Changes in Cognitive Function in Postmenopausal Women 1 Year after Completing Adjuvant Letrozole or Tamoxifen in the Breast International Group (BIG 1-98) Trial

Karin Ribi, Julie Aldridge, Kelly Anne Phillips, Zhuoxin Sun, Alastair Thompson, Vernon Harvey, Beat Thürlimann, Fatima Cardoso, Alan S. Coates, and Jürg Bernhard

Background

■Cognitive dysfunction is recognized as a potential long-term side-effect of adjuvant endocrine therapy for breast cancer treatment (Phillips et al. 2010; Schilder et al. 2010).

■Existing studies either report about changes in cognitive function during adjuvant endocrine therapy, or compared breast cancer survivors to healthy controls.

■No data is available about changes in cognitive function from on- to off-treatment in patients receiving endocrine treatment.

Objectives

■To evaluate if there is improvement in cognitive function one year after cessation of adjuvant Tamoxifen (TAM), Letrozole (LET) or a sequential combination of these.

Study design BIG 1-98 (NEJM, 2005)

Cognitive function and psychosocial assessment

Cognitive function and psychosocial assessment

AA

LetrozoleLetrozoleBB

TamoxifenTamoxifenCC LetrozoleLetrozole

DD LetrozoleLetrozole TamoxifenTamoxifen

Surg

ery

Ran

dom

izati

on

TamoxifenTamoxifen

1 2 3 4 5 6Year

Str

ati

fy Institution Adjuvant CT- prior- none- concurrent

T1 T2

Eligibility criteria

■Enrolled in an institution with at least 10 patients recruited to parent protocol

■Within the fifth year of trial treatment (T1) still taking assigned endocrine treatment

■Off-trial treatment at year six (T2; i.e. women who continued on off-protocol endocrine treatment, extended letrozole, were excluded)

■Without breast cancer recurrence or second malignancy

■Give written informed consent

Cognitive function

Cognitive function was evaluated by a computerized series of cognitive tests (CogState Ltd) measuring 7 domains.

Accrual

■11 institutions in Australia, New Zealand and Europe participated in the substudy

■135 patients were enrolled between 04/2005 and 05/2008

■35 patients were excluded from the analysis of change between year 5 and 6:■ treatment completed prior to assessment year 5 N=9

■ late crossover from tamoxifen to letrozole N=1

■ extended letrozole N=13

■ incomplete data N=6

■ patient refusal N=5

■ patient death N=1

■100 patients were eligible for this analysis

Final sample size

Surg

ery

Year

AA

LetrozoleLetrozoleBB

TamoxifenTamoxifenCC LetrozoleLetrozole

DD LetrozoleLetrozole TamoxifenTamoxifen

Ran

dom

izati

on

TamoxifenTamoxifen

1 2 3 4

N=14

N=32

N=25

N=29

N=100

5

Cognitive function and psychosocial assessment

Cognitive function and psychosocial assessment

6

T2 T1

Statistical considerations

■Primary endpoint: composite score, calculated from all 7 tasks. Scores were standardized according to age-specific norms (z scores).

■ Improvement in cognitive function from T1 to T2 was tested by Wilcoxon signed-rank test.

■Difference in change in cognitive function from T1 to T2 between patients taking TAM (A and D) versus patients taking LET (B and C) for the last 3 of 5 years of the trial, were tested by 2-way ANOVA.

Resultspatient and disease characteristics

Resultsmean changes in cognitive function from T1 to T2

1mean difference between T1 and T2 measurements divided by the standard deviation of the difference

Resultscomparisons of mean changes between treatment groups

Resultsproportion of patients with impaired1 scores

1 z scores 1.96 SD below age-specific norms

Limitations

■Practice effects were not assessed due to lack of an untreated control group in BIG 198, but CogState is known to be free from practice effect.

■Due to the lack of a baseline assessment before starting endocrine treatment, it‘s not known how cognitive function at T2 compares with cognitive function before initiation of endocrine treatment.

Conclusions

■In postmenopausal women with hormone-responsive breast cancer who receive 5 years of endocrine treatment of TAM, LET or a sequential combination, cognitive function was significantly better one year after completing endocrine treatment than during the fifth year of treatment.

■This information provides some reassurance for post-menopausal women currently taking these adjuvant endocrine therapies.