trial comparison: ‘arimidex’, tamoxifen, alone or in combination (atac) and breast international...

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


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


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)


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)


0

5

10

15

20

25Patients(%)


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: efficacy analysis (ITT and HR +ve)

HR (A:T) and 95% CI


Time to recurrence


Overall survival



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


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 recurrence

BIG 1-98: efficacy summary


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


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


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


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


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*


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


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


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%)


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)


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


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


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)


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)


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


Time to recurrence


Overall survival



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


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

trial comparison: ‘arimidex’, tamoxifen, alone or in combination (atac) and breast international...

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recurrence nonbreast

breast cancer recurrence

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breast international

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dcisdistant recurrence

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