial cancer** Ischaemic cerebrovascular event Venous thromboembolic events Deep venous thromboembolic events Joint symptoms Total fractures*** Completion analysis (%) A 35.7

5.4

3.5

0.2

2.0

T 40.9

10.2

13.2

0.8

2.8

p value <0.0001

<0.0001

<0.0001

0.02

0.03

2.8

1.6

35.6

11.0

4.5

2.4

29.4

7.7

0.0004

0.02

<0.0001

<0.0001

*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 Trialists’ Group. Lancet 2005;365:60-62

BIG 1-98: targeted adverse events

Hot flushes Vaginal bleeding Night sweats Nausea Thromboembolic events Vomiting CVA/TIA Other cardiovascular Bone fracture Hypercholesterolemia Primary core analysis (%) L 33.6

3.3

14 8.8 1.0

2.7

1.2 8.7

5.8

43.6

T 38.1

6.6

16.2 9.5 2.4

2.6

1.1

8.3

4.1

19.2

No arthralgia/joint symptoms or osteoporosis data are available from BIG 1-98 Endometrial cancer shows no significant difference between L and T

Adapted from Thürlimann B. St Gallen presentation 2005

ATAC vs BIG 1-98 : bone fractures

Patients Patients with bone fracture Odds ratio, p value ATAC (A vs T) 340 vs 237 (11.0% vs 7.7%) 1.49, p<0.0001

Bone fracture rate 2.2 vs 1.5 (per 100 patient years) BIG 1-98 (L vs T ) 228 vs 162 (5.8% vs 4.1%) 1.44, p=0.0006

2.3 vs 1.6 (per 100 patient years)

Adapted from ATAC Trialists’ Group. Lancet 2005;365:60-62 ; Thürlimann B. St Gallen presentation 2005

ATAC: fracture risk is predictable and manageable

Annual rates, %* 3 2.5

2 1.5

1 0.5

0 0 Number at risk Years Arimidex Tamoxifen 0 3092 3094 Anastrozole 1 mg od Tamoxifen 20 mg od 1 1 2923 2932 2 3 4 Years since randomisation 2 2724 2741 3 2553 2579 4 2393 2401 5 5 2070 2100 6 6 845 846 *Calculated using Kaplan-Meier estimates

Howell A. SABCS presentation 2004

ATAC vs BIG 1-98 : endometrial cancer

Patients Patients with endometrial cancer Odds ratio, p value ATAC (A vs T) 5 vs 17 (0.2% vs 0.8%) 0.29, p=0.02

BIG 1-98 (L vs T ) 6 vs 15 (0.2% vs 0.4%) 0.40, p=0.078

Adapted from ATAC Trialists’ Group. Lancet 2005;365:60-62 ; Thürlimann B. St Gallen presentation 2005

BIG 1-98: Grade 3-5 cardiovascular events

Patients CVA/TIA Thromboembolic Other cardiovascular Letrozole (n=3965) 46 (1.2%) 30 (0.8%) 143 (3.6%) Tamoxifen (n=3984) 42 (1.1%) 79 (2.0%) 101 (2.5%) There is a significantly higher number of other cardiovascular events on letrozole compared with tamoxifen (p=0.006)

Thürlimann B. St Gallen presentation 2005

BIG 1-98: death without recurrence

Cumulative incidence Proportion failure (%) 20 15 5-year difference (L-T) = 1.3



0.6% p=0.08 (based on CI) 10 5 0 0 Letrozole (L) Tamoxifen (T) 3.1% 1.4% 1 2 3 0.8% Years from randomisation 4 5 1.8%

Thürlimann B. St Gallen presentation 2005

BIG 1-98: deaths without recurrence (non-breast cancer deaths)

Patients Letrozole (n=4003) Tamoxifen (n=4007) Total CVA thromboembolic 55 7 3 cardiac other 26 19 Overall p value based on cumulative incidence 0.08

38 1 2 13 22 In ATAC, the numbers of cardiovascular deaths are comparable between anastrozole and tamoxifen (49 vs. 46, respectively)

Adapted from Thürlimann B. St Gallen presentation 2005

ATAC: deaths Median follow-up 68 months

Patients Anastrozole (n=3125) Tamoxifen (n=3116) All deaths non-breast cancer deaths cerebrovascular cardiac 411 176 14 49 420 155 21 46 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 ;365:60-62 ATAC Trialists’ Group. Lancet 2005 In Press

Comparison of safety between ATAC and BIG 1-98

Endometrial cancer Risk of stroke Venous thromboembolic events Cardiovascular deaths Joint symptoms Fractures Hot flushes Vaginal bleeding Vaginal discharge Hysterectomy ? – not reported

Compared with tamoxifen

A

 

L NS

 

NS

       

?

  

?

?

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

Only anastrozole has a tolerability profile of this robustness and maturity, as it covers more than 5 years’ follow-up

AEs = adverse events

;

SAEs = serious AEs

The ATAC Trialists’ Group. Lancet 2005; 365: 60-62; Howell A. Breast Cancer Res Treat 2004; 88 (Suppl 1): S7, abs 1

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 letrozole at 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 first 3 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

Mean age (years) Anastrozole (n=3125) 64.1

Tamoxifen (n=3116) 64.1

Receptor status (%) positive negative unknown Primary treatment (%) mastectomy radiotherapy chemotherapy 83.7

8.3

8.0

47.8

63.3

22.3

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

Median age (years) Primary treatment (%) chemotherapy Surgery/RT group (%) BC with RT BC without RT mastectomy with RT mastectomy without RT Letrozole (n=4003) 61.0

25.3

53.3

2.8

18.3

25.4

Tamoxifen (n=4007) 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

Anastrozole (n=3125) Tamoxifen (n=3116) 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

HR = hormone receptor; ER = oestrogen receptor; PgR = progesterone receptor

ATAC Trialists’ Group. Lancet 2002; 359: 2131-39

BIG 1-98: baseline disease characteristics Tumour size



2 cm (%) Letrozole (n=4003) 63.5

Tamoxifen (n=4007) 62.3

Nodal status (%) node-positive node-negative unknown HR status (%) ER+/PgR+ ER+/PgR ER+/PgR unknown ER-/PgR+ 41.5

52.0

6.5

41.2

52.3

6.5

63.5

20.2

14.5

1.5

62.7

20.5

14.3

2.1

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 *allows comparison with ATAC † no ATAC equivalent

Th ürlimann B et al. The Breast 2005;14; S3. Abstract S4

ATAC: efficacy analysis (ITT and HR +ve)

ITT HR+ Disease-free survival 0.87

0.83

Time to recurrence 0.79

0.74

Time to distant recurrence 0.86

0.84

Overall survival 0.97

0.97

Time to breast cancer death 0.88

0.87

Contralateral breast cancer 0.58 0.47

ITT population HR +ve population 0.2

0.4

0.6

0.8 1.0 1.2 1.5

HR (A:T) and 95% CI 2.0

Anastrozole (A) better Tamoxifen (T) better

ATAC Trialists’ Group. Lancet 2005;365:60-62

ATAC: recurrence in ER+/PgR- patients

Patients (%) 25 Anastrozole (A) Tamoxifen (T) 20 15 10 5 0 0 At risk: A T 451 429 1 435 412 2 3 4 Follow-up time (years) 417 375 400 353 390 327 5 347 276 6 124 96

ATAC: recurrence in ER+/PgR+ patients

Patients (%) 25 20 Anastrozole (A) Tamoxifen (T) 15 10 5 0 0 At risk: A T 1930 1904 1 1880 1849 2 3 Follow-up time (years) 4 1820 1779 1755 1716 1690 1639 5 1505 1459 6 641 597

ATAC: retrospective analysis of HR subgroups



Anastrozole was more effective than tamoxifen in the overall HR+ group

 

There was even greater improvement with anastrozole in the ER+PgR- subgroup



The improvement with anastrozole in the ER+PgR+ subgroup was comparable to that for the HR+ group 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

ER+ PgR+ (n=5055) ER+ PgR- (n=1631) ER+ PgR unknown (n=1154) *Based on local assessment 0.5

0.75

1.0

1.33

Hazard Ratio (A:T) and 95% CI 2.0

Letrozole better Tamoxifen (T) better

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

Most recurrences occur within the first 5 years of primary therapy

Recurrence 16 rate/year (%) 14 Node (–) Node (+) 12 Need to give most effective treatment first to reduce risk of recurrence 10 8 6 4 2 0 0 1 2 3 4 5 Year 6 7 8 9 10

Saphner et al JCO 1996; 14: 2738-2746

Annual risk of recurrence: ECOG data

Total Hazard of 25 recurrence by yearly 20 interval (%) 15 Positive nodes (0) Positive nodes (>4) Tumour size (<1 cm) Tumour size (>3 cm) ER -ve ER +ve Premenopausal Postmenopausal 10 5 0 0.5

1.5

2.5

3.5

ECOG = Eastern Cooperative Oncology Group 4.5

5.5

6.5

Time (years) 7.5

8.5

9.5

10.5

Saphner T et al. J Clin Oncol 1996;14:2738-2746

Timing of recurrence in the first 10 years post-diagnosis Adapted from EBCTCG meta –analysis Proportion of recurrence (%) 80 60 40 20 0 62% 61% 0-5 years Node +ve Node -ve 38% 39% 5-10 years

EBCTCG, Lancet 1998; 351; 1451-1467

ATAC: smoothed hazard rates for recurrence (

HR-positive population

)

Annual hazard rates (%) 3.0

2.5

2.0

1.5

1.0

0.5

0 0 1 2 3 4 Follow-up time (years) Anastrozole Tamoxifen 5 6

Patients deserve the best treatment first



Recurrence rates in early breast cancer are highest in the first 5 years after surgery, with a peak at 2 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