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however they have not been able to demonstrate an impact on

overall survival.1620 A meta-analysis by Jonat and Gnant included

three trials that compared sequenced therapy with anastrozole

following two to three years of tamoxifen, versus tamoxifen on its

own.21 Disease free survival was significantly prolonged in favour of

sequenced therapy (HR 0.59 [95% CI 0.480.78] p < 0.0001). There

was evidence of prolonged overall survival (HR 0.71, [0.520.98]

p 0.0377). Their methodology had some limitations; no more

than two databases were searched (PubMedandClinicalTrials.gov)

and no discussion of potential conflict of interest despite funding

from the pharmaceutical industry. The addition of newstudies such

as BIG 1-98 trial and ABCSG 8, and updates of previous trials, such

as the IE study, adds to the call for a new review that includes the

three types of AIs.16,18,22 This review will not only look at the role of

AIs as sequenced therapy, but also as monotherapy and extended

therapy. Patient groups have highlighted the importance of quality

of life (QoL) in the choice of hormonal therapy.1 RCTs on QoL were

therefore actively sought.

The results from the RCTs have led to changes in the British and

American guidelines, which now recommend clinicians to consider

AIs in specific patients.1,23 However, many questions still remain on

the optimal therapy regime. A review that studies all three treat-

ments regimes andincludes quality of life as an outcome measure isneeded to provide clinicians and patients with more information

when choosing adjuvant therapy. The aim was therefore to

systematically review all currently available evidence from rando-

mised controlled trials on the optimal hormonal adjuvant therapy

regime for post-menopausal women with oestrogen sensitive early

breast cancer.

Materials and methods

Study selection

All RCTs that compare the following treatment regimes; direct

comparison between tamoxifen versus an AI, sequenced therapy,

and extended therapy (AI versus placebo or no treatment followingadjuvant treatment), was searched for. Any types of AIs in standard

dosages wereaccepted. Participants had to be post-menopausal and

have undergone surgery for oestrogen sensitive early breast cancer.

Outcomes

The primary outcome measures were overall survival (OS)

(including death from any cause), disease free survival (DFS)

(defined as time to recurrence at any site, contra-lateral breast

cancer or death from any cause) and QoL. Trials containing data on

at least one of the primary outcomes were included. Secondary

outcomes were event-free survival (defined as time to recurrence

at any site), distant-recurrence-free survival, number of drop-outs,

adverse events and other outcomes, which were not pre-specifiedbut were considered important in the trial.

Search methods

The databases Cochrane Central Register of Controlled Trials

(CENTER), MEDLINE(R) and EMBASE (via OVID), in addition to

reference and abstract lists, were searched in February 2009. No

language restrictions were used. The Clinical Trial Register (http://

www.clinicaltrial.gov) was searched to identify additional unpub-

lished trials. The following free text search terms were used; breast

cancer, breast neoplasm, breast carcinoma, breast tumour, breast

tumor, tamoxifen, nolvadex, aromatase inhibitor, anastrozole, ari-

midex, letrozole, exemestane, aromasin and femara. MeSH terms

included aromatase inhibitors, tamoxifen and breast neoplasm. The

investigator reviewed each title to identify clearly irrelevant

studies. A pre-specified Inclusion/Exclusion form was used to

identify eligible studies. The inclusion requirements were the

following: RCT, female subjects, oestrogen sensitive tumours,

confirmed post-menopausal status and early stage cancer. The full

text was obtained if a paper could not be rejected by evaluation of

the title or abstract alone. The computer software EndNote was

used to manage references. Any duplicates were excluded by

comparing authors, location, participants and dates. The latest

report was used in case trials had been reported more than once.

Quality assessment

Internal validity was assessed by using a risk of biases table in

the data extraction form. The questions were adopted from The

Cochrane Collaborations tool for assessing risk of the following

biases; selection, performance, detection, reporting and attrition.24

Data extraction

Data extractionwas carried out by MLJ using a standardised data

extraction form, and validated by the second reviewer SJL. The data

extraction form was piloted on a few studies and revised accord-

ingly. Data from multiple papers of the same trial was recorded on

a single data extraction sheet. Details of study design, risk of bias

assessment, participants, and data on outcomes was collected. The

author was contacted in case of missing information. No outcome

was obtained by reading curves. Definitions of post-menopausal

status were included as arbitrary use between trials has been

reported.25

Data analysis

Meta-analyses were undertaken in the Review Manager Soft-

ware (version 5.0) and based on the intention-to-treat principle.

Hazard ratios for survival outcomes, and relative risks for adverse

events, were calculated with 95% confidence interval for eachsubgroup. The random effect model was used in the meta-analyses

to take into account the variability that exists between patients.

Heterogeneity was assessed with the MantelHaentszel Chi-square

test andI2 test. Allp-values are two-sided.

Results

Description of included studies

Our search identified 836 references (see Fig. 1), of which 677

could be excluded from screening the title alone or because they

were duplicates. The abstracts, or the paper if required, of 159

potential RCTs were evaluated further. 132 were excluded because

they did not fulfil the requirements in the inclusion/exclusion form.

Fig. 1. Flow chart of the process of inclusion of trials for review.

M.L. Josefsson, S.J. Leinster / The Breast 19 (2010) 7683 77
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Two ongoing studies (TEAM and NSABP B-42) were excluded prior

to the analysis as no data was yet available.26,27 The ABCSG trial 6

was excluded as it studied aminoglutethimide in combination with

tamoxifen.28 The Italian co-operative trial, which explored amino-

glutethimide as sequenced therapy, failed to recruit the planned

number of participants and was excluded due to lack of outcome

data.29 Nine trials of 28 632 patients in total were included in this

review. SeeTable 1for trial characteristics. The included trials are

divided into three subgroups depending on their treatment regime;

monotherapy (AI vs. tamoxifen), sequenced therapy (tamoxifen

switched to an AI vs. tamoxifen on its own) and extended therapy

(extended AI treatment following adjuvant therapy for 5 years vs.

placebo or no treatment). Two studies, ATAC (ISRCTN18233230)

and BIG 1-98 (NCT00004205), report data on AI as mono-

therapy.18,3038 BIG 1-98 consisted of four arms (letrozole mono-

therapy, tamoxifen monotherapy, sequential tamoxifen followed by

letrozole, and sequential letrozole followed by tamoxifen). Results

from the monotherapy subgroup only areincludedin this review, as

the sequential arms are compared with letrozole, rather than

tamoxifen.38 Four trials were identified for sequenced therapy;

ABCSG trial 8 (NCT00291759), ARNO-95 (NCT00287534), IE study

(ISRCTN11883920) and ITA (NCT00286117).16,22,39-42Three RCTs on

extended therapy were identified; MA.17 (NCT00003140), NSABPB-33 and ABCSG trial 6a (NCT00300508).20,43-45 Four studies

included QoL as outcome measures (NSABP B-33, and substudies of

the ATAC trial, the IE study and MA.17).45,46-48 The latest reports on

adverse events in the included trials were used for the safety

analyses.

Methodological quality

The following studies were assessed as of high quality; the ATAC

trial,BIG 1-98, IE studyand MA.17. ABCSG6a, ARNO-95 andITAwere

open-labelled and of weaker methodological quality. NSABP B-33

was transformed from a blinded trial into an open-labelled study

when it wasstoppedprematurely. The methodological quality of the

ABCSG 8 could not be assessed, as it is yet unpublished.

Monotherapy

The ATAC trial compared anastrozole and tamoxifen for five

years and the results after 100 months are included in this review.

They initially included a trial arm of combined anastrozole and

tamoxifen, which was stopped prematurely as no efficacy benefit

could be demonstrated. The BIG 1-98 trial compared letrozole and

tamoxifen for five years. Pooled data from the two trials demon-

strated a statistical significant benefit in DFS in favour of AI treat-

ment for five years compared with tamoxifen (HR 0.89, [0.830.96]

p 0.002) (seeFig. 2). No difference was seen in overall survival

(HR 0.94, [0.821.08]p 0.39) (seeFig. 3).

Sequenced therapy

The IE Study compared sequenced therapy with tamoxifen

followed by exemestane for five years in total, versus tamoxifen

on its own. There was a high number of drop-outs in both

intervention and control groups (1012/2372 and 1026/2352

respectively). The ITA study and ARNO-95 both examined

sequenced therapy with tamoxifen followed by anastrozole

compared with tamoxifen alone for five years. When their data

on DFS was pooled together there was a statistical significant

benefit seen in patients on sequenced therapy (HR 0.72,

[0.630.83] p < 0.00001) (see Fig. 2). Sequenced therapy with

tamoxifen and anastrozole was also studied in ABCSG trial 8.

Their data is not yet published; however it was presented at theSan Antonio conference in December 2008. Relapse free survival

(RFS) is their main outcome, which is different to DFS in that it

does not include death. Their unpublished data suggest a benefit

in RFS for sequenced therapy (HR 0.79, [0.650.95] p 0.038).

Meta-analysis of OS for the three published trials showed a weak

statistically significant benefit in favour of the switching regime

(HR 0.72 [0.521.00] p 0.05) (figure provided in online mate-

rial). A statistically more robust result (HR for OS 0.78,

[0.680.91] p 0.001), in favour of sequenced therapy, could be

seen when data from ABCSG 8 was included in the meta-analysis

(seeFig. 3).

Extended therapy

The trial ABCSG 6a, continuing on from ABCSG 6, compared

anastrozole versus no further treatment, following five years of

adjuvant therapy. There was a large number of drop-outs in both

intervention and control groups (128/386 and 109/466 respec-

tively). Their main outcome was RFS, similarly to ABCSG 8. Patients

Table 1

Characteristics of included studies. Yrs years, ATAC Arimidex, Tamoxifen, Alone or in Combination, BIG 1-98 The Breast International Group 1-98, ABCSG 8 Austrian

Breast and Colorectal Cancer Study Group trial 8. ARNO-95 Arimidex-Nolvadex trial 95, ITA Italian tamoxifen anastrozole trial, IE study Intergroup Exemestane Study,

ABCSG 6a Austrian Breast and Colorectal Cancer Study Group trial 6a, NSABP B-33 National Surgical Adjuvant Breast and Bowel Project B-33 Trial.

Intervention regime Control Follow-up

(months)

Study

sample

Age Node-positive Node-negative

Monotherapy

ATAC Anastrozole 5 yrs Tamoxifen 5 yrs 100 6241 64.1 34.0% 50.0%

BIG 1-98 Letrozole 5 yrs Tamoxifen 5 yrs 76 4922 61 57.3% 41.3%Total 11163

Sequenced therapy

ABCSG 8 Tamoxifen 2 yrs/anastrozole 3 yrs Tamoxifen 5 yrs 72 3714 33.5% < 60 25.4% 74.6%

66.5% 60

ARNO-95 Tamoxifen 2 yrs/anastrozole 3 yrs TamoxIfen 5 yrs 30.1 979 60.7 26.5% 73.5%

IE Study Tamoxifen 23 yrs /exemestane 23 yrs Tamoxifen 5 yrs 55.7 4724 60.3 44.2% 51.8%

ITA Tamoxifen 23 yrs/anastrozole 23 yrs Tamoxifen 5 yrs 64 448 63 >99%


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on extended therapy were seen to survive longer without any loco-

regional recurrences, contra-lateral breast cancer or distant

metastasis (HR 0.62 [0.400.96] p 0.31). No data on DFS was

reported. The MA.17 trial compared letrozole versus placebo as

extended therapy. Their findings suggested a benefit in DFS for

extended letrozole therapy (HR 0.68, [0.550.83] p 0.0001).

Meta-analysis of data from MA.17 and ABCSG 6a showed no

difference in OS between extended therapy and placebo or no

treatment (HR 0.85 [0.651.11]p 0.24) (seeFig. 3). The placebo-

controlled trial NSABP B-33 studied exemestane as extended

therapy. It was stopped early due to efficiency benefits seen in

MA.17. Patients were unblinded and the control group was

permitted to switch to exemestane. The results, based on the ITT

population prior to unblinding, did not demonstrate any statisti-

cally significant improvement in four-year DFS (HR 0.68,p 0.07,

95%CI not stated). Conclusions on OS could not be drawn because of

too few deaths, and their results are therefore not included in the

meta-analysis.

Study or Subgroup

2.1.1 Monotherapy

BIG 1-98

ATAC

Subtotal (95% CI)

Heterogeneity: Tau = 0.00; Chi = 2.04, df = 1 (P = 0.15); I = 51%

Test for overall effect: Z = 0.85 (P = 0.39)

2.1.2 Sequenced therapy

ARNO-95

ITA

ABSCG trial 8

IE study

Subtotal (95% CI)

Heterogeneity: Tau = 0.00; Chi = 3.24, df = 3 (P = 0.36); I = 7%Test for overall effect: Z = 3.25 (P = 0.001)

2.1.3 Extended therapy

MA.17

ABCSG trial 6a

Subtotal (95% CI)



log[Hazard Ratio]

-0.1393

0

-0.6349

-0.5798

-0.2614

-0.1625

-0.1985

-0.1165

SE

0.0795

0.0567

0.3124

0.3598

0.1155

0.0912

0.1862

0.2046

Weight

43.3%

56.7%100.0%

7.2%

5.5%

37.4%

49.8%100.0%

54.0%

46.0%100.0%

IV, Random, 95% CI

0.87 [0.74, 1.02]

1.00 [0.89, 1.12]0.94 [0.82, 1.08]

0.53 [0.29, 0.98]

0.56 [0.28, 1.13]

0.77 [0.61, 0.97]

0.85 [0.71, 1.02]0.78 [0.68, 0.91]

0.82 [0.57, 1.18]

0.89 [0.60, 1.33]0.85 [0.65, 1.11]

Hazard Ratio Hazard Ratio

IV, Random, 95% CI

0.2 0.5 1 2 5Favours experimental Favours control

Fig. 3. Forest plot of Overall Survival (OS). SE

standard error, CI

confidence interval.

Study or Subgroup

1.1.1 Monotherapy

BIG 1-98

ATAC

Subtotal (95% CI)



1.1.2 Sequenced therapy

ITA

ARNO-95

IE study

Subtotal (95% CI)


Test for overall effect: Z = 4.68 (P < 0.00001)

log[Hazard Ratio]

-0.1278

-0.1054

-0.5621

-0.4155

-0.2744

SE

0.0589

0.0477

0.1998

0.2078

0.0733

Weight

47.4%

52.6%

100.0%

18.6%

17.4%

64.0%

100.0%

IV, Random, 95% CI

0.88 [0.78, 0.99]

0.90 [0.82, 0.99]

0.89 [0.83, 0.96]

0.57 [0.39, 0.84]

0.66 [0.44, 0.99]

0.76 [0.66, 0.88]

0.72 [0.63, 0.83]

Hazard Ratio Hazard Ratio

IV, Random, 95% CI

0.2 0.5 1 2 5

Favours experimental Favours control

Fig. 2. Forest plot of Disease Free Survival (DFS). SE standard error, CI confidence interval.



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Subset analyses of nodal status

Attempts were made to undertake subset meta-analyses of

node-negative and node-positive patients; however few trials

reporteddata on OS (BIG 1-98 andMA.17) or DFS(BIG 1-98, IE study,

MA.17 and NSABP B-33). OS benefit for node-positive patients was

initially seen in MA.17, although no difference was demonstrated in

the follow-up (node ve HR 0.84 [95% CI 0.631.12]).43 No differ-

ence in OS was seen in BIG 1-98 (node ve HR 0.82 [0.681.00] vs.

node-ve HR 0.91 [0.701.18]). DFS benefit for node-positivepatients,

but not for node-negative were reported in BIG 1-98 (node ve HR

0.83 [0.710.98] vs. node-ve HR 0.89 [0.741.08]), and NSABP B-33

(HR0.50 [0.290.85] vs. HR 1.13 [0.622.07]). Theresult from NSABP

B-33 should be viewed with some caution because of its study

design. DFS benefits were seen for both subgroups in the IE study

(HR 0.74, [0.590.94], vs.HR 0.72[0.610.86]),and in MA.17 (HR 0.45

[0.280.72] vs. HR 0.60 [0.440.82]). ATAC and ABCSG 6a used time

to recurrence (excluding death) instead of DFS (ATAC HR 0.84

[0.711.00] vs. HR 0.68 [0.510.81], and ABCSG 6a HR 0.61

[0.341.09] vs. HR 0.61 [0.321.16]).

Safety analyses

Meta-analyses were performed for skeletal, endometrial and

cardiovascular adverse events where data was available (seeFig. 4).

Significant differences in fracture risks in favour of tamoxifen were

seen in the monotherapy (RR 1.43 [1.261.62] p < 0.0001), and

sequenced therapy subgroup (RR 1.36 [1.051.76] p 0.02),

whereas no difference was observed between AIs and placebo in

the extended setting (RR 1.17 [0.941.46] p 0.15). The risk of

endometrial cancer was lower for AIs, compared with tamoxifen

(RR 0.34 [0.160.71] p 0.005). The risk was similar between

sequenced therapy and tamoxifen (RR 0.45 [0.151.37] p 0.16.),

although there was a significant difference in risk of endometrial

hyperplasia (RR 0.14 [0.040.51] p 0.003). No differences

were seen for cardiovascular disease (RR for monotherapy 1.13

[0.961.33] p 0.14; RR for sequenced therapy 1.16 [0.921.46]p 0.21, and RR for extended therapy 1.50 [0.415.49] p 0.54).

However, a lower risk of thromboembolic events was observed for

AIs compared with tamoxifen (RR 0.53 [0.370.74] p 0.0003).

Meta-analyses on additional adverse events (i.e. lipids alterations

and osteoporosis) could not be performed because of lack of data

and varying definitions being used between trials.

Quality of life impact

No clinically important differences in overall QoL between the

intervention and the control were seen in any of the four QoL sub-

studies to the ATAC trial, IE study, MA.17 and NSABP B-33. Not

enough data was available to perform meta-analyses; however the

differencesin median changes between intervention and control arepresented in Table 2, together with study characteristics. Three

questionnaires were used; the Functional Assessment of Cancer

Therapy Breast (FACT-B) (ATAC and IE study), 36-Item Short Form

Health Survey (SF-36) (MA.17) and Menopause-specific QoL ques-

tionnaire (MENQOL) (NSABP B-33 and MA.17). The number of drop-

outs increased with time in all trials, the response rate was for

example 54.6% at 24 months in MA.17. However, ATAC and IE study

reported that 83% and 85.3% respectively, of their questionnaires

had been completed. Both intervention and control groups in the

ATAC substudy reported a median increase in QoL of 2.9 points over

60 months. A small difference in favour of tamoxifen was seen in

theIE studyduring thetrialperiodof 24months (0.89 [0.221.99]).

A change in five points is considered clinically important and thus

the difference was not significant. The SF-36 scores of patients

receiving letrozole and placebo were similar over 36 months in

MA.17. No significant differences were seen in any of the four

MENQOL domains (vasomotor, psychosocial,physical and sexual) in

NSABP B-33, while a worsening in QoL related to vasomotor

symptoms were reported in MA.17 (p < 0.001) but not in any of the

other domains. Results from the MENQOL questionnaire were not

included in the table as not enough information was available.

Fig. 4. Forest plot of adverse events. SE standard error, CI confidence interval.

M.L. Josefsson, S.J. Leinster / The Breast 19 (2010) 768380


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Discussion

We report efficiency benefits seen in treatment regimes that

contain aromatase inhibitors. Evidence from all three subgroups

showed that treatment regimes that include an aromatase inhibitorprolong disease free survival. The biggest effect was seen for

sequencedtherapy (HR 0.72 [95% CI 0.630.83]p < 0.00001). This is

in accordance with the meta-analysis of sequenced therapy by Jonat

and Gnant (HR for DFS 0.59 [0.480.78] p < 0.0001).21 Ingle et al.

have presented data from their yet unpublished meta-analyses of

monotherapy and sequenced therapy.49 Their results show reduced

rates of breast cancer recurrences in patients on AI therapy, both in

the monotherapy cohort (absolute reduction 2.7%, standard error

[SE] 0.7) and in the sequenced therapy cohort (absolute reduction

3.5%, SE1.1). So far no study, which weare aware of, has been able to

demonstrate a long-term benefit in overall survival in the mono-

therapy andextended therapy setting. An explanation might be that

second line treatment can be added to the management of patients

in the control group when the cancer recurs, which is not an alter-native to patients in the intervention group. Jonat and Gnant found

some evidence forprolonged OS in favour of sequencedtherapy (HR

0.71 [0.520.98]p 0.0377). Our meta-analysis provides stronger

statistical evidence (HR for sequenced therapy: 0.78 [0.680.91]

p 0.001). The result should be viewed with some caution as the

analysis includes unpublished data from the ABCSG trial 8.

This review does not provide information on the efficiency of

sequenced therapy compared with AI monotherapy. The findings

fromthe sequential arms ofBIG 1-98 showed nodifferences in DFSor

OS compared with letrozole on its own (tamoxifen/ letrozole: DFS

HR 1.05 [99%CI 0.841.32], OS HR 1.13 [0.831.53], and letrozole/

tamoxifen: DFS HR 0.96 [0.761.21], OS HR 0.90 [0.841.32]).38

Further research that directly compares sequenced therapy and AI

monotherapy are needed.The reported adverse events were generally consistent with

previous studies.57,14,15 The number of total events was low for

some of the included trials in the meta-analyses, particularly for

endometrial events. Larger studies with longer follow-up are

necessary to better assess adverse events, particularly rare condi-

tions such as endometrial cancer.

Types of AIs and the presence of lymph node metastasis vary

between the trials included in the meta-analyses, and could have

an effect on the results. However, it is unlikely as the trials are

homogeneous, which was confirmed with the Mantel-Haentszel

Chi-square test and I2 test. Variability between patients was further

accounted for by using the random effect model. Conflicting

evidence of the importance of nodal status was provided by the few

trials included in this review, although the majority did not show

any difference in efficiency benefit between node-positive and

node-negative patients.

Quality of life and cost-effectiveness need to be considered, in

addition to the efficiency data presented here, when discussing

optimal adjuvant regime. Patient groups have highlighted thesignificance of QoL on the choice of treatment.1 QoL is further

important as it may affect drug adherence. The QoL studies

included in this review showed that although side effects varies,

the QoL is overall comparable between the studied AI/sequenced

therapy and tamoxifen, or placebo in the extended setting. 44,4648

Further research that examines QoL as their main outcome is

needed to provide patients with information to aid the decision-

making process. Studies have shown AI therapy to be cost-effective

in all three settings.5054 Sequenced therapy with tamoxifen fol-

lowed by AI treatment was suggested as the most economically

preferred option in a Belgian cost-utility analysis by Skedgel et al.

that included data from the ATAC trial, IE study and MA.17.50

Conclusions

Evidence that AIs should be included in adjuvant therapy for

oestrogen sensitive early breast cancer is provided in this review,

which is the first study to include meta-analyses of three treatment

regimes: monotherapy, sequenced therapy and extended therapy.

Disease free survival was prolonged in all settings, with the biggest

effect seen for sequenced therapy. While extended AIs had no

impact on overall survival, upfront AIs were as effective as

tamoxifen. Importantly, women who switched to AI treatment after

two to three years of tamoxifen had prolonged overall survival

compared with those who stayed on tamoxifen for five years. We

conclude that sequenced therapy appears to be the preferred

treatment regime, even after its cost-effectiveness is considered.

Studies that evaluate QoL are needed to provide patients and healthcare professionals with further information when choosing adju-

vant hormonal therapy.

Conflict of interest statement

No conflict of interest declared.

Acknowledgments

We thank R. Jakesz and K. Thomanek for ABCSG trial 8 data, L.

Hooper for methodological advice, L. Shepstone for statistical

advice and J. de Boniface for translation. This work was supported

by the Jean Shanks Foundation Intercalated Grant (to MLJ).

Table 2

Characteristics of included Quality of Life studies and differences in median scores between intervention and control at 12, 24 and 36 months. ATAC HRQoL Arimidex,

Tamoxifen,Aloneor in Combination Health RelatedQualityof Life, IE studyQoL Intergroup ExemestaneStudy Quality of Life,NSABPB-33 NationalSurgical Adjuvant Breast

and Bowel Project B-33 Trial, FACT-B Functional Assessment of Cancer Therapy Breast, SF-36 36-Item Short Form Health Survey, MENQOL Menopause-specific QoL

questionnaire, yrs years.

Intervention regime Control Study

sample

Health

questionnaire

Median score difference (intervention control)

12 months 24 months 36 months

ATAC HRQoL Subscale Anastrozole Tamoxifen 682 FACT-B 1.7 0.4 0.4

IE Study QoL Substudy Tamoxifen /exemestane TamoxiFen 582 FACT-B 0.3 1.05 No dataMA.17 QoL Substudy Letrozole following 5 yrs of

adjuvant therapy

Placebo 3612 SF-36 0.0 0.0 0.05

NSABP B-33 Exemestane following 5 yrs

of tamoxifen

Placebo 454 MENQOL

Vasomotor 0.25 0.3

Psychosocial 0.1 0.55 No data

Physical 0.25 0.4

Sexual 0.1 0.4

Total 5330



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Appendix. Supplementary material

Supplementary data associated with this article can be found in

the online version, atdoi:10.1016/j.breast.2009.12.010

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