Cancer Treatment Reviews 38 (2012) 318–328

Contents lists available at ScienceDirect

Cancer Treatment Reviews

journal homepage: www.elsevierheal th.com/ journals /c t rv

Complications of Treatment

Endometrial cancer and venous thromboembolism in women under age 50who take tamoxifen for prevention of breast cancer: A systematic review

Javaid Iqbal a, Ophira M. Ginsburg a,b,f, Thiwanka D. Wijeratne c,g, Anthony Howell d,h,Gareth Evans d,i, Ivana Sestak e,j, Steven A. Narod a,⇑a Women’s College Research Institute, 790 Bay Street, 7th Floor, Toronto, ON, Canada M5G 1N8b Department of Medicine, University of Toronto, Toronto, ON, Canadac Department of Medicine, Queen’s University, Kingston, ON, Canada K7L 1S5d The Christie Hospital NHS Foundation Trust, University of South Manchester, Manchester M20 4BX, United Kingdome Wolfson Institute of Preventive Medicine, Queen Mary University, London, United Kingdom

a r t i c l e i n f o

Article history:Received 31 May 2011Received in revised form 21 June 2011Accepted 25 June 2011

Keywords:TamoxifenChemopreventionBreast cancerYoung womenEndometrial cancerDeep vein thrombosisPulmonary embolism

0305-7372/$ - see front matter � 2011 Elsevier Ltd. Adoi:10.1016/j.ctrv.2011.06.009

⇑ Corresponding author. Tel.: +1 416 351 3765; faxE-mail addresses: javaidiqbalmd@gmail.com (

wchospital.ca (O.M. Ginsburg), thiwankawijeratneAnthony. Howell@christie.nhs.uk (A. Howell), G. Evi.sestak@ qmul.ac.uk (I. Sestak), Steven.narod@wchos

f Tel.: +1 416 351 3765; fax: +1 416 351 3767.g Tel.: +1 613 546 0986.h Tel.: +44 161 446 3747; fax: +44 161 446 8000.i Tel.: +1 44 161 276 6206.j Tel.: +44 20 7882 3522.

a b s t r a c t

Background: Breast cancer prevention with tamoxifen in high-risk women is limited due to concerns ofendometrial cancer and thromboembolism. We report the risk of endometrial cancer, deep vein throm-bosis and pulmonary embolism in women <50 years given tamoxifen for breast cancer prevention.Methods: We searched the Cochrane Central Register of Controlled Trials and National Library of Medi-cine for published data from January 1970 to December 2010. We contacted principal investigators ofclinical trials, and searched Grey literature and conference proceedings for unpublished data. Wereviewed three breast cancer prevention trials comparing tamoxifen (20 mg per day) with placebo for fiveyears in high-risk women <50 years. The absolute risk and relative risk (RR) for each outcome were esti-mated.Results: The RR for endometrial cancer in women <50 years given tamoxifen is 1.19 (95% CI, 0.53–2.65;p = 0.6) as compared to the placebo. The RR for deep vein thrombosis with tamoxifen is 2.30 (95% CI,1.23–4.31; p = 0.009) in the active phase of treatment. The risk decreases to 1.00 (95% CI, 0.38–2.67;p = 0.9) in the follow-up phase. The RR for pulmonary embolism with tamoxifen is 1.16 (95% CI, 0.55–2.43; p = 0.6).Interpretation: The risk of endometrial cancer, deep vein thrombosis and pulmonary embolism is low inwomen <50 years who take tamoxifen for breast cancer prevention. The risk decreases from the active tofollow-up phase of treatment. Education and counseling are the cornerstones of breast cancerchemoprevention.

� 2011 Elsevier Ltd. All rights reserved.

Introduction

Tamoxifen is a selective estrogen receptor modulator (SERM) andan adjuvant hormonal treatment used to reduce the risk of breastcancer recurrence and death in premenopausal and postmenopausalwomen with breast cancer.1–3 In a meta-analysis of the Early BreastCancer Trialists’ Collaborative Group (EBCTCG), adjuvant treatment

ll rights reserved.

: +1 416 351 3767.J. Iqbal), Ophira.Ginsburg@@yahoo.ca (T.D. Wijeratne),ans@cmft.nhs.uk (G. Evans),pital.ca (S.A. Narod).

with tamoxifen was associated with a 41% reduction in the risk ofbreast cancer recurrence (recurrence rate ratio = 0.59) and a 34%reduction in mortality (death rate ratio = 0.66) in premenopausalwomen with hormone receptor-positive breast cancer.4 The inci-dence of contralateral breast cancer was decreased by one-third inwomen with ER-positive disease (incidence rate 4.0 vs. 6.0 per1000 women per year; p < 0.00001). The protective effect of tamox-ifen extended beyond the treatment period, with significant reduc-tions in the 15-year recurrence rate (11.8% [SE 1.3]; p < 0.00001)and the 15-year mortality rate (9.2% [SE 1.2]; p < 0.00001). Thereduction in contralateral breast cancer risk led to the evaluationof tamoxifen as chemoprevention for women at high risk of breastcancer. Between 1986 and 1992, four large randomized, double-blinded, placebo-controlled breast cancer prevention clinical trialsof tamoxifen (RCT) were initiated. Each was designed to compare fiveyears of tamoxifen use at a (standard) dose of 20 mg/day with pla-cebo in women at increased risk of breast cancer.5–8 The risk of breast

J. Iqbal et al. / Cancer Treatment Reviews 38 (2012) 318–328 319

cancer was estimated by different methods, including a modifiedGail model5,9,10 and a family history of breast cancer model.6,7 Inthe two largest RCTs, NSABP-P1 and IBIS-1, tamoxifen reduced thebreast cancer incidence by up to 50%5,6,11–13 and the protective effectof tamoxifen extended beyond the treatment period. Based on thesefindings, the U.S. Food and Drug Administration (FDA) approvedtamoxifen in 1998 for chemoprevention in high-risk women.14

Despite these encouraging results and the approval of tamoxi-fen for chemoprevention, these studies also raised concerns aboutthe safety of tamoxifen in the preventive setting. Of note were in-creased incidences of endometrial cancer and of venous thrombo-embolic events, in particular of deep vein thrombosis andpulmonary embolism. Thus, despite much attention in the layand professional media promoting tamoxifen for eligible women,tamoxifen use in healthy women has remained below expectationsin women of all ages and risk categories.15 This review highlightsour current knowledge of the frequency of serious side-effects re-lated to tamoxifen, when used in women under the age of 50.

Objectives

The purpose of this systematic review is to summarize and tocritically evaluate all available data on the safety of tamoxifenfor breast cancer prevention in women under the age of 50. Ourprimary objective was to estimate the incidence of endometrialcancer, deep vein thrombosis and pulmonary embolism in womenbelow age 50 who are given tamoxifen for breast cancer preven-tion. The secondary objective was to estimate mortality secondaryto endometrial cancer, deep vein thrombosis and pulmonaryembolism in these women.

Methods

Participants, interventions and study designs

This systematic review was structured according to the guide-lines provided by The Cochrane Collaboration. The guidelines can

Table 1Predefined inclusion and exclusion criteria.

Question component Inclusion criteria

Population (1) Adult females with either age less than 50 years orpremenopausal women

(2) No pre-existing breast cancer(3) High risk of breast cancer – (family history of breast

cancer in 1st or 2nd degree relatives, Gail’s score of1.6 or more, LCIS or BRCA1 or BRCA2 carrier)

Intervention Chemoprevention, Placebo-controlledTamoxifen, 20 mg per day compared with Placebo for atleast 5-years

Outcomes Primary outcomes(1) Incidence of endometrial cancer(2) Incidence of venous thromboembolism (deep vein

thrombosis and pulmonary embolism)Secondary outcomes

(1) Mortality due to endometrial cancer and venousthromboembolism (deep vein thrombosis and pulmon

Study design (1) Randomized, double-blind, placebo-controlled trials(2) Experimental studies with Quasi randomization(3) Experimental studies without randomization

LCIS, lobular carcinoma in situ; SERM, selective estrogen receptor modulator.

be accessed at the Cochrane’s web site.16 A predefined inclusionand exclusion criteria key was formulated for each question com-ponent of review (Table 1). The question components includedwere the study population, study arms and assigned interventionin each arm, study designs and outcomes.

Only randomized controlled studies that enrolled women youn-ger than 50 years without preexisting invasive breast cancer orductal carcinoma in situ were included in this review. The studiescomprised solely of women greater than 50 years, of postmeno-pausal women, and which included women with a prior hysterec-tomy were excluded. Studies were included if the participantswere randomized to either the standard dose of 20 mg per day oftamoxifen or to placebo for at least five years duration, with thegoal of chemoprevention. Studies in which participants receivedtamoxifen alone or were compared with an intervention other thanplacebo were excluded. Similarly, studies comparing other SERMs(e.g. raloxifene and lasofoxifene) aromatase inhibitors or andro-gens were also excluded. Systematic reviews and meta-analyseswere excluded for review.

Outcome measures

Three outcome measures were: (1) endometrial cancer, (2) deepvein thrombosis, and (3) pulmonary embolism. Outcomes wereestimated at all points in the follow-up of study participants. Theprimary outcome measures were the incidence of endometrial can-cer, deep vein thrombosis and pulmonary embolism. The mortalitydata was collected as the secondary outcome.

Search methods for identification of studiesThe literature search and identification of studies was indepen-

dently conducted by two authors (J.I. and O.G.). This method re-duces the chance of omission of a relevant study.17 A thirdauthor (SN) acted as arbitrator to resolve any conflict of opinionand disagreement between the two authors. A thorough datasearch was conducted for both published and unpublished medicalliterature from January 1970 to November 2010.

Exclusion criteria

(1) Patients with pre-existing breast cancer(2) Studies that solely included women with age greater

than 50 years or postmenopausal women(3) Women with history of Prothrombotic conditions e.g.

Factor V Leiden, Protein C & S deficiency etc.(4) Women with hysterectomy(1) Non-placebo-controlled trials(2) Studies comparing tamoxifen with other SERMs

(Raloxifene, Lasofoxifene)(3) Studies comparing tamoxifen with androgens(4) Studies in which any other therapy was offered during

intervention period(5) Comparisons that include non-conventional

medications

ary embolism)(1) Cohort/case control studies(2) Case studies/series and reports(3) Cross over studies(4) Studies with no comparator group(5) Systematic Reviews; meta-analyses

320 J. Iqbal et al. / Cancer Treatment Reviews 38 (2012) 318–328

Information resources

Two major electronic databases used for literature search wereThe Cochrane Central Register of Controlled Trials (CENTRAL) andNational Library of Medicine (NLM). The CENTRAL is the most com-prehensive source of RCTs and includes the reports from MEDLINEand EMBASE.18 The National Library of Medicine is the largestmedical database and allows access to PubMed and MEDLINE.19

The inclusion of PubMed was important for the fact that it includesup-to-date citations which have not yet appeared in MEDLINE, andcontains articles from journals not indexed for MEDLINE. To avoidlanguage bias, the literature search was expanded to include arti-cles published in languages other than English. The NLM providesthe option to include literature published in other languages.

Other resources

The authors also searched the Grey literature for unpublishedjournal articles and conference proceedings. Clinical Trial Regis-tries were searched for ongoing and unpublished trials. Principalinvestigators of clinical trials were also contacted for unpublisheddata and information packets were requested from manufacturersfor any additional data. Citations of selected publications were alsoscreened for additional studies.

Records identified through (The CENTRAL, NLM, GreyTrial Registries)2 and after r

(n = 232

Identification

Records screened for abstreview

(n = 464)

Screening

Full-text articles assessedeligibility

(n = 15)

Eligibility

Full-text articles selected systematic review

(n = 7)

Included

Fig. 1. Flow diagram 1 of database search. (1) Adopted from: Moher D, Liberati A, Tetzlaffand Meta-Analyses: The PRISMA Statement. PLoS Med 2009;6(6):e1000097. doi:10.1371of Controlled Trials; NLM represents National Library of Medicine.

Data collection and analysis

Selection of studies

Fig. 1 shows the flowchart of identification, screening, eligibil-ity and inclusion or exclusion of studies. The authors used vari-ous key words, alone or in combination, to produce maximumresults during the literature search. The following key wordswere used: ‘‘women younger than 50 years or premenopausal;chemoprevention or tamoxifen; serious adverse-events or endo-metrial cancer/carcinoma or venous thromboembolism or deepvein thrombosis or pulmonary embolism; and incidence or mor-bidity or mortality. To minimize the possibility of duplication, allkey fields of a particular study were downloaded including un-ique identifier (e.g. PMID), digital object identifier (DOI), clinicaltrial number (from www.clinicaltrials.gov), abstract and keywords. The initial citations were then merged into one file usingthe Endnote software and duplicate results were removed. Thetitle of each study was individually reviewed by designatedauthors to identify the studies addressing the research question.Thereafter, abstracts of selected studies were reviewed accordingto the predefined inclusion and exclusion criteria and irrelevantstudies were removed. Studies meeting all inclusion and exclu-sion criteria were selected for full-text review and dataextraction.

database searching literature and Clinical emoval of duplicates

7)

ract Records excluded (articles not addressing study question)

(n = 1863)

for Abstracts (not meeting the predefined criteria) excluded

(n = 449)

for Full-text articles excluded from review with reasons

(n = 8)

J, Altman DG, The PRISMA Group. Preferred Reporting Items for Systematic Reviews/journal.pmed1000097. (2) The CENTRAL represents The Cochrane’s Central Register

Table 2Risk of bias assessment of studies.

NSABP P-1 IBIS-1 Royal Marsden trialRisk of bias Risk of bias Risk of bias

Yes (lowrisk)

No (highrisk)

Unclear Yes (lowrisk)

No (highrisk)

Unclear Yes (lowrisk)

No (highrisk)

Unclear

Adequate sequence generation? U U U

Adequate allocation concealment? U U U

Blinding of participants, personnel and outcomeassessors

U U U

Incomplete data outcome addressed? U Ub

Ub

Free of selective reporting? U Ub

Ub

Free of other bias? Ua

Ua,c

Ua,c

Overall quality of data (good, fair, and bad) Good Fair Fair

Abbreviations: NSABP P-1, National Surgical Adjuvant Breast and Bowel Project P-1; IBIS-1, International Breast Cancer Intervention Study-1.a Selection bias for ethnicity.b Inadequate data reporting for according to age or menopausal status.c The use of Hormone replacement therapy (HRT) was permitted during intervention period.

J. Iqbal et al. / Cancer Treatment Reviews 38 (2012) 318–328 321

Data extraction and management

A data form was designed prior to data extraction. The eligibil-ity of each study, as explained above, was confirmed. Informationwas collected on study design, methodology, participant character-istics, intervention arms and assigned interventions (dose, timingand duration). Data was also collected on the compliance and lostto follow-up participants. Each study was then reviewed for theprimary and secondary outcomes. The level of agreement betweentwo authors designated for the literature search was assessed bycalculating kappa statistics. A value of kappa between 0.40 and0.59 was considered a fair agreement between two authors.20 Fi-nally, information on the funding sources and disclosures was alsocollected.

Assessment of risk of bias

The Cochrane Collaboration’s tool to assess the risk of bias wasused to judge the credibility and applicability of included studies(Table 2). The risk was assessed with the following criteria: (1)allocation sequence generation (2) allocation concealment (3) ade-quate blinding (4) incomplete data outcome reporting (5) selectivereporting and (6) other bias e.g. ethnicity, funding and concomitantmedications. Although the risk of bias was evaluated by all criteria,the allocation concealment and adequate blinding were consideredthe major criteria for risk assessment. Based on this evaluation,each study was categorized into low, high and unclear risk of bias;subsequently, the overall quality and applicability of data was cat-egorized as good, fair or bad.

Measurement and analysis of outcomes

Outcomes were evaluated for definition, unit of measurementand scales. The results were then extracted and evaluated with re-gards to the number of participants enrolled in each interventiongroup, adequacy of sample size to detect a minimally importantdifference between intervention arms, completeness of treatmentand missing data. The primary and secondary outcomes were mea-sured as dichotomous data based on the reported frequencies ofevents. The dichotomous data for all outcomes was then put intoa 2 � 2 table and risk ratios (RR) were calculated by Fisher’s exacttest. We calculated the estimates of effects in terms of relativerisks, confidence intervals and p-values. A two sided p-value wascalculated for each outcome. We performed subgroup analyses tomeasure the effect of outcomes among different subsets of studypopulations. These analyses were performed according to age less

than 50 and equal to or greater than 50 years; and menopausal sta-tus (premenopausal vs. postmenopausal). Confidence intervalswere measured for each outcome at 95% confidence level and a riskdifference was calculated from observed risks in study groups. Theannual rates of outcomes in study arms were calculated with thecount (numerator) and person-time at risk (denominator). The per-son-time at risk was calculated as an intention to treat analysisusing the total number of participants in each study arm multi-plied with the average follow-up time in years. The function calcu-lates the rate and confidence interval as rate per thousand units ofperson-time.21 A sensitivity analysis was performed on the pri-mary outcome based on the bias assessment. RevMan 5 and Epi-Calc 2000 software were used for all analyses.

Results

Results of initial search

The initial literature search from electronic databases and otherresources yielded 2327 results (Fig. 1). The titles of all articles wereexamined and 464 articles addressing the research question wereselected for abstract review. Out of these, seven articles from threeRCTs were selected for detailed systematic review.

Description of included studies

Characteristics of the three RCTs included for analysis are sum-marized in Table 3: the National Surgical Adjuvant Breast andBowel Project (NSABP) P-1 trial (also known as Breast Cancer Pre-vention Trial or BCPT)5,11; International Breast Cancer InterventionStudy-1 (IBIS-1)6,12; and Royal Marsden hospital tamoxifen breastcancer prevention trial7,22. The three studies were Phase III ran-domized, double-blind, placebo-controlled clinical trials whichcompared tamoxifen at a dose of 20 mg/day with placebo for5 years (NSABP-P1 and IBIS-1) or 8 years (Royal Marsden study).The incidence of breast cancer was primary end-point in all RCTs.Because NSABP P-1 study was unblinded in 1998, we decided to in-clude only the results prior to unblinding (active treatment phase).Generally, all studies met either good or fair criteria on the basis ofrisk of bias assessment (Table 2).

The enrollment criteria in each RCT were based on the riskassessment of breast cancer, although different risk assessmentmethods were employed in each study. In the NSABP P-1 study,breast cancer risk was determined either by age, benign high riskbreast lesion or modified Gail’s model.9,10 The IBIS-1 and RoyalMarsden studies used family history of breast cancer as the major

Table 3Characteristics of Randomized Controlled Trials included in review.

Study Design Participants (n)P/T

Inclusion criteria Exclusion criteria Treatment

NSABP P-1 RCTDouble-blind

n = 13,175P = 6599T = 6576Age <50 yearsP = 2596 (39.3%)T = 2581 (39.2%)Total = 5177(39.2%)United States ofAmericaCanada

(1) Women with either the age P60years or between 35 and 69 yearswith a 5-year predicted risk forbreast cancer of 1.66a

(2) LCIS(3) Life expectancy of at least 10 years

(1) Previous breast cancer(2) Previous DVT and PE(3) Estrogen and/or progesterone

replacement therapy or oralcontraceptives

(4) Pregnancy

T vs. P for 5yearsT, 20 mg/day

IBIS-1 RCTDouble-blind

n = 7154P = 3575T = 3579Age <50 years:P = 1653 (46.3%)T = 1644 (45.9%)Total = 3297 (46%)United Kingdomand EuropeAustraliaNew Zealand

(1) Twofold relative risk (RR) of breastcancer if the age between 45 and70 years

(2) Fourfold RR of breast cancer if theage between 40 and 44 years

(3) Tenfold RR of breast cancer if theage between 35 and 39 yearsb

(1) Previous invasive cancer(2) Previous deep vein thrombosis or

pulmonary embolism(3) Users of anticoagulants(4) Pregnancy

T vs. P for 5yearsT, 20 mg/day

Royal Marsdentrial

RCTDouble-blind

n = 2471P = 1233T = 1238Age <50 years:P = 749 (60.7%)T = 774 (62.5%)Total = 1523(61.6%)United Kingdom

Women between ages 30–70 years andwith family history of breast cancerc

(1) Previous cancer(2) Previous DVT and PE(3) Oral contraceptives(4) Pregnancy

T vs. P for 8yearsT, 20 mg/day

Abbreviations: P, placebo; T, tamoxifen; LCIS, lobular carcinoma in situ; DCIS, ductal carcinoma in situ; EC, endometrial cancer; VTE, venous thromboembolism; DVT, deep veinthrombosis; PE, pulmonary embolism; NSABP P-1, National Surgical Adjuvant Breast and Bowel Project P-1; IBIS-1, International Breast Cancer Intervention Study-1.

a NSABP P-1 participant’s risk assessment: participants were enrolled on the basis of breast cancer risk assessment. A modified Gail’s model was used to assess the risk. Themodel incorporates the age, number of first-degree relatives with breast cancer, nulliparity or age at first live birth, number of breast biopsies, pathologic diagnosis of atypicalhyperplasia, and age at menarche.

b IBIS-1 participant’s risk assessment: participants were enrolled on the basis of family history of breast cancer and presence of LCIS. Specifically, the eligibility criteria fromage 45 years include (1) breast cancer in mother or sister before the age of 50 years, (2) breast cancer in 2 first- or second-degree relatives at any age, or (3) breast cancer infirst-degree relative at any age, were nulliparous or had previous hyperplastic benign lesion. Eligibility criteria from age 40 years include (1) history of atypical ductal orlobular hyperplasia, (2) one first-degree relative with bilateral breast cancer at any age, or (3) one of the two first- or second-degree relatives with breast cancer diagnosedbefore age 50 years. Eligibility criteria from age 35 years include (1) lobular carcinoma in situ or (2) two first-degree relatives with breast cancer, both diagnosed before age50 years. Also, any women with a 10-year risk of 5% or more based on a complex model were also included in the study.

c Royal Marsden trial participant’s risk assessment: participants were enrolled on the basis of family history of breast cancer including (1) one first-degree relative withbreast cancer diagnosed at the age younger than 50 years, (2) one first-degree relative with bilateral breast cancer, (3) one first-degree relative with breast cancer diagnosedat any age and one other first- or second-degree relative with breast cancer and 4) women with benign breast biopsy and a first-degree relative with breast cancer.

322 J. Iqbal et al. / Cancer Treatment Reviews 38 (2012) 318–328

enrollment criterion. The participants of Royal Marsden study hadstrong family history of breast cancer, as compared to participantsin IBIS-1. Overall, about one quarter of the women in the NSABP P-1 study had no family history of breast cancers whereas 97% wo-men in the IBIS-1 and 99% women in the Royal Marsden study re-ported a family history of breast cancer. Because the participantswere categorized according to age in the NSABP P-1 study andmenopausal status was not defined unlike in the IBIS-1 and theRoyal Marsden study; we categorized all study participants asage less than 50 years, or equal to or greater than 50 years.

The studies also differed in the frequency of follow-up, studyduration and treatment compliance. In the NSABP P-1 study,21.6% women stopped their assigned treatment (19.7% in placeboand 23.7% in tamoxifen) and additional 2.3% were lost to follow-up. Overall, complete follow-up was available on approximately92% participants. In the IBIS-1 study, the follow-up was availableon 85% women and the data on lost to follow-up women was notreported. In the Royal Marsden study, about 35% women stoppedtheir assigned treatment (30.8% in placebo and 40% in tamoxifengroup) and additional 11% participants were lost to follow-up; thusa lower compliance rate was observed as compared to other stud-ies. The median follow-up time was 54.6 months in NSABP P-1study, while it was 96 months in the IBIS-1 study and 13 years in

the Royal Marsden study. The IBIS-1 and Royal Marsden studiespermitted the use of hormone replacement therapy during theintervention periods.

Incomplete data outcome

Because this review was specifically designed to address thedata pertaining to women under the age 50, every effort was madeto extract the data on this particular age group. The NSABP-P1 wasthe only study which reported each outcome measure (endome-trial cancer, deep vein thrombosis and pulmonary embolism)according to different age groups. In the IBIS-1 study, only endo-metrial cancer events were reported according to age. In the RoyalMarsden study, none of the outcome measures were reportedaccording to age or menopausal status.

Summary of results

Table 4 summarizes the evidence extracted from three RCTs se-lected for review. Table 5 summarizes the events in RCTs accordingto phase of treatment (active phase, follow-up phase and overallevents).

Tabl

e4

Sum

mar

yof

evid

ence

from

rand

omiz

edco

ntro

lled

tria

ls.

Stu

dyn,

P/T

Ou

tcom

em

easu

rePl

aceb

oev

ents

Tam

oxif

enev

ents

RR

(95%

CI)

bp-

Val

ueb

Age

(yea

rs)

Plac

ebo

even

tsTa

mox

ifen

even

tsR

R(9

5%C

I)b

p-V

alu

eb

NSA

BP

P-1a

13,1

75,6

599/

6576

Endo

met

rial

can

cerc

1536

2.46

(1.3

5–4.

48)

0.00

3<5

08

91.

13(0

.44–

2.93

)0.

9P

507

273.

86(1

.69–

8.86

)0.

0002

Dee

pve

inth

rom

bosi

s22

351.

60(0

.94–

2.72

)0.

1<5

08

111.

13(0

.44–

2.93

)0.

9P

5014

241.

72(0

.89–

3.32

)0.

1Pu

lmon

ary

embo

lism

618

3.01

(1.2

0–1.

58)

0.02

<50

12

2.01

(0.1

8–22

.17)

0.9

P50

516

3.21

(1.1

8–8.

74)

0.02

IBIS

-171

54,3

575/

3579

Endo

met

rial

can

cerc

1117

1.51

(0.7

1–3.

22)

0.3

<50

21

0.50

(0.0

5–5.

54)

0.9

P50

916

1.77

(0.7

8–3.

99)

0.2

Dee

pve

inth

rom

bosi

s38

641.

68(1

.13–

2.51

)0.

01<5

010

242.

41(1

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5.03

)0.

02P

5028

401.

42(0

.88–

2.29

)0.

1Pu

lmon

ary

embo

lism

3244

1.37

(0.8

7–2.

16)

0.2

<50

1111

1.01

(0.4

4–2.

31)

0.8

P50

2123

1.09

(0.6

0–1.

96)

0.8

Roy

alM

arsd

enst

udy

2471

,123

3/12

38En

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132.

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06<5

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Dat

an

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914

1.55

(0.6

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57)

0.3

<50

Dat

an

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port

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P50

Dat

an

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Abb

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atio

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Adj

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nt

Bre

ast

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Bow

elPr

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tP-

1;IB

IS-1

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tern

atio

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Bre

ast

Can

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Inte

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omen

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was

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J. Iqbal et al. / Cancer Treatment Reviews 38 (2012) 318–328 323

A. Endometrial cancer(a) NSABP-P1 Breast Cancer Prevention TrialAs mentioned earlier, due to the unblinding of NSABP-P1 trial in

1998, only the results prior to unblinding (active treatment phase)are included here in primary analysis. The results of the activephase are compared with the follow-up phase to determine if therisk extends beyond the period of treatment. Endometrial biopsyfor screening of participants in the NSABP-P1 study was optionalduring the active phase until July 1994 (two years after the studywas initiated) and was compulsory thereafter. The number of wo-men who had an endometrial biopsy after July 1994 is not re-ported. Endometrial biopsy was not done routinely during thefollow-up phase. A total of 51 invasive endometrial cancers oc-curred in the active phase of treatment; 15 in the placebo armand 36 in the tamoxifen arm (p = 0.003). However, when catego-rized according to age, the difference in the annual rate of endome-trial cancer was not statistically significant in women less than50 years (placebo = 1.09 per 1000 women per year, tamoxi-fen = 1.32 per 1000 women per year; p = 0.4). In contrast, the dif-ference was significant in women equal to or greater than50 years (placebo = 0.76 per 1000 women per year, tamoxi-fen = 3.05 per 1000 women per year; p = 0.0003). Fourteen endo-metrial cancers in the placebo group were of InternationalFederation of Gynecology and Obstetrics (FIGO) stage 1 and onecancer was FIGO stage IV. All 36 invasive cancers in the tamoxifengroup were of FIGO stage 1.

When categorized according to the phase of treatment (Table 5);a total of 71 endometrial cancers occurred, 21 in women less than50 years and 49 in women equal to or greater than 50 years. Of 21cases of endometrial cancers in women less than 50 years in, 17(80%) cases occurred during the active phase of treatment (8 outof 2596 [0.30%] women in the placebo arm, and 9 out of 2581[0.34%] women in the tamoxifen arm) and four occurred in the fol-low-up phase (1 out of 2600 [0.03%] women in the placebo armwhile 3 out of 2589 [0.11%] women in the tamoxifen arm). The rateof events decreased from active to the follow-up phase (pla-cebo = 1.09 to 0.06 per 1000 women per year, tamoxifen 1.32 to0.19 per 1000 women per year). Of 128 deaths, only one wasreportedly related to endometrial cancer. This event occurred inthe placebo group and the age was not reported.

(b) The IBIS-1 studyTwenty-eight cases of invasive endometrial cancer were re-

ported; 11 in the placebo arm and 17 in the tamoxifen arm(p = 0.3). The difference in the annual rate of endometrial cancerin the placebo and in the tamoxifen arm was not statisticallysignificant either for women less than 50 years (placebo = 0.15per 1000 women per year, tamoxifen 0.08 per 1000 womenper year; p = 0.8) or women equal to or greater than 50 years(placebo = 1.67 per 1000 women per year, tamoxifen = 2.28 per1000 women per year; p = 0.2). All three cases of endometrialcancer in women less than 50 years were diagnosed in the activephase of treatment (2 out of 1826 [0.10%] women in the placeboarm, and 1 out of 1812 [0.05%] women in the tamoxifen arm.There were no new cases of endometrial cancer in women lessthan 50 years during the follow-up. Nine out of 11 women inthe placebo arm had FIGO stage 1 endometrial cancer while 14out of 17 cancers in the tamoxifen arm were of FIGO stage 1.Out of 28 women with endometrial cancer, 13 women (6 in pla-cebo and 7 in tamoxifen group) reported the use of hormonereplacement therapy (HRT). All 6 women in the placebo armand 3 women in the tamoxifen arm used HRT during the inter-vention period; while 4 women in tamoxifen arm used HRT be-fore the assigned intervention. Only one death due toendometrial cancer was reported (in the tamoxifen arm); how-ever, the age group was not specified.

Table 5Summary of events in randomized controlled trialsb according to age and phase of treatment (active phase, follow-up phase and overall events).

NSABP-P1 IBIS-1

Phase of treatment Active phase Follow-up phasec Overall eventse Active phase Follow-up phase Overall eventse

Number analyzed (P vs. T) 6599 vs. 6576 6610 vs. 6597 6610 vs. 6597 3566 vs. 3573 3575 vs. 3579 3575 vs. 3579

Endometrial cancera P vs. T P vs. T P vs. T P vs. T P vs. T P vs. TAge < 50 2596 vs. 2581 2600 vs. 2589 2600 vs. 2589 1826 vs. 1812 1653 vs. 1644 1653 vs. 1644

Total events 8 vs. 9 1 vs. 3 9 vs. 12 2 vs. 1 2 vs. 1Rate (per 1000 women)d 1.09 vs. 1.32 0.06 vs. 0.19 0.56 vs. 0.75 0.26 vs. 0.13 No new cases of endometrial cancer 0.15 vs. 0.08RR (95% CI) 1.13 (0.44–2.93) 3.01 (0.31–28.95) 1.34 (0.57–3.17) 0.50 (0.05–5.55) 0.50 (0.05–5.54)p-value 0.9 0.6 0.6 0.9 0.9

Age P50 1598 vs. 1561 1600 vs. 1522 1600 vs. 1522 457 vs. 529 639 vs. 703 639 vs. 703Total events 7 vs. 27 1 vs. 14 8 vs. 41 3 vs. 10 6 vs. 6 9 vs. 16Rate (per 1000 women)d 0.76 vs. 3.05 0.1 vs. 1.5 0.81 vs. 4.38 1.5 vs. 5.6 1.11 vs. 0.85 1.67 vs. 2.28RR (95% CI) 3.86 (1.69–8.86) 14.7 (1.94–111.7) 5.39 (2.53–11.45) 3.05 (0.98–12.82) 0.7 (0.25–2.36) 1.77 (0.78–3.99)p-value 0.0002 0.001 0.00002 0.07 0.8 0.2

Deep vein thrombosisAge < 50

Total events 8 vs. 11 4 vs. 5 12 vs. 16 6 vs. 21 4 vs. 3 10 vs. 24Rate (per 1000 women) 0.78 vs. 1.08 0.25 vs. 0.31 0.75 vs. 1.0 0.79 vs. 2.79 0.30 vs. 0.23 0.77 vs. 1.85RR (95% CI) 1.13 (0.44–2.93) 1.26 (0.34–4.67) 1.34 (0.63–2.82) 3.53 (1.43–8.72) 0.75 (0.17–3.36) 2.41 (1.16–5.03)p-value 0.9 0.9 0.5 0.006 0.9 0.02

Age P 50Total events 14 vs. 24 8 vs. 9 22 vs. 33 13 vs. 26 15 vs. 14 28 vs. 40Rate (per 1000 women) 0.88 vs. 1.55 0.32 vs. 0.37 0.89 vs. 1.34 1.80 vs. 3.55 0.98 vs. 0.91 1.84 vs. 2.62RR (95% CI) 1.72 (0.89–3.32) 1.13 (0.43–2.91) 1.50 (0.88–2.57) 1.98 (1.02–3.83) 0.93 (0.45–1.92) 1.42 (0.88–2.29)p-Value 0.1 0.9 0.1 0.05 0.9 0.1

Pulmonary embolismAge < 50

Total events 1 vs. 2 1 vs. 2 2 vs. 4 8 vs. 10 3 vs. 1 11 vs. 11Rate (per 1000 women) 0.1 vs. 0.2 0.02 vs. 0.05 0.13 vs. 0.25 1.05 vs. 1.33 0.44 vs. 0.15 0.84 vs. 0.84RR (95% CI) 2.01 (0.18–22.17) 2.0 (0.10–22.70) 2.01 (0.37–10.96) 1.26 (0.50–3.18) 0.34 (0.03–3.22) 1.01 (0.44–2.31)p-Value 0.9 0.9 0.6 0.8 0.6 0.8

Age P 50Total events 5 vs. 16 6 vs. 8 11 vs. 24 10 vs. 11 11 vs. 12 21 vs. 23Rate (per 1000 women) 0.3 vs. 1.0 0.24 vs. 0.32 0.45 vs. 0.97 1.38 vs. 1.50 0.72 vs. 0.78 1.37 vs. 1.49RR (95% CI) 3.21 (1.18–8.74) 1.33 (0.46–3.84) 2.19 (1.08–4.46) 1.09 (0.46–2.55) 1.08 (0.48–2.45) 1.09 (0.60–1.96)p-Value 0.02 0.7 0.04 0.9 0.9 0.8

Abbreviations: NSABP-P1, National Surgical Adjuvant Breast and Bowel Project-P1; IBIS-1, International Breast Cancer Intervention Study-1; P, placebo; T, tamoxifen; RR, riskratio; CI, confidence interval.

a Data calculated in women with intact uterus.b The Royal Marsden Study is not included because the data is not reported according to age for all primary outcome measures (endometrial cancer, deep vein thrombosis

and pulmonary embolism).c Because NSABP-P1 study was unblinded in 1998; the follow-up phase of NSABP-P1 is not included in the primary analysis of this review.d Rate = Annual rate per 1000 women per year.e Overall events include events in both active and follow-up phases of treatment.

324 J. Iqbal et al. / Cancer Treatment Reviews 38 (2012) 318–328

(c) The Royal Marsden studyA total of 18 cases of endometrial cancer occurred, 5 in the pla-

cebo arm and 13 in the tamoxifen arm (p = 0.06). The annual ratesof endometrial cancer were 0.31 per 1000 women per year in theplacebo group and 0.80 per 1000 women per year in the tamoxifengroup (p = 0.05). The events were not reported by age or by phaseof treatment. Mortality data was not reported.

B. Deep vein thrombosis(a) The NSABP-P1 Breast Cancer Prevention TrialFifty-seven women reported a deep vein thrombosis; 22 in the

placebo arm and 35 in the tamoxifen arm (p = 0.1). In women lessthan 50 years, the difference in the annual rates of deep veinthrombosis was not statistically significant (placebo = 0.78 per1000 women per year, tamoxifen = 1.08 per 1000 women per year;p = 0.3). In women equal to or greater than 50 years, the rates were0.88 per 1000 women per year for the placebo arm and 1.55 per1000 women per year for women in the tamoxifen arms(p = 0.07). Of 28 cases of deep vein thrombosis in women less than50 years; 19 (67.8%) cases were diagnosed in the active phase oftreatment (8 out of 2596 [0.31%] women in the placebo arm, and11 out of 2581 [0.43%] women in the tamoxifen arm) and nine inthe follow-up phase (4 out of 2600 [0.15%] women in the placebo

arm, and 5 out of 2589 [0.19%] women in the tamoxifen arm). Theannual rate of deep vein thrombosis decreased from the active tothe follow-up phase (placebo = 0.78 to 0.25 per 1000 women peryear; tamoxifen = 1.08 to 0.31 per 1000 women per year).

(b) The IBIS-1 studyOverall, 102 women reported a deep vein thrombosis; 38 in the

placebo arm and 64 in the tamoxifen arm (p = 0.01). The differencein the annual rate of deep vein thrombosis was significant in wo-men less than 50 years (placebo = 0.77 per 1000 women per year,tamoxifen = 1.85 per 1000 women per year; p = 0.01). In womenequal to or greater than 50 years, the rates were 1.84 per 1000 wo-men per year for the placebo arm and 2.62 per 1000 women peryear for the tamoxifen arm (p = 0.09). Of 34 cases of deep veinthrombosis in women less than 50 years; 27 (79.4%) cases werediagnosed in active phase of treatment (6 out of 1826 [0.3%] wo-men in the placebo arm, and 21 out of 1812 [1.16%] cases in thetamoxifen arm) and seven in the follow-up phase (4 out of 1653[0.24%] women in the placebo arm, and 3 out of 1644 [0.18%] wo-men in the tamoxifen arm). The annual rate of deep vein thrombo-sis decreased from the active to follow-up phase (placebo = 0.79 to0.30 per 1000 women per year; tamoxifen = 2.78 to 0.23 per 1000women per year).

J. Iqbal et al. / Cancer Treatment Reviews 38 (2012) 318–328 325

About half of events in the tamoxifen arm occurred withinthree months of an event that was a risk factor for deep veinthrombosis or pulmonary embolism (i.e. surgery, fracture orimmobility).6 Five women died of a thromboembolic event (1due to deep vein thrombosis and 4 due to pulmonary embolism);two of the deaths were in the placebo arm and three in thetamoxifen arm. Two of the five deaths were reported in womenless than 50 years (1 in the placebo arm and 1 in tamoxifenarm). All of the deaths related to deep vein thrombosis and pul-monary embolism in the tamoxifen arm occurred after a majorsurgery.6

(c) The Royal Marsden studyTwenty-three women reported venous thromboembolic event

(deep vein thrombosis or pulmonary embolism); 9 in the placeboarm and 14 in the tamoxifen arm (p = 0.3). The annual rates of deepvein thrombosis and pulmonary embolism were 0.55 per 1000 wo-men per year in the placebo group and 0.86 per 1000 women peryear in the tamoxifen group (p = 0.2). The events were not reportedby age or by the phase of treatment. Mortality data was notreported.

C. Pulmonary embolism(a) The NSABP-P1 Breast Cancer Prevention TrialTwenty-four pulmonary emboli were reported; 6 in the placebo

arm and 18 in the tamoxifen arm (p = 0.02). The difference in theannual rate of pulmonary embolism was not significant in womenless than 50 years (placebo = 0.10 per 1000 women per year,tamoxifen = 0.20 per 1000 women per year; p = 0.4). In womenequal to or greater than 50 years, the rates were much higher;0.3 per 1000 women per year for the placebo arm and 1.0 per1000 women per year for the tamoxifen arm (p = 0.01). Of six casesof pulmonary embolism in women less than 50 years; three (50%)cases were diagnosed in the active phase of treatment (1 out of2596 [0.04%] women in the placebo arm, and 2 out of 2581[0.08%] women in the tamoxifen arm) and three were diagnosedin the follow-up phase (1 out of 2600 [0.04%] women in the pla-cebo arm, and 2 out of 2589 [0.08%] women in the tamoxifenarm). The annual rate of pulmonary embolism decreased in womenless than 50 years from the active to the follow-up phase (pla-cebo = 0.1 to 0.02 per 1000 women per year; tamoxifen = 0.2 to0.05 per 1000 women per year). In total, three deaths were re-ported due to pulmonary embolism; all of three occurred in wo-men taking tamoxifen. All three women had other co-morbidconditions and the exact cause of death was uncertain.5 Distribu-tion of deaths according to age was not reported.

(b) The IBIS-1 studySeventy-six women were diagnosed with pulmonary embo-

lism; 32 in the placebo arm and 44 in the tamoxifen arm(p = 0.2). The difference in the annual rate of pulmonary embo-lism was not significant in either women less than 50 years (pla-cebo = 0.84 per 1000 women per year, tamoxifen = 0.84 per 1000women per year; p = 0.4), or in women greater than or equal to50 years (placebo = 1.38 per 1000 women per year, tamoxi-fen = 1.50 per 1000 women per year; p = 0.3). Of 22 total casesof pulmonary embolism in women less than 50 years; 18(81.8%) cases were diagnosed in active phase of treatment (8out of 1826 [0.44%] women in the placebo arm, and 10 out of1812 [0.55%] women in the tamoxifen arm) and four were diag-nosed in the follow-up phase (3 out of 1653 [0.18%] women inthe placebo arm, and 1 out of 1644 [0.06%] women in the tamox-ifen arm). The annual rate of pulmonary embolism decreased inwomen less than 50 years from active to the follow-up phase(placebo = 1.05 to 0.44 per 1000 women per year; tamoxi-fen = 1.33 to 0.15 per 1000 women per year). The mortality withpulmonary embolism is reported elsewhere in the text.

In the Royal Marsden study, the data on pulmonary embolismwas reported with deep vein thrombosis (please see the previoussection on deep vein thrombosis).

Discussion

This systematic review was performed to estimate the inci-dence of and mortality from serious side-effects in women lessthan 50 years who were treated with tamoxifen for breast cancerprevention. Based on predefined inclusion and exclusion criteria,three randomized controlled trials compared tamoxifen with pla-cebo and were considered eligible for review. The trials reviewedwere the NSABP-P1 study5,11, IBIS-1 study6,12 and Royal MarsdenHospital study.7,22 The NSABP-P1 and IBIS-1 studies reported thedata on endometrial cancer, deep vein thrombosis and pulmonaryembolism in women less than 50 years while the Royal MarsdenHospital study did not report the data according to age groups.On the basis of available data, we report that the risk of endome-trial cancer, deep vein thrombosis and pulmonary embolism islow in women under the age 50 years compared to women equalto or greater than 50 years treated with tamoxifen for breast can-cer prevention.

Risk of endometrial cancer, deep vein thrombosis and pulmonaryembolism

Based on the estimates from the NSABP-P1 and IBIS-1 trials, wo-men less than 50 years of age who receive tamoxifen for breastcancer chemoprevention do not have a significantly increased riskof endometrial cancer as compared to women given placebo (riskratio, 1.19; 95% CI, 0.53–2.65; p = 0.6). However, the risk is signifi-cantly higher in women greater than 50 years who are giventamoxifen (risk ratio, 3.32; 95% CI, 1.95–5.67; p = < 0.0001).Although the combined estimates from NSABP-P1 and IBIS-1 stud-ies suggest that the overall risk (active and follow-up phases oftreatment) of deep vein thrombosis with tamoxifen is significantin women less than 50 years (risk ratio, 1.45; 95% CI, 1.09–3.07;p = 0.02); however, it is only during the active phase that the riskis higher (risk ratio, 2.30; 95% CI, 1.23–4.31; p = 0.009). Therewas no excess of deep vein thrombosis in the follow-up phase oftreatment (risk ratio, 1.00; 95% CI, 0.38–2.67; p = 0.9). The differ-ence in risk of pulmonary embolism was not significant in womenless than 50 years (risk ratio, 1.16; 95% CI, 0.55–2.43; p = 0.6) or inwomen equal to or greater than 50 years (risk ratio, 1.46; 95% CI,1.46 (0.94–2.29); p = 0.1).

This review was limited by our strict selection criteria. One lim-itation was the lack of data according to the age and menopausalstatus in Royal Marsden Hospital study, and thus, the estimationof a true effect of tamoxifen on primary and secondary outcomeswas not possible this particular study. Further, generalizability ofthe RCTs selected was limited by the selection of study partici-pants. Thus far, only the NSABP-P1 study has reported on ethnicity[11]. In their 2005 update, Fisher and colleagues reported that 96%of participants in the NSABP P-1 study self-identified as Caucasian/white. Although, the race and ethnicity were not reported in theIBIS-I and Royal Marsden studies, it is presumed that majority ofparticipants in these studies were whites of European ancestry.Figure 4 of the NSABP-P1 2005 report5 shows thromboembolicevents and endometrial cancer for whites and African Americanstudy participants. A higher rate of thromboembolic events amongAfrican American women, and a higher rate of endometrial canceramong white women are shown; however this difference wasmore apparent for women over age 50 years. In general, Caucasianshave higher rates of endometrial cancer than African American wo-men.23 To our knowledge, none of the major tamoxifen chemopre-

326 J. Iqbal et al. / Cancer Treatment Reviews 38 (2012) 318–328

vention RCTs have yet reported on ethnicities other than African-American.

Hormone replacement therapy (HRT) is an established risk fac-tor for venous thromboembolism, including both deep vein throm-bosis and pulmonary embolism.24–26 The use of HRT withtamoxifen in both the IBIS-1 and Royal Marsden studies may havehad additive effects on venous thromboembolic events related totamoxifen treatment. Although women with a history of endome-trial cancer, deep vein thrombosis or pulmonary embolism wereexcluded from study participation, no screening methods at enroll-ment were reported to detect women at increased risk of theseconditions. The endometrial cancer screening by endometrialbiopsy was not compulsory in NSABP-P1 study until two yearsafter the initiation of study when more than two-third of womenwere enrolled in the study.5 Given that most cases of endometrialcancer were detected in the early phase of these studies, the possi-bility exists that occult cancers were present at the time ofenrollment.

Implications for practice

Several factors have likely contributed to the extremely low useof tamoxifen for chemoprevention in eligible women.15 It has beensuggested that the net benefit of tamoxifen on overall breast can-cer mortality outweighs its hazards in women age less than50 years.27 In a study by Kaplan et al., almost 60% of high risk wo-men were aware of the importance of tamoxifen for breast cancerprevention yet only 4% took the drug.28 One major obstacle in deci-sion-making was the lack of discussion about prevention of breastcancer. The fear of side-effects appears to be another principaldeterminant in decision-making.29–31 Many women will considertamoxifen for chemoprevention if their primary care physiciansrecommend it, provided they adequately address their concernsregarding side effects.31–33 In one study, approximately 20% of phy-sicians believed that they were insufficiently informed about theimportance of breast cancer risk reduction from tamoxifen.34

Therefore, one potential avenue to increase its uptake is educationabout chemoprevention with tamoxifen, in particular the informa-tion regarding side-effects. The information provided here regard-ing the actual rates of endometrial cancer, deep vein thrombosisand pulmonary embolism may be particularly helpful for youngwomen at high risk.

Since the approval of tamoxifen for breast cancer prevention,other breast cancer prevention trials have been initiated usingthe second and third generation SERMs, raloxifene and lasofoxif-ene, respectively.35–37 However, these studies included only post-menopausal women. Due to concerns regarding ovarianhyperstimulation, aromatase inhibitors are only recommendedfor postmenopausal women for breast cancer treatment; chemo-prevention studies (in progress) have excluded premenopausalwomen. Thus, tamoxifen is the only current option for chemopre-vention of breast cancer in young, premenopausal women.

We conclude that the rationale for recommending tamoxifenchemoprevention in young women at high risk of breast canceris well supported by this analysis of the risks. This review suggeststhat the risk of endometrial cancer attributable to tamoxifen inyoung women is minimal. Postmenopausal women are more likelyto develop endometrial hyperplasia (and subsequent cancer) thanare premenopausal women. The effects of tamoxifen on the uterineendometrium are directly related to circulatory ambient plasmaestradiol (E2) levels and low levels of E2 confer an increased riskof endometrial thickening.38–41 In other words, endometrial hyper-plasia is related to the menopausal status and hence, postmeno-pausal women are more susceptible. Women with persistentovarian function are less likely to develop endometrial thicknessas a result of tamoxifen use. Tamoxifen seems to act as an anti-

estrogenic agent on the endometrium in the presence of high E2

concentrations and thus, is less likely to cause endometrial hyper-plasia and cancer.42 The data from NSABP-P1 and IBIS-1 studiessuggest that tamoxifen is more likely to cause benign gynecologicconditions (e.g. leiomyomas and ovarian cysts) and menopausalsymptoms (e.g. hot flashes, vaginal discharge and irregular vaginalbleeding) in premenopausal women as compared to postmeno-pausal women13,43 without a significant effect on quality oflife.44,45 The appearance of vasomotor symptoms may be a markerof response to tamoxifen therapy.46 Although the Italian breastcancer prevention study was excluded from this review; the datafrom that study suggests that age equal to or greater than 60 anindependent risk factor for venous thromboembolism, includingdeep vein thrombosis and pulmonary embolism.47 Others havealso concluded that the net benefit of tamoxifen outweighs therisks in premenopausal women at high risk of breast cancer.48 Che-moprevention with tamoxifen has also been found to be cost-effec-tive, particularly in younger women.49–51

Implications for research

The risks of serious adverse effects from tamoxifen (includingendometrial cancer, deep vein thrombosis and pulmonary embo-lism), although small, may be associated with the dose and dura-tion of tamoxifen. This suggests that low-dose and a shortduration of prophylactic tamoxifen may have a better side-effectprofile than 20 mg per day for five years. The pharmacokineticproperties of tamoxifen enable it to maintain its anti-proliferativeactivity at doses below the conventional dose of 20 mg/day.52–56 Asignificant decrease in the proliferative index (Ki-67), mitotic activ-ity and estrogen and progesterone receptor expression is achiev-able in normal breast tissue treated with low-dosetamoxifen.57,58 Furthermore, the carcinogenic effects of tamoxifenon the uterus and other tissues appear to be highly dependent onthe dose and duration of exposure.59,60 However, the benefit of ashort course of tamoxifen in high-risk healthy women has notyet been compared to a traditional five year course. Andersonet al. showed that tamoxifen treatment for one or two years wasnot associated with inferior disease-free survival or overall survivalin women with high-risk breast cancer.61 In another study, a shortduration of adjuvant tamoxifen reduced the incidence of secondprimary breast cancer without any increase in endometrial can-cer.62 These factors suggest that short-term prophylaxis withlow-dose tamoxifen might be an effective option with a favorablesafety profile in high-risk women. It is important that this compar-ison be addressed in a randomized trial.

Conflict of interest

None.

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