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American Society of Clinical Oncology Clinical PracticeGuideline: Update on Adjuvant Endocrine Therapy forWomen With Hormone Receptor–Positive Breast CancerHarold J. Burstein, Ann Alexis Prestrud, Jerome Seidenfeld, Holly Anderson, Thomas A. Buchholz,Nancy E. Davidson, Karen E. Gelmon, Sharon H. Giordano, Clifford A. Hudis, Jennifer Malin,Eleftherios P. Mamounas, Diana Rowden, Alexander J. Solky, MaryFran R. Sowers, Vered Stearns,Eric P. Winer, Mark R. Somerfield, and Jennifer J. Griggs

From the Dana-Farber Cancer Institute,Boston, MA; American Society of Clini-cal Oncology, Alexandria, VA; BreastCancer Coalition of Rochester; Inter-lakes Oncology and Hematology, Roch-ester; Memorial Sloan-Kettering CancerCenter, New York, NY; M. D. AndersonCancer Center, Houston; Susan G.Komen for the Cure, Dallas, TX; Univer-sity of Pittsburgh Cancer Institute, Pitts-burgh, PA; British Columbia CancerAgency, Vancouver, British Columbia,Canada; Greater Los Angeles VeteransAffairs Healthcare System, Los Ange-les, CA; Aultman Health Foundation,Canton, OH; Johns Hopkins School ofMedicine, Baltimore, MD; and Univer-sity of Michigan and University of Mich-igan Comprehensive Cancer Center,Ann Arbor, MI.

Submitted September 30, 2009;accepted May 20, 2010; publishedonline ahead of print at www.jco.org onJuly 12, 2010.

This represents an abridged versionof the complete guideline update andcontains updated recommendationswith a brief discussion of the relevantliterature. The complete guideline,with a comprehensive discussion ofthe literature and additional tables, isavailable at www.asco.org/guidelines/endocrinebreast.

Authors’ disclosures of potential con-flicts of interest and author contribu-tions are found at the end of thisarticle.

Corresponding author: American Soci-ety of Clinical Oncology, 2318 Mill Rd,Suite 800, Alexandria, VA 22314;e-mail: [email protected].

© 2010 by American Society of ClinicalOncology

0732-183X/10/2899-1/$20.00

DOI: 10.1200/JCO.2009.26.3756

A B S T R A C T

PurposeTo develop evidence-based guidelines, based on a systematic review, for endocrine therapy forpostmenopausal women with hormone receptor–positive breast cancer.

MethodsA literature search identified relevant randomized trials. Databases searched included MEDLINE,PREMEDLINE, the Cochrane Collaboration Library, and those for the Annual Meetings of theAmerican Society of Clinical Oncology (ASCO) and the San Antonio Breast Cancer Symposium(SABCS). The primary outcomes of interest were disease-free survival, overall survival, and timeto contralateral breast cancer. Secondary outcomes included adverse events and quality of life.An expert panel reviewed the literature, especially 12 major trials, and developed up-dated recommendations.

ResultsAn adjuvant treatment strategy incorporating an aromatase inhibitor (AI) as primary (initialendocrine therapy), sequential (using both tamoxifen and an AI in either order), or extended (AIafter 5 years of tamoxifen) therapy reduces the risk of breast cancer recurrence compared with 5years of tamoxifen alone. Data suggest that including an AI as primary monotherapy or assequential treatment after 2 to 3 years of tamoxifen yields similar outcomes. Tamoxifen and AIsdiffer in their adverse effect profiles, and these differences may inform treatment preferences.

ConclusionThe Update Committee recommends that postmenopausal women with hormone receptor–positivebreast cancer consider incorporating AI therapy at some point during adjuvant treatment, either asup-front therapy or as sequential treatment after tamoxifen. The optimal timing and duration ofendocrine treatment remain unresolved. The Update Committee supports careful consideration ofadverse effect profiles and patient preferences in deciding whether and when to incorporate AI therapy.

J Clin Oncol 28. © 2010 by American Society of Clinical Oncology

INTRODUCTION

The first technology assessment for the adjuvant useof aromatase inhibitors (AIs) for women with hor-mone receptor–positive breast cancer was pub-lished by the American Society of ClinicalOncology (ASCO) in 2002.1 The technology as-sessment was updated in 20032 and 2004.3 Sincethen, additional reports from large-scale trials ofadjuvant endocrine therapy have been published.These developments warranted an update andsystematic review.

ASCO’s practice guidelines reflect expert con-sensus based on clinical evidence and literature

available at the time they are written and are in-tended to assist physicians in clinical decision mak-ing and to identify questions and settings for furtherresearch. Because of the rapid flow of scientific in-formation in oncology, new evidence may haveemerged since a guideline was submitted for publi-cation. Guidelines and assessments are not continu-ally updated and may not reflect the most recentevidence. Guidelines address only the topics specifi-cally identified in the guideline and are not applica-ble to interventions, disease, or stages of disease notspecifically identified. Guidelines cannot accountfor individual variation among patients and cannotbe considered inclusive of all proper methods of care

JOURNAL OF CLINICAL ONCOLOGY A S C O S P E C I A L A R T I C L E

© 2010 by American Society of Clinical Oncology 1

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or exclusive of other treatments. It is the responsibility of the treatingphysician or other health care provider, relying on independent expe-rience and knowledge of the patient, to determine the best course oftreatment for the patient. Accordingly, adherence to any guideline isvoluntary, with the ultimate determination regarding its applicationto be made by the physician in light of each patient’s individualcircumstances. ASCO guidelines describe the use of procedures andtherapies in clinical practice and cannot be assumed to apply to the useof these interventions in the context of clinical trials. ASCO assumesno responsibility for any injury or damage to persons or propertyarising out of or related to any use of ASCO’s guidelines, or for anyerrors or omissions.

UPDATE METHODOLOGY

Guideline Questions

The Update Committee (Appendix Table A1, online only) fo-cused on the optimal adjuvant endocrine strategy with use of eithertamoxifen, AIs, or both in sequence; duration of AI therapy; long-term adverse effects of AI therapy; identification of subpopulationswho might derive selective benefit from either AIs or tamoxifen-based treatments; efficacy of AIs among premenopausal women;and similarities or differences among commercially availablethird-generation AIs.

Literature Review and Analysis

Literature search strategy. For this update, ASCO staff evalu-ated a recent systematic review completed by Cancer Care Ontario(CCO) that included literature through May 2007.4 MEDLINE,PREMEDLINE, and the Cochrane Collaboration databases weresearched from May 2007 through February 2009 (Appendix, onlineonly), as were electronic databases for the San Antonio Breast CancerSymposium (SABCS) and ASCO Annual Meetings from 2007 to 2009.

Inclusion and exclusion criteria. Articles identified for inclusionin this systematic review met the following criteria: (1) the interven-tion was for the adjuvant therapy of breast cancer, (2) participantswere randomly assigned to any of the treatments described previ-ously, and (3) reports included at least one of the following primaryoutcomes of interest: overall survival, disease-free survival, or breastcancer–specific survival. Three different treatment strategies wereidentified on the basis of the timing of AI therapy: initial endocrinetherapy (hereafter referred to as a primary adjuvant strategy), sequen-tial therapy with treatment divergence if the patient was disease freefollowing 1 to 4 years of initial treatment with adjuvant endocrineagents (most often tamoxifen), or extended therapy with randomassignment if the patient was disease free following 5 years of treat-ment with adjuvant tamoxifen.

Twelve prospective, randomized clinical trials originally identi-fied by the co-chairs were the focus of this systematic review. Thesesame trials were identified in the CCO systematic review, as well as ina systematic review completed by the National Institute for HealthResearch (NIHR) in the United Kingdom.5

Several important limitations of the existing literature were iden-tified. Of particular note is the timing of randomization (Fig 1). Mostsequential trials and all of the extended trials randomly assignedwomen who were free of recurrence through multiple years of tamox-ifen therapy, effectively excluding women with early recurrence. For

this reason, the patient populations in the sequential and extendedtrials may differ importantly from one another and from patients inthe primary therapy studies. Another limitation is the relatively shortfollow-up; disease recurrence decades after diagnosis is not uncom-mon. The longest available median follow-up in the present trials is

Table 1. Summary of 2010 Recommendations

Clinical Question Recommendation

1a. What adjuvantendocrine treatmentsshould be offered topostmenopausalwomen with hormonereceptor–positivebreast cancer?

Postmenopausal women should considertaking an AI during the course of adjuvanttreatment to lower recurrence risk, eitheras primary therapy or after 2 to 3 years oftamoxifen. Duration of AI therapy shouldnot exceed 5 years.

1b. What is the appropriateduration of adjuvantendocrine therapy?

Therapy with an AI should not extendbeyond 5 years in either the primary orextended adjuvant settings outside theclinical trials setting. In the sequentialsetting, patients should receive an AI after2 or 3 years of tamoxifen for a total of 5years of adjuvant endocrine therapy.Patients initially treated with an AI butwho discontinue treatment before 5 yearsof therapy should consider incorporatingtamoxifen for a total of 5 years ofadjuvant endocrine therapy.

1c. If tamoxifen isadministered first, howlong should it becontinued before theswitch to an AI?

Patients who initially receive tamoxifen asadjuvant therapy may be offered an AIafter 2 to 3 years (sequential) or after 5years (extended) of therapy. The besttime to switch from an AI to tamoxifen (orthe converse) is not known. Switching at2 to 3 years is recommended, butswitching at 5 years is also supported byavailable data.

2. Are there specificpatient populations thatderive differing degreesof benefit from an AI incomparison totamoxifen?

A specific marker or clinical subset thatpredicts which adjuvant treatmentstrategy (tamoxifen alone, AI alone, or AIand tamoxifen-based) is best has notbeen identified. Among men with breastcancer, tamoxifen remains the standardadjuvant endocrine treatment. TheCYP2D6 genotype is not recommended toselect adjuvant endocrine therapy. Cautionwith concurrent use of CYP2D6 inhibitors(such as bupropion, paroxetine, orfluoxetine) and tamoxifen isrecommended because of drug-druginteractions.

3. What are the toxicitiesand risks of adjuvantendocrine therapy?

Clinicians should consider adverse effectprofiles, patient preferences, and pre-existing conditions when discussingadjuvant endocrine strategies. Adverseeffect profiles should be discussed withpatients when presenting availabletreatment options. Clinicians mayrecommend that patients changetreatments if adverse effects areintolerable or patients are persistentlynoncompliant with therapy.

4. Are AIs effectiveadjuvant therapy forwomen who arepremenopausal at thetime of diagnosis?

Women who are pre- or perimenopausal atdiagnosis should be treated with 5 yearsof tamoxifen.

5. Can the third-generation AIs be usedinterchangeably?

Meaningful clinical differences between thecommercially available third-generation AIshave not been demonstrated to date. TheUpdate Committee believes thatpostmenopausal patients intolerant of oneAI may be advised to consider tamoxifenor a different AI.

Abbreviation: AI, aromatase inhibitor.

Burstein et al

2 © 2010 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

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slightly more than 8 years; most studies have considerably shorterfollow-up. For the majority of the efficacy outcomes across all studies,the median time to event has yet to be reached. The relatively modestnumber of events may also limit study conclusions.

The number of actual events was modest because of the generallyfavorable prognosis among patients. Owing to the vagaries of datacollection and patient participation, as well as the distribution ofclinical subsets, subgroup evaluations are hindered by relatively smallsample sizes. Small sample size is also a limitation in analyzing avail-able quality-of-life data. Finally, comparisons between trials are hin-dered because of different definitions of study end points.6

Consensus Development Based on Evidence

The Update Committee was charged with reviewing evidencefrom the systematic review and drafting new recommendations (Ta-ble 1). Per standard ASCO practice, the guideline was submitted to theJournal of Clinical Oncology for peer review. The content of the guide-line was reviewed and approved by both the ASCO Clinical PracticeGuideline Committee and the Board of Directors before publication.

Guideline and Conflicts of Interest

The Update Committee was assembled in accordance withASCO’s Conflict of Interest Management Procedures for ClinicalPractice Guidelines (“Procedures,” summarized at www.asco.org/

guidelinescoi). Members completed ASCO’s disclosure form, whichrequires disclosure of financial and other interests relevant to thesubject matter of the guideline, including relationships with commer-cial entities that are reasonably likely to experience direct regulatory orcommercial impact as the result of promulgation of the guideline.Categories for disclosure include employment relationships, consult-ing arrangements, stock ownership, honoraria, research funding,and expert testimony. In accordance with the Procedures, themajority of the members of the Update Committee did not discloseany such relationships.

RESULTS

Summary of the Literature Review Results

Since the last ASCO update, 442 published articles and 42presentations, posters, or abstracts were identified (Appendix FigA1). Of these, 49 reported either findings from one of 12 trials7-49

or were systematic reviews or meta-analyses of this same set oflandmark trials for adjuvant endocrine therapy.4,50-54 Thirteenarticles with primary data were retrieved to complement extrac-tion. Five reports available after completion of the initial searchwere also considered.55,56

Table 2. Disease-Free Survival

Trial Arm

MedianFollow-Up(months)

Range(months)

No. of PatientsObserved

Disease-Free SurvivalEvents

HR 95% CI P

AI Comparator

AI Comparator No. % No. %

PrimaryATAC20 ANA v TAM ITT 100 0-126 3,125 3,116 817 26.1 887 28.5 0.90 0.82 to 0.99 .025BIG 1-9841 LET v TAM ITT 76 2,463 2,459 509 20.7 565 23.0 0.88 0.78 to 0.99a .03ABCSG-1222 ANA v TAM 47.8 903 900 72 8.0 65 7.2 1.10 0.78 to 1.53 .59

SequentialBIG 1-9841 TAM/LET v LET 71 1,548 1,546 259 16.7 248 16.0 1.05 0.84 to 1.32b NR

LET/TAM v LET 71 1,540 1,546 236 15.3 248 16.0 0.96 0.76 to 1.21b NRABCSG-829 TAM/ANA v TAM ITT 72 1,865 1,849 227 12.2 261 14.1 0.85 0.71 to 1.01c,d .067ITA9 ITT 64 12-93 223 225 39 17.5 63 28 0.57 0.38 to 0.85e .005TEAM56 TAM/EXE v EXE ITT 61 4,868 4,898 714 712 0.97 0.88 to 1.08 .604IES13 ITT 55.7 0-89.7 2,352 2,372 354 455 0.76 0.66 to 0.88 � .001N-SAS BC-038 42 3.2-60 347 349 26 7.5 37 10.6 0.69 0.42 to 1.14 .14f

ARNO 9533 30.1 � 12 to � 84 489 490 38 7.8 56 11.4 0.66 0.44 to 1.00 .049Extended

MA.1725 ITTg 64 16-95 2,583 2,587 164 6.3 235 9.1 0.68 0.55 to 0.83 � .001ABCSG-6a30 62.3 386 466 30 7.8 57 12.2 0.62 0.40 to 0.96h .031NSABP B-3336 30 783 779 37 4.7 52 6.7 0.68 .07

NOTE. Percent calculated as number of events divided by number of patients observed.Abbreviations: AI, aromatase inhibitor; HR, hazard ratio; ATAC, Arimidex, Tamoxifen, Alone or in Combination (trial); ANA, anastrozole; TAM, tamoxifen; ITT, intent

to treat; BIG, Breast International Group; LET, letrozole; ABCSG, Austrian Breast and Colorectal Cancer Study Group; NR, not reported; ITA, Italian TamoxifenAnastrozole (trial); TEAM, Tamoxifen Exemestane Adjuvant Multinational (trial); EXE, exemestane; IES, Intergroup Exemestane Study; N-SAS, National SurgicalAdjuvant Study (Group); ARNO, Arimidex-Nolvadex (trial); NSABP, National Surgical Adjuvant Breast and Bowel Project.

aAnalysis includes only patients from monotherapy arms; crossovers not censored.b99% CIs used to account for multiple comparisons.cRelapse-free survival includes local and distant recurrence, contralateral breast cancer, and death without recurrence.dPatients who crossed over were censored at time of crossover.eEvent-free survival includes locoregional or distant recurrence, second primary (including contralateral breast cancer), and deaths without recurrence.fTwo different P values reported (P � .06 in abstract, P � .14 on poster).gSeventeen patients omitted from ITT analysis.hRecurrence-free survival.

ASCO Guideline for Adjuvant Endocrine Therapy for Breast Cancer

www.jco.org © 2010 by American Society of Clinical Oncology 3


GUIDELINE RECOMMENDATIONS

Clinical question 1a. What adjuvant endocrine treatments shouldbe offered to postmenopausal women with hormone receptor–positivebreast cancer?

Recommendation 1a. The Update Committee recommends,on the basis of data from randomized, controlled trials, that mostpostmenopausal women consider taking an AI during the course ofadjuvant treatment to lower recurrence risk, either as primarytherapy or after 2 to 3 years of tamoxifen—strategies that yield

Table 3. Contralateral Breast Cancer

Trial Arm


Range(months)


Contralateral Breast CancerEvents

HR 95% CI P

AI Comparator


PrimaryATAC20 ANA v TAM ITT 100 3,125 3,116 61 1.9 87 2.8 0.68 0.49 to 0.94 .02BIG 1-985 LET v TAM 68 4,003 4,007 16 0.4 27 0.7 NR NR NRTEAM32 EXE v TAM ITT� 33† 4,898 4,868 21 0.4 17 0.3 NR NR NR

SequentialABCSG-829 TAM/ANA v TAM ITT 72 1,865 1,849 19 1.0 29 1.6 0.64 0.36 to 1.13 NRIES13 ITT 55.7 0-89.7 2,352 2,372 18 0.76 35 1.5 0.57 0.33 to 0.98 .04ARNO 9533 30.1 � 12 to � 84 489 490 7 1.4 5 1 NR NR NR

ExtendedMA.1728 64 2,583 2,587 30 1.16 49 1.89 0.61 0.39 to 0.97 .033ABCSG-6a30 62.3 386 466 6 1.6 11 2.4 0.67 0.25 to 1.80‡ .422

NOTE. Percent calculated as number of events divided by number of patients observed.Abbreviations: AI, aromatase inhibitor; HR, hazard ratio; ATAC, Arimidex, Tamoxifen, Alone or in Combination (trial); ITT, intent to treat; BIG, Breast International

Group; LET, letrozole; TAM, tamoxifen; NR, not reported; TEAM, Tamoxifen Exemestane Adjuvant Multinational (trial); EXE, exemestane; ABCSG, Austrian Breastand Colorectal Cancer Study Group; ANA, anastrozole; IES, Intergroup Exemestane Study; ARNO, Arimidex-Nolvadex (trial).

�Data for contralateral risk in the TEAM trial have been reported for comparison of initial therapy of TAM v EXE but not for TAM/EXE v EXE at this time.†Follow-up for all TEAM patients is 33 months (data beyond that censored).‡Risk of contralateral breast cancer.

Table 4. Overall Survival

Trial Arm


Range(months)


Overall Survival Deaths

HR 95% CI P

AI Comparator


PrimaryATAC20 ANA v TAM ITT 100 3,125 3,116 629 20.1 624 20.0 1.00 0.89 to 1.12 .99BIG 1-9841 LET v TAM ITT 76 2,463 2,459 303 12.3 343 14.0 0.81 0.69 to 0.94� .08ABCSG-1222 ANA v TAM 47.8 903 900 27 3.0 15 1.7 1.8 0.95 to 3.38 .70

SequentialABCSG-829 TAM/ANA v TAM ITT 72 1,865 1,849 138 7.4 165 9.0 0.78 0.62 to 0.98† .032BIG 1-9841 TAM/LET v LET 71 1,548 1,546 154 9.9 137 8.9 1.13 0.83 to 1.53‡ NR

LET/TAM v LET 71 1,540 1,546 123 8.0 137 8.9 0.90 0.65 to 1.24‡ NRITA9 ITT 64 12-93 223 225 12 5.4 21 9.3 0.56 0.28 to 1.15 .1TEAM56 TAM/EXE v EXE ITT 61 4,868 4,898 NR (90.6%

survival)NR (90.5%

survival)1.00 0.89 to 1.14 .999

IES13 ITT 55.7 0-89.7 2,352 2,372 222 9.4 261 11.0 0.85 0.71 to 1.02 .08N-SAS BC-038 42 3.2-60 347 349 NR NR NR .59ARNO 9533 30.1 � 12 to � 84 489 490 15 3.1 28 5.7 0.53 0.28 to 0.99 .045

ExtendedMA.1725 ITT§ 64 16-95 2,583 2,587 154 6.0 155 6.0 0.98 0.78 to 1.22 .853ABCSG-6a30 62.3 386 466 40 10.4 55 11.8 0.89 0.59 to 1.34 .570NSABP B-3336 30 783 779 16 2.0 13 1.7 NR NR


to treat; BIG, Breast International Group; LET, letrozole; ABCSG, Austrian Breast and Colorectal Cancer Study Group; NR, not reported; ITA, Italian TamoxifenAnastrozole (trial); TEAM, Tamoxifen Exemestane Adjuvant Multinational (trial); EXE, exemestane; IES, Intergroup Exemestane Study; N-SAS, National SurgicalAdjuvant Study (Group); ARNO, Arimidex-Nolvadex (trial); NSABP, National Surgical Adjuvant Breast and Bowel Project.

�Analysis includes only patients from monotherapy arms; crossovers not censored.†Patients who crossed over were censored.‡99% CIs used to account for multiple comparisons.§Seventeen patients omitted from ITT analysis.

Burstein et al



TrialTime Since Random Assignment

Primary Adjuvant

Sequencing

Extended Adjuvant

60-month strategy; median follow-up 100 mos Postmenopausal, HR (+)

TAM ANA TAM + ANA

60-month strategy Median follow-up 76 mos (monotx), 71 mos (switching) Postmenopausal, HR (+)

LET TAM LET (2 yrs), TAM (3 yrs) TAM (2 yrs), LET (3 yrs)

36 month strategy Median follow-up 47.8 mos Premenopausal, ER and/ or PR (+)

TAM + GOS ANA + GOS TAM + GOS + ZOL ANA + GOS + ZOL

Primary random assignment60 month strategy; median follow-up 72 mos Postmenopausal, ER(+)/PR(+), no chemo

TAM TAM (2 yrs), ANA (3 yrs)

Randomly assigned to 2-3 yrs tx (5 yrs total)Median follow-up 64 mos Postmenopausal, ER(+), Node (+)

TAM (2-3 yrs) TAM

ANA

Primary random assignment60 month strategy; Follow-up 61 mos Postmenopausal, ER and/or PR (+)

TAM (2½ yrs), EXE (2½ yrs)

EXE

Randomly assigned to 2-3 yrs tx (5 yrs total)Median follow-up 55.7 mos Postmenopausal, ER(+) or unknown

TAM (2-3 yrs) TAM

EXE

Randomly assigned to 1-4 yrs tx (5 yrs total)Median follow-up 42 mos Postmenopausal

TAM (1-4 yrs) TAM

ANA

Randomly assigned to 3 yrs tx (5 yrs total)Median follow-up 30.1 mos Postmenopausal, hormone responsive

TAM (2 yrs) TAM

ANA

5 yrs of TAM, randomly assigned to 60 mos of txMedian follow-up 64 mos Postmenopausal, HR(+)

TAM LET

Placebo

5 yrs TAM, randomly assigned to 36 mos of txMedian follow-up 62.3 mos Postmenopausal, endocrine responsive

TAM ANA

Placebo

5 yrs of TAM, randomly assigned to 60 mos of txMedian follow-up 30 mos Postmenopausal, ER or PR (+)

TAM EXE

Placebo

-5 -4 -3 -2 -1 0 1 2 3 4 5

BIG 1-9839

ATAC111

ABCSG-1222

ABCSG-859

ITA112

TEAM31

IES113

NSAS BC-038

ARNO 95114

MA.17115

ABCSG-6a116

NSABP B-33117

Fig 1. Schema of included trials. ATAC, Arimidex, Tamoxifen, Alone or in Combination (trial); mos, months; HR (�), hormone receptor–positive; TAM, tamoxifen; ANA,anastrozole; BIG, Breast International Group; FU, follow-up; monotx, monotherapy; LET, letrozole; yrs, years; ABCSG, Austrian Breast and Colorectal Cancer StudyGroup; ER (�), estrogen receptor–positive; PR (�), progesterone receptor–positive; GOS, goserelin; ZOL, zoledronic acid; ABCSG, Austrian Breast and ColorectalCancer Study Group; Chemo, chemotherapy; ITA, Italian Tamoxifen Anastrozole (trial); tx, therapy; TEAM, Tamoxifen Exemestane Adjuvant Multinational (trial); EXE,exemestane; IES, Intergroup Exemestane Study; Unk, unknown; N-SAS, National Surgical Adjuvant Study (Group); ARNO, Arimidex-Nolvadex (trial); NSABP, NationalSurgical Adjuvant Breast and Bowel Project.




equivalent outcomes in prospective studies. Duration of AI ther-apy should not exceed 5 years.

Literature update and discussion 1a. In comparison to 5 years oftamoxifen alone, use of an AI in either primary, sequential, or ex-tended treatment improves disease-free survival and reduces the riskof breast cancer events, including distant recurrence, locoregionalrecurrence, and contralateral breast cancer (Tables 2 and 3; Fig 1). Inabsolute terms, the reduction in risk of recurrence associated withAI-based therapy compared with tamoxifen is modest, typicallyamounting to � 5% through multiple years of follow-up (Table 2).Tamoxifen and AI-based therapy are equivalent in terms of overallsurvival when used as either a primary or extended treatment strategy(Table 4). Two of the six trials of sequential treatment strategiesyielded statistically significant improvements in overall survival com-pared with tamoxifen alone, although the absolute difference in over-all survival is modest (Table 4).

Breast cancer events such as locoregional recurrence, contralat-eral breast cancer, and early distant metastatic recurrence are clinicallyimportant to patients. For this reason, the Update Committee recom-mended consideration of AI therapy at some time during adjuvantendocrine therapy even though few trials demonstrated statisticallysignificant differences in overall survival.

Sequential therapy. Two trials directly compared primarymonotherapy with sequential therapy as an initial 5-year adjuvantendocrine regimen. The Breast International Group 1-98 (BIG 1-98)trial compared primary tamoxifen or AI monotherapy against se-quences of tamoxifen followed by an AI or an AI followed by tamox-ifen.39 The Tamoxifen Exemestane Adjuvant Multicenter (TEAM)trial compared a sequential treatment of tamoxifen followed by an AIagainst an AI alone.56,57 Neither study demonstrated clinical or statis-tically significant differences between patients who received an AIalone, tamoxifen sequenced with an AI, or in the case of BIG 1-98, anAI sequenced with tamoxifen, with respect to disease-free or overallsurvival. In BIG 1-98, however, each AI-based therapy was superior totamoxifen monotherapy with respect to disease-free survival (Table2).39 These data support the recommendation to incorporate AI ther-apy at some point during the first 5 years of adjuvant endocrinetherapy, either as primary therapy or in sequence with tamoxifen.

Clinical question 1b. What is the appropriate duration of adju-vant endocrine therapy?

Recommendation 1b. Therapy with an AI should not extendbeyond 5 years in either the primary or extended adjuvant settings,outside of clinical trials. In the sequential setting, the Update Commit-tee recommends, on the basis of available evidence from randomized,controlled trials, that patients receive an AI after 2 or 3 years oftamoxifen for a total of 5 years of adjuvant endocrine therapy. TheUpdate Committee recommends that patients who are initiallytreated with an AI but discontinue treatment before 5 years oftherapy consider taking tamoxifen for a total of 5 years of adjuvantendocrine therapy.

Literature update and discussion 1b. Importantly, no trials di-rectly compared sequential or extended adjuvant strategies againstone another or primary against extended strategies. Studies used dif-ferent durations of total endocrine therapy and different durations ofAI and tamoxifen treatment. It is not known whether these differencesin duration of therapy are clinically significant. Optimal duration oftherapy in the extended setting is unclear at this time. Safety andefficacy data from the primary trials support up to 5 years of AI therapy

as a primary adjuvant strategy, a duration used in two trials of ex-tended therapy after 5 years of tamoxifen.

The treatment regimen for patients in the sequencing trialsspanned 5 years. No data support clinical benefits for durations of AIslonger than 2 or 3 years in a sequencing strategy. Data from random-ized, controlled trials demonstrate that women who receive primaryAI therapy should be treated for a total of 5 years; women whoinitially receive tamoxifen and switch to an AI should also receive atleast five total years of endocrine therapy. Women who receive ex-tended adjuvant therapy should receive 8 to 10 years of total endocrinetreatment—5 years of tamoxifen followed by 3 to 5 years of an AI.

The Update Committee acknowledges that these recommenda-tions yield an unfamiliar pattern of different durations of adjuvantendocrine treatment based on the treatment strategy used. This is afunction of offering an AI at a different time point in accordance witheach strategy. The recommended limit on AI treatment is 5 years total,across strategies. Two trials—MA.17R and National Surgical Adju-vant Breast and Bowel Project B-42 (NSABP B-42)—are evaluatingwhether longer durations of AI therapy improve outcomes, but resultsare not yet available.

Clinical question 1c. If tamoxifen is administered first, how longshould it be continued before the switch to an AI?

Recommendation 1c. The Update Committee recommendsthat, on the basis of available evidence from randomized, controlledtrials, patients who initially receive tamoxifen as adjuvant therapy maybe offered an AI after 2 to 3 years (sequential) or after 5 years (ex-tended) of therapy. The time to switch from an AI to tamoxifen (or theconverse) that maximally improves outcomes is not known fromavailable direct evidence. The Update Committee recommendsswitching at 2 to 3 years on the basis of data from sequential trials thatused this strategy. Switching at 5 years is also a strategy supported bythe extended adjuvant randomized trials.

Literature update and discussion 1c. Most trials of sequentialtherapy switched patients from tamoxifen to an AI after 2 to 3 years oftherapy. Some specified an exact cross-over point while others permit-ted switching within a broad window. Trials of extended therapyenrolled patients who already received an average of 5 years of tamox-ifen (Fig 1). Of the trials of sequencing or switching, only BIG 1-98,58

TEAM,31 and Austrian Breast and Colorectal Cancer Study GroupABCSG-859 enrolled patients before commencement of adjuvant en-docrine therapy. The other sequencing and all the extended trialsrandomly assigned patients free of recurrence after multiple years oftamoxifen. Data are lacking to establish the best duration of tamoxifentherapy before switching to an AI.

Three trials of extended adjuvant therapy that used AI treatmentfor 3 to 5 years after 5 years of tamoxifen demonstrated that extendedtherapy can lower the risk of breast cancer recurrence (Table 2 andAppendix Table A2, online only) and contralateral breast cancer (Ta-ble 3) but does not improve overall survival (Table 4). The UpdateCommittee recommends extended therapy with an AI for postmeno-pausal patients who complete 5 years of tamoxifen.

For a newly diagnosed patient or a patient who has taken tamox-ifen for 2 to 5 years, it is not known whether switching from tamoxifento an AI earlier or later is more effective for long-term disease-freesurvival. Lacking direct comparative data, the Update Committeerecommends considering a switch to an AI after 2 or 3 years oftamoxifen therapy. This recommendation is informed by several ob-servations. First, both the Arimidex-Nolvadex (ARNO) 95 and

Burstein et al



ABCSG-8 trials, which transitioned patients from tamoxifen to an AIafter 2 or 3 years, demonstrated survival advantages, as did a meta-analysis of sequential trials29,33,60 (Table 3). Second, each AI-basedarm of BIG 1-98, including those with switching at 2 years, hadimproved disease-free survival relative to 5 years of tamoxifen39

(Table 2). Incorporating an AI into the adjuvant treatment regi-men at some point during the first 5 years of endocrine therapyyields clinical improvements.

Clinical question 2. Are there specific patient populations thatderivedifferingdegreesofbenefitfromanAIincomparisontotamoxifen?

Recommendation 2. Direct evidence from randomized trialsdoes not identify a specific marker or clinical subset that predictedwhich adjuvant treatment strategy, tamoxifen or AI monotherapy orsequential therapy, would maximally improve outcomes for a givenpatient. Among men with breast cancer, tamoxifen remains the stan-dard adjuvant endocrine treatment. The Update Committee recom-mends against using CYP2D6 genotype to select adjuvant endocrinetherapy. The Update Committee encourages caution with concur-rent use of CYP2D6 inhibitors (such as bupropion, paroxetine, orfluoxetine; Table 5) and tamoxifen because of the known drug-drug interactions.

Literature update and discussion 2. Endocrine therapy is effectiveonly among patients with tumors that express hormone receptorssuch as estrogen receptor (ER) and/or progesterone receptor.61,62 Tu-mor size, nodal status, grade, quantitative levels of hormone receptorexpression, HER2 overexpression, markers of proliferation, and the21-gene recurrence score63 are prognostic factors among patients re-ceiving endocrine therapy.37 These prognostic markers help to definerelative risk of recurrence in the first 5 to 10 years after diagnosis.

The major trials of adjuvant AI therapy included patients withhormone receptor–positive tumors, generally irrespective of othermarkers or staging. Retrospective subset analyses from some trialsconsidered a variety of prognostic factors among patients receivingtamoxifen or AI therapy. In these retrospective studies, tumor size,nodal status, age, quantitative ER and progesterone receptor levels,HER2 expression,44,60 grade, Ki-67,49 and the 21-gene recurrencescore64 seem to serve as prognostic factors for risk of breast cancerrecurrence among patients receiving either tamoxifen or AI therapy(Appendix Table A3, online only).

Traditional assumptions about proportionate risk reductionachieved with adjuvant therapy suggest that differences in clinical

outcome between various treatments are likely to be of greater abso-lute magnitude among patients with higher-risk breast cancers. Con-versely, among women with lower-risk tumors, differences inoutcomes between AI-based therapies and tamoxifen or between pri-mary or sequential use of AIs are likely to be smaller if present at all.Emerging data from BIG 1-98 seem to validate these assumptions.37,65

However, available retrospective subset analyses are constrained bymissing data on some patients, technical limitations in the perfor-mance of correlative marker testing, multiple hypothesis testing,varying assays used by different trials, and lack of prospective,corroborative data.

On the basis of evidence from randomized clinical trials andconsistent with the recommendation, the Update Committee recom-mended treatment with either upfront use of an AI or sequentialtherapy with tamoxifen, followed by an AI, irrespective of any specificclinical subset or prognostic marker.

Male breast cancer. There is no evidence to evaluate the efficacyof adjuvant AI therapy in men. Tamoxifen remains the standardadjuvant endocrine therapy for male breast cancer.66

CYP2D6 genotype. Accumulating data suggest that variability intamoxifen metabolism may affect serum levels of the tamoxifen me-tabolite endoxifen, which may in turn affect the likelihood of cancerrecurrence in tamoxifen-treated patients.66-73 Factors that contributeto this variability include concurrent use of other drugs that inhibit theCYP2D6 isoenzyme (which converts tamoxifen to endoxifen) andpharmacogenetic variation (polymorphisms) in CYP2D6 alleles. Itis not known whether variations in CYP2D6 genotype account fordifferences in outcomes among patients treated with tamoxifen.Available data on CYP2D6 pharmacogenetics are insufficient to rec-ommend testing as a tool to determine an adjuvant endocrine strategy.

The Update Committee recognized the accumulating evidenceon drug-drug interactions between tamoxifen and other drugs thatinhibit CYP2D6 (such as buproprion, paroxetine, or fluoxetine; Table5). Evidence linking such interactions to breast cancer outcomes re-mains limited and indirect. Patients clearly benefiting from knownCYP2D6 inhibitors might avoid tamoxifen because of potential phar-macologic interactions. Conversely, women taking tamoxifen mayprefer to avoid concurrent use of known CYP2D6 inhibitors if suitablealternatives are available.

Clinical question 3. What are the toxicities and risks of adjuvantendocrine therapy?

Recommendation 3. The Update Committee recommends thatclinicians consider adverse effect profiles, patient preferences, andpre-existing conditions when recommending an adjuvant endocrinestrategy for postmenopausal women. Clinicians should discuss ad-verse effect profiles when presenting available treatment options. TheUpdate Committee suggests that clinicians consider recommendingthat patients change treatment if adverse effects are intolerable or ifpatients are persistently noncompliant with therapy.

Literature update and discussion 3. Tamoxifen and AIs are gen-erally well tolerated but are associated with specific toxicities includingeffects on bone, cardiovascular, and gynecologic health. The differingadverse effect profiles are functions of differing mechanisms of action.Tamoxifen is a selective ER modulator with mixed pro- and antiestro-genic activities, while AIs achieve near complete estrogen deprivationin postmenopausal women. The Update Committee did not find

Table 5. Commonly Used CYP2D6 Inhibitors

Strong inhibitorsBupropionFluoxetineParoxetineQuinidine

Moderate inhibitorsDuloxetineTerbinafine

Weak inhibitorsAmiodaroneCimetidineSertraline

Flockhart DA: http://medicine.iupui.edu/clinpharm/ddis/table.asz.




evidence that AI therapy is less toxic or better tolerated than tamox-ifen. Both drug classes have distinct adverse effect profiles that arerelevant to individualizing therapy for patients.

Substudies from the large, randomized trials show generally well-maintained and similar quality of life scores in women receiving any ofthe adjuvant endocrine therapies.18,36,43,48,74-77 The severity of themost common adverse effects is mild to moderate for the majority ofpatients; serious adverse effects are rare. The long-term adverse effectprofiles for tamoxifen-treated patients are established from historicalliterature.78 Late effects of AI therapy remain to be fully characterized.

Appendix Tables A4 through A8 (online only) include an abbre-viated list of the adverse effects tabulated from the therapies evaluatedin the prospective, randomized trials discussed herein. Tamoxifen andAIs have differing effects on cardiovascular health. Data suggest thatAIs are associated with increased cardiovascular disease, possibly in-cluding ischemic cardiac disease, though in absolute terms, at present,any differences are believed to be small.40,51 In comparison to tamox-ifen, AI therapy is associated with an increased risk of both hypercho-lesterolemia and hypertension. Data are insufficient to excludeclinically significant differences in cardiovascular disease associatedwith the AIs. Tamoxifen is associated with an increased risk of venousthromboembolic events, giving rise to a 1% to 2% greater risk of deepvein thrombosis compared with women taking AIs (Appendix TableA5).51 Data on the relative incidence of stroke with either tamoxifen oran AI are inconclusive. Longer follow-up is required to better charac-terize the potential cardiac toxicity of AI therapy.

Tamoxifen and AIs have differing effects on musculoskeletalhealth and symptoms. In comparison to tamoxifen, AIs are associatedwith greater loss of bone mineral density17 and fractures (AppendixTable A6). The incidence of osteoporosis and bone fractures79 differsby approximately 2% to 4% in trials of primary adjuvant endocrinetherapy comparing tamoxifen with an AI11,19,21; risk is increased withAI therapy. Randomized clinical trials suggest that bisphosphonatetherapy can mitigate AI-associated loss of bone density.21,80-82 Thelong-term impact of AI treatment on osteoporosis risk and fracturerisk has not been characterized.

With maturation of clinical data and accumulating clinical expe-rience, it is clear that AIs cause a musculoskeletal/arthralgia syndrome.This syndrome is characterized by bone and joint symptoms, fre-quently described by patients as pain, stiffness, or achiness that issymmetric and not associated with other signs of rheumatologicdisorders.46,83-86 The prevalence of this syndrome is unclear, though itseems to be widespread; most patients have mild to moderate symp-toms. There are no known interventions of proven value for AI-associated musculoskeletal symptoms. Discontinuation of AI therapyusually relieves symptoms within 8 to 10 weeks.

Tamoxifen and AIs have differing effects on gynecologic health;adverse events are more common among women receiving tamox-ifen. In general, tamoxifen is associated with an increased risk ofuterine cancer (approximately 1% of patients), benign endometrialpathology (including bleeding, polyps, and hyperplasia), hysterec-tomy, and vaginal discharge (Appendix Table A7). AIs seem to be lessfrequently associated with hot flashes than tamoxifen is (AppendixTable A8). The Arimidex, Tamoxifen, Alone or in Combination(ATAC) and MA.17 trials both reported a lower incidence of vaginaldryness among patients treated with tamoxifen.74,77 Alternatively, theIntergroup Exemestane Study (IES) documented similar rates of vag-inal dryness among both treatment arms,18 and the TEAM trial re-

ported a statistically higher rate of vaginal dryness in patients whoreceived sequential tamoxifen and exemestane compared with ex-emestane alone.56 Findings were mixed with respect to loss of libido:MA.17 and IES noted similar rates, while AI-treated patients hadhigher rates in the ATAC trial (Appendix Table A8).31,75,76

Clinical question 4. Are AIs effective adjuvant therapy forwomen who are premenopausal at the time of diagnosis?

Recommendation 4. The Update Committee recommends thatwomen who are pre- or perimenopausal at the time of breast cancerdiagnosis be treated with 5 years of tamoxifen.

Additional considerations. The Update Committee recom-mends that clinicians use caution in evaluating menopausal status ofpatients who were pre- or perimenopausal at diagnosis. Unequivocaldetermination of menopausal status may be challenging to prove.Even among women who have not experienced menses for more than1 year, laboratory testing is inadequate because patients may recoverovarian function. This particularly applies to those patients who expe-rience chemotherapy- or tamoxifen-induced amenorrhea.

Literature update and discussion 4. AI therapy has been shown tobe effective only in postmenopausal women and is contraindicated inpatients with residual ovarian function. Patients accrued to ABCSG-12, the only trial to include premenopausal women, were all treatedwith gonadotropin-releasing hormone agonist therapy to achieve apostmenopausal state.22 Eligible patients had favorable prognosis andlow-grade breast cancer, and none received adjuvant chemotherapy,though 5% did receive neoadjuvant chemotherapy. These patients arenot necessarily representative of younger women with early-stagebreast cancer. ABCSG-12 demonstrated equivalence with respect totime to recurrence, disease-free survival, and overall survival betweentamoxifen and AI therapy in premenopausal women given ovariansuppression.22 Because of tamoxifen equivalence with AI therapy inthat setting and the occasional failure to achieve menopausal statuswith ovarian suppression, the Update Committee strongly recom-mends tamoxifen as primary adjuvant endocrine therapy for allpre- or perimenopausal women and women with treatment-induced amenorrhea.

Some women who were pre- or perimenopausal at the time ofdiagnosis may become unequivocally postmenopausal in subse-quent years. For these patients, the Update Committee suggestsincorporating AIs as either sequential or extended adjuvant endo-crine therapy. Relatively few women in the studies of sequential orextended therapy met this description. Thus, the magnitude of benefitfor introducing an AI in the subsequent treatment of such women isnot well characterized.87

Both chemotherapy and tamoxifen can contribute to amenor-rhea. This effect may be transient or permanent, depending on thepatient’s age and therapies received. Multiple reports document lateclinical recovery of ovarian function among women with treatment-induced amenorrhea, which could render AI therapy ineffective.88,89

Cessation of menses for 1 year is the clinical hallmark of menopause.However, this clinical definition applies only to women without healthconditions, surgery, or medications that contribute to amenorrhea,such as chemotherapy or tamoxifen and, thus, may not apply to manybreast cancer patients.

At present, the role of ovarian suppression in addition to tamox-ifen for premenopausal patients is not known. The Suppression ofOvarian Function Trial (SOFT) is comparing tamoxifen, tamoxifenplus ovarian suppression, and exemestane plus ovarian suppression,

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and it continues to accrue patients. Findings from this trial will furtherdefine best practices for premenopausal patients as well as those pa-tients who experience treatment-induced menopause.

Clinical question 5. Can the third-generation AIs beused interchangeably?

Recommendation 5. In the absence of direct comparisons, theUpdate Committee interprets available data as suggesting that benefitsof AI therapy represent a “class effect.” Meaningful clinical differencesbetween the commercially available third-generation AIs have notbeen demonstrated to date. In the clinical opinion of the UpdateCommittee (rather than direct evidence from randomized trials),postmenopausal patients intolerant of one AI but who are still candi-dates for adjuvant endocrine therapy may be advised to considertamoxifen or a different AI.

Literature update and discussion 5. Previous results were limitedto reports for principal use of a single AI in each of the clinical settingsof primary, sequential, or extended adjuvant therapy. There are still nodata from head-to-head comparisons of AIs. However, there are datafrom randomized trials for each of the commercially available third-generation AIs for all of the adjuvant treatment strategies (primary,sequential, and extended; Fig 1). The Update Committee interpretsthe existing data comparing the AIs with tamoxifen as qualitativelysimilar with respect to efficacy and tolerability. Toxicity reports (Ap-pendix Tables A4 through A8) have not suggested obvious clinicaladvantages of one AI over another with respect to compliance, consti-tutional or menopausal symptoms, bone health, cardiovascular dis-ease, or quality of life. Anecdotal experience suggests that patients maytolerate one AI better than another, but patterns are neither predict-able nor consistent. Two trials—MA.27 and Femara versus Anastro-zole Clinical Evaluation (FACE)—are directly comparing one AIagainst another as primary adjuvant therapy. However, data are notyet available from either trial.

PATIENT COMMUNICATION

The purpose of this section is to address aspects of patient-providercommunication that play a role in decision making about the use ofadjuvant endocrine therapy, the selection of agent, and the barriers toadherence to treatment regimens (taking medication as prescribed)and persistence with the medication schedule (taking medication forthe full duration prescribed). Separate literature searches and UpdateCommittee members’ suggestions, rather than the systematic review,were used to prepare this section.

Patients need to be informed about risk factors for tumor recur-rence, the role of residual subclinical (ie, microscopic) disease in caus-ing recurrence, and the potential benefit of adjuvant endocrinetherapy. Clinicians can base risk estimates in women with hormonereceptor–positive disease on well-established prognostic markerssuch as stage, HER2 status, and grade. Emerging molecular diag-nostic assays such as the 21-gene recurrence score also seem to serve asprognostic markers in ER-positive, node-negative breast cancer.90,91

Decision tools such as Adjuvant! Online92 quantify and communi-cate, in broad terms, both the risk of cancer recurrence and thebenefit of various adjuvant endocrine treatment strategies on thebasis of a patient’s tumor characteristics, comorbidity, age, andreceipt of chemotherapy.93

Rates of nonpersistence (early discontinuation of medications)in women who start taking tamoxifen are as high as 30% at 3 years afterfilling a first prescription. For example, a study of 2,816 women iden-tified a 22% rate of nonpersistence 12 months after starting tamox-ifen.94 In another study of 392 patients, 32% of women discontinuedadjuvant tamoxifen at 2 years and 39% at 3 years.95 Similarly, in asample of 961 women 65 years of age or older, 24% discontinuedtamoxifen after 2 years of treatment, 33% discontinued tamoxifenafter 3 years of treatment, and 50% discontinued tamoxifen before 5years; discontinuation was not due to recurrent disease.96

Data from clinical trials97 and claims-based research98 indicatethat persistence is no better with AIs. Physicians may underestimaterates of nonadherence and nonpersistence, and patients may be reluc-tant to disclose problems with adherence and persistence. Patientbeliefs about the benefits and risks of medications are associated withadherence and persistence; thus, discussing and addressing such be-liefs is warranted.99

Adverse effects are particularly important in precipitating earlydiscontinuation of therapy. Patients who experience treatment-related adverse effects are more likely to discontinue adjuvant endo-crine therapy, particularly during the first years.100,101 Adverse effectswere the most common reason for discontinuation, particularlyduring the first year according to one study. Among those whostopped tamoxifen in the first year, 70% stopped because of adverseeffects.96 Patients who experience adverse effects for which theywere not prepared seem to be at particularly high risk for nonper-sistence.101 Similarly, musculoskeletal adverse effects of the AIshave been shown to prompt discontinuation in more than 10% ofpatients who start an AI.85 Information support for patients aboutanticipated adverse effects and management of those adverse ef-fects may increase persistence.91

Financial constraints are another reported cause of nonpersis-tence with therapy. One study of patients taking tamoxifen noted that60% of patients who discontinued therapy early reported this issue asa key factor.96 It is likely that the out-of-pocket costs of AIs (Table 6)pose an even greater barrier to patients. Although physicians are gen-erally reluctant to discuss costs of cancer therapies,102 inquiring aboutpatients’ cost concerns may help direct patients to assistance programsand create opportunities to stress the benefits of persistence withadjuvant endocrine therapy. ASCO supports the development of re-sources to facilitate patient-provider communication about costs ofcancer care.103

In summary, optimal adjuvant endocrine therapy includes care-ful consideration of tumor risk, treatment benefits and adverse effects,and patient adherence. Clinicians should discuss realistic, quantitative

Table 6. Cost of Therapies

Drug

Cost ($)

Per Unit30-DaySupply

Anastrozole (Arimidex), 1 mg 12.66 379.80Exemestane (Aromasin), 25 mg 11.38 341.40Letrozole (Femara), 2.5 mg 13.91 417.30Tamoxifen (Nolvadex), 20 mg 3.67 110.10Tamoxifen, 20 mg 0.73 21.90

NOTE. US dollars; www.drugstore.com.




risks of cancer recurrence and death and benefits from cancer therapyas part of the adjuvant therapy decision-making process. Cliniciansshould alert patients to common adverse effects of therapy and seriallyinquire about treatment-related toxicities, patient adherence, and fac-tors that may affect adherence and persistence.

HEALTH DISPARITIES

ASCO clinical practice guidelines represent expert recommendationsderived from high-quality evidence on the best practices in diseasemanagement. However, racial, ethnic, and socioeconomic disparitiesin quality of health care exist and persist in the United States. Membersof racial and ethnic minority groups and patients with fewer financialresources tend to have a higher burden of comorbid illness, are morelikely to be uninsured or underinsured, face more challenges in access-ing care, and are at greater risk of receiving poor-quality care thanother Americans.104-108

Representation of minorities in clinical trials of adjuvant endo-crine therapy is low. To date, no evidence indicates differences intherapeutic benefit between black and white women receiving adju-vant tamoxifen in the clinical trials setting. A few studies suggest thatwomen who belong to minority groups are less likely to receiveguideline-concordant endocrine therapy. One study of prescribingpatterns109 indicated that rates of guideline-concordant adjuvant en-docrine therapy prescribing were lower in Hispanic (71%) and black(75%) patients compared with non-Hispanic white (85%) patients.

Only small samples of minority patients were included in persis-tence studies, largely preventing an examination of correlates andmechanisms of optimal therapy in minorities. Hispanics have largelybeen omitted. In one study,95 nonwhite patients (who were pooledbecause they represented only 17% of the sample) were more likely tostop adjuvant endocrine therapy before completing planned treat-ment. Other studies addressing racial differences in adherence to orpersistence with endocrine therapy generated mixed results.96,101 Racewas not associated with adherence or persistence in one recently pub-lished claims-based study of low-income patients with Medicaid110;80% of patients who started adjuvant endocrine therapy were persis-tent with medication at 1 year of follow-up. Awareness of disparities inquality of care should be considered in the context of this clinicalpractice guideline.

SUMMARY AND FUTURE DIRECTIONS

Incorporation of an AI improves disease-free survival in post-menopausal women with hormone receptor–positive breast can-cer compared with tamoxifen alone. Thus, the Update Committeerecommends AI therapy at some point during adjuvant treatment,either as upfront therapy or as sequential or extended treatment aftertamoxifen. The optimal timing and duration of AI treatment remainunresolved; it is unclear whether sequential treatment strategies yieldadvantages over monotherapy with AIs. The Update Committeerecognizes distinct adverse effect profiles of tamoxifen and AIs andbelieves that consideration of adverse effect profiles and patientpreferences are relevant to deciding whether and when to incorpo-rate AI therapy.

Important and unanswered questions about adjuvant endocrinetherapy in postmenopausal women persist. The Update Committee

identified the following issues as clinically significant for ongoingresearch studies and treatment recommendations:

● Long-term follow-up to characterize the lasting clinical effectsof AIs and impact on survival, survivorship, and quality of life

● Comparisons of currently available AIs against one another● Determination of optimal schedules for endocrine therapy,

including duration of treatment, interrupted treatmentschedules, and sequencing

● Late adverse effects of AI therapy● Strategies to improve adherence and minimize disparities in

access to therapy● Interventions to minimize treatment-related adverse effects

among women receiving adjuvant endocrine therapy● Comparative effectiveness analyses of adjuvant endocrine

strategies based on efficacy, toxicity, and cost● Development of biomarker(s) for selection of endocrine strat-

egies and for refining risk estimates in postmenopausal, ER-positive breast cancer

● Identification of predictors of late (after 5 or 10 years) recur-rence to tailor durations of therapy

● Definitive analyses of the role of drug metabolism and phar-macogenetics as predictors of benefit and/or treatment op-tions in adjuvant endocrine therapy

● Incorporation of novel antiestrogens or other treatments toenhance endocrine therapy and reduce recurrence risk

● Clarification of the role of AI therapy and ovarian suppressionamong women who are premenopausal at the time of breastcancer diagnosisThe Update Committee anticipates that the results from pro-

spective randomized trials, ongoing correlative science studies, long-term follow-up from major adjuvant studies, and smaller, focusedinvestigations of related scientific and clinical questions regardingendocrine treatment will continue to inform and revise the recom-mendations for adjuvant endocrine therapy in the years ahead.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

Although all authors completed the disclosure declaration, the followingauthor(s) indicated a financial or other interest that is relevant to the subjectmatter under consideration in this article. Certain relationships markedwith a “U” are those for which no compensation was received; thoserelationships marked with a “C” were compensated. For a detaileddescription of the disclosure categories, or for more information aboutASCO’s conflict of interest policy, please refer to the Author DisclosureDeclaration and the Disclosures of Potential Conflicts of Interest section inInformation for Contributors.Employment or Leadership Position: None Consultant or AdvisoryRole: Jennifer Malin, Pfizer (C); Eleftherios P. Mamounas, Novartis (C),Pfizer (C) Stock Ownership: None Honoraria: Karen E. Gelmon,Novartis, AstraZeneca, Pfizer; Eleftherios P. Mamounas, Pfizer, Novartis;Vered Stearns, AstraZeneca Research Funding: Vered Stearns, Novartis,Pfizer Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS

Conception and design: Harold J. Burstein, Jennifer J. GriggsAdministrative support: Ann Alexis Prestrud, Jerome Seidenfeld,Mark R. Somerfield

Burstein et al



Collection and assembly of data: Harold J. Burstein, Ann AlexisPrestrud, Jerome Seidenfeld, Jennifer J. GriggsData analysis and interpretation: Harold J. Burstein, Ann AlexisPrestrud, Jerome Seidenfeld, Holly Anderson, Thomas A. Buchholz,Nancy E. Davidson, Karen E. Gelmon, Sharon H. Giordano, Clifford A.Hudis, Jennifer Malin, Eleftherios P. Mamounas, Diana Rowden,Alexander J. Solky, MaryFran R. Sowers, Vered Stearns, Eric P. Winer,Mark R. Somerfield, Jennifer J. GriggsManuscript writing: Harold J. Burstein, Ann Alexis Prestrud, JeromeSeidenfeld, Holly Anderson, Thomas A. Buchholz, Nancy E. Davidson,

Karen E. Gelmon, Sharon H. Giordano, Clifford A. Hudis, JenniferMalin, Eleftherios P. Mamounas, Diana Rowden, Alexander J. Solky,MaryFran R. Sowers, Vered Stearns, Eric P. Winer, Mark R. Somerfield,Jennifer J. GriggsFinal approval of manuscript: Harold J. Burstein, Ann Alexis Prestrud,Jerome Seidenfeld, Holly Anderson, Thomas A. Buchholz, Nancy E.Davidson, Karen E. Gelmon, Sharon H. Giordano, Clifford A. Hudis,Jennifer Malin, Eleftherios P. Mamounas, Diana Rowden, Alexander J.Solky, MaryFran R. Sowers, Vered Stearns, Eric P. Winer, Mark R.Somerfield, Jennifer J. Griggs

REFERENCES

1. Winer EP, Hudis C, Burstein HJ, et al: Amer-ican Society of Clinical Oncology technology assess-ment on the use of aromatase inhibitors as adjuvanttherapy for women with hormone receptor-positivebreast cancer: Status report 2002. J Clin Oncol20:3317-3327, 2002

2. Winer EP, Hudis C, Burstein HJ, et al: Amer-ican Society of Clinical Oncology technology assess-ment working group update: Use of aromataseinhibitors in the adjuvant setting. J Clin Oncol 21:2597-2599, 2003

3. Winer EP, Hudis C, Burstein HJ, et al: Amer-ican Society of Clinical Oncology technology assess-ment on the use of aromatase inhibitors as adjuvanttherapy for postmenopausal women with hormonereceptor-positive breast cancer: Status report 2004.J Clin Oncol 23:619-629, 2005

4. Eisen A, Trudeau M, Shelley W, et al: Aro-matase inhibitors in adjuvant therapy for hormonereceptor positive breast cancer: A systematic re-view. Cancer Treat Rev 34:157-174, 2008

5. Hind D, Ward S, De Nigris E, et al: Hormonaltherapies for early breast cancer: Systematic reviewand economic evaluation. Health Technol Assess11:iii-iv, ix-xi, 1-134, 2007

6. Hudis CA, Barlow WE, Costantino JP, et al:Proposal for standardized definitions for efficacy endpoints in adjuvant breast cancer trials: The STEEPsystem. J Clin Oncol 25:2127-2132, 2007

7. Aihara T, Hozumi Y, Suemasu K, et al: Theeffects of exemestane, anastrozole and tamoxifenon bone mineral density and bone turnover markersin postmenopausal early breast cancer patients:Preliminary results of N-SAS (national surgical adju-vant study) BC04, the TEAM Japan sub-study. Pre-sented at the 30th Annual San Antonio BreastCancer Symposium, San Antonio, TX, December13-16, 2007 (abstr 2086)

8. Aihara T, Takatsuka Y, Osumi S, et al: PhaseIII randomized adjuvant study of tamoxifen aloneversus sequential tamoxifen and anastrozole in post-menopausal women with hormone-responsivebreast cancer: N-SAS BC03 study. Presented at the31st Annual San Antonio Breast Cancer Sympo-sium, San Antonio, TX, December 10-14, 2008 (ab-str 1138)

9. Boccardo F, Rubagotti A, Guglielmini P, et al:Switching to anastrozole versus continued tamox-ifen treatment of early breast cancer: Updated re-sults of the Italian tamoxifen anastrozole (ITA) trial.Ann Oncol 17:vii10-14, 2006 (suppl 7)

10. Chapman JA, Meng D, Shepherd L, et al:Competing causes of death from a randomized trialof extended adjuvant endocrine therapy for breastcancer. J Natl Cancer Inst 100:252-260, 2008

11. Coleman RE: Long-term effects of anastro-zole on bone mineral density: Seven-year results

from the ATAC trial. J Clin Oncol 26:27s, 2008(suppl; abstr 587)

12. Coleman RE, Banks LM, Girgis S, et al:Reversal of skeletal effects of endocrine treatmentsin the intergroup exemestane study. Presented atthe 31st Annual San Antonio Breast Cancer Sympo-sium, San Antonio, TX, December 10-14, 2008 (ab-str 1128)

13. Coombes RC, Kilburn LS, Snowdon CF, et al:Survival and safety of exemestane versus tamoxifenafter 2-3 years’ tamoxifen treatment (IntergroupExemestane Study): A randomised controlled trial.Lancet 369:559-570, 2007

14. Crivellari D, Sun Z, Coates AS, et al: Letro-zole compared with tamoxifen for elderly patientswith endocrine-responsive early breast cancer: TheBIG 1-98 trial. J Clin Oncol 26:1972-1979, 2008

15. Cuzick J: Hot flushes and the risk of recur-rence retrospective, exploratory results from theATAC trial. Presented at the 30th Annual San Anto-nio Breast Cancer Symposium, San Antonio, TX,December 13-16, 2007 (abstr 2069)

16. Cuzick J, Sestak I, Cella D, et al: Treatment-emergent endocrine symptoms and the risk ofbreast cancer recurrence: A retrospective analysisof the ATAC trial. Lancet Oncol 9:1143-1148, 2008

17. Eastell R, Adams JE, Coleman RE, et al:Effect of anastrozole on bone mineral density:5-year results from the anastrozole, tamoxifen,alone or in combination trial 18233230. J Clin Oncol26:1051-1057, 2008

18. Fallowfield LJ, Langridge CI, Kilburn LS, et al:Quality of life in the Intergroup Exemestane Study(IES) 5 years post-randomisation. Presented at the30th Annual San Antonio Breast Cancer Sympo-sium, San Antonio, TX, December 13-16, 2007 (ab-str 1091)

19. Forbes JF, Cuzick J, Buzdar A, et al: ATAC:100 month median follow-up (FU) shows continuedsuperior efficacy and no excess fracture risk foranastrozole (A) compared with tamoxifen (T) aftertreatment completion. Presented at the 30th AnnualSan Antonio Breast Cancer Symposium, San Anto-nio, TX, December 13-16, 2007 (abstr 40)

20. Arimidex, Tamoxifen, Alone or in Combina-tion (ATAC) Trialists’ Group, Forbes JF, Cuzick J, etal: Effect of anastrozole and tamoxifen as adjuvanttreatment for early-stage breast cancer: 100-monthanalysis of the ATAC trial. Lancet Oncol 9:45-53,2008

21. Gnant M, Mlineritsch B, Luschin-EbengreuthG, et al: Adjuvant endocrine therapy plus zoledronicacid in premenopausal women with early-stagebreast cancer: 5-year follow-up of the ABCSG-12bone-mineral density substudy. Lancet Oncol 9:840-849, 2008

22. Gnant M, Mlineritsch B, Schippinger W, et al:Endocrine therapy plus zoledronic acid in premeno-pausal breast cancer. N Engl J Med 360:679-691,2009

23. Goetz M, Ames M, Gnant M, et al: Pharma-cogenetic (CYP2D6) and gene expression profiles(HOXB13/IL17BR and molecular grade index) forprediction of adjuvant endocrine therapy benefit inthe ABCSG 8 trial. Presented at the 31st Annual SanAntonio Breast Cancer Symposium, San Antonio,TX, December 10-14, 2008 (abstr 57)

24. Goss PE: Letrozole in the extended adjuvantsetting: MA.17. Breast Cancer Res Treat 105:45-53,2007 (suppl 1)

25. Goss PE, Ingle JN, Martino S, et al: Efficacyof letrozole extended adjuvant therapy according toestrogen receptor and progesterone receptor statusof the primary tumor: National Cancer Institute ofCanada Clinical Trials Group MA.17. J Clin Oncol25:2006-2011, 2007

26. Hadji P, Ziller M, Kieback D, et al: Boneeffects of exemestane vs. tamoxifen within theTEAM trial: Results of a prospective randomizedbone sub study. Presented at the 31st Annual SanAntonio Breast Cancer Symposium, San Antonio,TX, December 10-14, 2008 (abstr 1143)

27. Hozumi Y, Aihara T, Takatsuka Y, et al:Chronological changes of side effect profile of anas-trozole compared with tamoxifen in Japanesewomen: Findings from N-SAS BC03 trial every 3months after one year of randomization. Presentedat the 30th Annual San Antonio Breast CancerSymposium, San Antonio, TX, December 13-16,2007 (abstr 3059)

28. Ingle JN, Tu D, Pater JL, et al: Intent-to-treatanalysis of the placebo-controlled trial of letrozolefor extended adjuvant therapy in early breastcancer: NCIC CTG MA.17. Ann Oncol 19:877-882,2008

29. Jakesz R, Gnant M, Griel R, et al: Tamoxifenand anastrozole as a sequencing strategy in post-menopausal women with hormone-responsive earlybreast cancer: Updated data from the Austrianbreast and colorectal cancer study group trial 8.Presented at the 31st Annual San Antonio BreastCancer Symposium, San Antonio, TX, December10-14, 2008 (abstr 14)

30. Jakesz R, Greil R, Gnant M, et al: Extendedadjuvant therapy with anastrozole among post-menopausal breast cancer patients: Results fromthe randomized Austrian Breast and Colorectal Can-cer Study Group Trial 6a. J Natl Cancer Inst 99:1845-1853, 2007

31. Jones SE, Cantrell J, Vukelja S, et al: Com-parison of menopausal symptoms during the firstyear of adjuvant therapy with either exemestane ortamoxifen in early breast cancer: Report of a Tamox-ifen Exemestane Adjuvant Multicenter trial sub-study. J Clin Oncol 25:4765-4771, 2007

32. Jones SE, Seynaeve C, Hasenburg A, et al:Results of the first planned analysis of TEAM (ta-moxifen exemestane adjuvant multinational) pro-spective randomized phase III trial in hormone




sensitive postmenopausal early breast cancer. Pre-sented at the 31st Annual San Antonio Breast Can-cer Symposium, San Antonio, TX, December 10-14,2008 (abstr 15)

33. Kaufmann M, Jonat W, Hilfrich J, et al:Improved overall survival in postmenopausalwomen with early breast cancer after anastrozoleinitiated after treatment with tamoxifen comparedwith continued tamoxifen: The ARNO 95 Study.J Clin Oncol 25:2664-2670, 2007

34. Kieback DG, Harbeck N, Bauer W, et al:Endometrial effects of exemestane compared totamoxifen within the TEAM trial: Results of a pro-spective randomized study. J Clin Oncol 25:20s,2007 (suppl; abstract 572)

35. Koeberle D, Thuerlimann B: Letrozole asupfront endocrine therapy for postmenopausalwomen with hormone-sensitive breast cancer: BIG1-98. Breast Cancer Res Treat 105:55-66, 2007(suppl 1)

36. Mamounas EP, Jeong JH, Wickerham DL,et al: Benefit from exemestane as extended adju-vant therapy after 5 years of adjuvant tamoxifen:Intention-to-treat analysis of the National SurgicalAdjuvant Breast And Bowel Project B-33 trial. J ClinOncol 26:1965-1971, 2008

37. Mauriac L, Keshaviah A, Debled M, et al:Predictors of early relapse in postmenopausalwomen with hormone receptor-positive breast can-cer in the BIG 1-98 trial. Ann Oncol 18:859-867,2007

38. Monnier AM: The Breast International Group1-98 trial: Big results for women with hormone-sensitive early breast cancer. Expert Rev AnticancerTher 7:627-634, 2007

39. BIG 1-98 Collaborative Group, Mouridsen H,Giobbie-Hurder A, et al: Letrozole therapy alone or insequence with tamoxifen in women with breastcancer. N Engl J Med 361:766-776, 2009

40. Mouridsen H, Keshaviah A, Coates AS, et al:Cardiovascular adverse events during adjuvant en-docrine therapy for early breast cancer using letro-zole or tamoxifen: Safety analysis of BIG 1-98 trial.J Clin Oncol 25:5715-5722, 2007

41. Mouridsen HT, Giobbie-Hurder A, Mauriac L,et al: BIG 1-98: A randomized, double blind phase IIIstudy evaluating letrozole with tamoxifen given insequence as adjuvant endocrine therapy for post-menopausal women with receptor (�) breast can-cer. Presented at the 31st Annual San AntonioBreast Cancer Symposium, San Antonio, TX, De-cember 10-14, 2008 (abstr 13)

42. Muss HB, Tu D, Ingle JN, et al: Efficacy,toxicity, and quality of life in older women withearly-stage breast cancer treated with letrozole orplacebo after 5 years of tamoxifen: NCIC CTG inter-group trial MA.17. J Clin Oncol 26:1956-1964, 2008

43. Ohsumi S, Shimozuma K, Ohashi Y, et al:Health-related quality-of-life and psychological dis-tress of postmenopausal breast cancer patientsafter surgery during the randomized trial, N-SAS BC03, comparing further tamoxifen with switching toanastrozole after adjuvant tamoxifen for 1 to 4 years:The final results. Presented at the 31st Annual SanAntonio Breast Cancer Symposium, San Antonio,TX, December 10-14, 2008 (abstr 1136)

44. Rasmussen BB, Regan MM, Lykkesfeldt AE,et al: Adjuvant letrozole versus tamoxifen accordingto centrally-assessed ERBB2 status for postmeno-pausal women with endocrine-responsive earlybreast cancer: Supplementary results from the BIG1-98 randomised trial. Lancet Oncol 9:23-28, 2008

45. Schilder CM, Seynaeve C, Linn SC, et al:Effects of tamoxifen and exemestane on cognitive

functioning of postmenopausal patients with earlybreast cancer: Results from the TEAM trial. Pre-sented at the 31st Annual San Antonio Breast Can-cer Symposium, San Antonio, TX, December 10-14,2008 (abstr 1133)

46. Sestak I, Cuzick J, Sapunar F, et al: Riskfactors for joint symptoms in patients enrolled in theATAC trial: A retrospective, exploratory analysis.Lancet Oncol 9:866-872, 2008

47. Takehara M, Ohsumi S, Takei H, et al:Health-related quality of life and psychological dis-tress in Japanese patients with breast cancertreated with tamoxifen, exemestane or anastrozolefor adjuvant therapy: A phase III randomized studyof National Surgical Adjuvant Study of Breast Cancer(N-SAS BC) 04. Presented at the 30th Annual SanAntonio Breast Cancer Symposium, San Antonio,TX, December 13-16, 2007 (abstr 2088)

48. van Nes JG, Voskuil DW, van Leeuwen FE,et al: Quality of life in relation to hormonal treatmentof postmenopausal women in the Dutch TamoxifenExemestane Adjuvant Multicentre (TEAM) trial. Pre-sented at the 31st Annual San Antonio Breast Can-cer Symposium, San Antonio, TX, December 10-14,2008 (abstr 21)

49. Viale G, Giobbie-Hurder A, Regan MM, et al:Prognostic and predictive value of centrally re-viewed Ki-67 labeling index in postmenopausalwomen with endocrine-responsive breast cancer:Results from Breast International Group Trial 1-98comparing adjuvant tamoxifen with letrozole. J ClinOncol 26:5569-5575, 2008

50. Aydiner A, Tas F: Meta-analysis of trialscomparing anastrozole and tamoxifen for adjuvanttreatment of postmenopausal women with earlybreast cancer. Trials 9:47, 2008

51. Cuppone F, Bria E, Verma S, et al: Do adju-vant aromatase inhibitors increase the cardiovascu-lar risk in postmenopausal women with early breastcancer? Meta-analysis of randomized trials. Cancer112:260-267, 2008

52. Ingle JN, Dowsett M, Cuzick J, et al: Aro-matase inhibitors versus tamoxifen as adjuvant ther-apy for postmenopausal women with estrogenreceptor positive breast cancer: Meta-analyses ofrandomized trials of monotherapy and switchingstrategies. Presented at the 31st Annual San Anto-nio Breast Cancer Symposium, San Antonio, TX,December 10-14, 2008 (abstr 12)

53. Kalder M, Hadji P: Bone health in postmeno-pausal women (PMW) with hormone-sensitivebreast cancer (HSBC) receiving adjuvant aromataseinhibitor (AI) therapy. J Clin Oncol 26:611s, 2008(suppl; abstr 11556)

54. Vakaet LA: Meta-analysis of side effects(SEs) of aromatase inhibitors (AI) and of tamoxifen(TAM) in large randomized clinical trials (RCT). J ClinOncol 25:595s, 2007 (suppl; abstr 11015)

55. Bliss JM, Kilburn LS, Coleman RE, et al:Disease related outcome with long term follow-up:An updated analysis of the Intergroup ExemestaneStudy (IES). Presented at the 32nd Annual SanAntonio Breast Cancer Symposium, San Antonio,TX, December 9-13, 2009

56. Rea D, Hasenburg A, Seynaeve C, et al: Fiveyears of exemestane as initial therapy compared to5 years of tamoxifen followed by exemestane: TheTEAM Trial, a prospective, randomized, phase III trialin postmenopausal women with hormone-sensitiveearly breast cancer. Presented at the 32nd AnnualSan Antonio Breast Cancer Symposium, San Anto-nio, TX, December 9-13, 2009

57. Reference deleted

58. Breast International Group (BIG) 1-98 Collab-orative Group, Thurlimann B, Keshaviah A, et al: Acomparison of letrozole and tamoxifen in postmeno-pausal women with early breast cancer. N EnglJ Med 353:2747-2757, 2005

59. Jakesz R, Gnant M, Greil R, et al: The bene-fits of sequencing adjuvant tamoxifen and anastro-zole in postmenopausal women with hormone-responsive early breast cancer: 5 year-analysis ofABCSG Trial 8. Presented at the 28th Annual SanAntonio Breast Cancer Symposium, San Antonio,TX, December 8-11, 2005 (abstr 13)

60. Dowsett M, Cuzick J, Ingle JN, et al: Meta-analysis of breast cancer outcomes in adjuvant trialsof aromatase inhibitors versus tamoxifen J ClinOncol 28:509-518, 2010

61. Early Breast Cancer Trialists’ CollaborativeGroup (EBCTCG): Effects of chemotherapy and hor-monal therapy for early breast cancer on recurrenceand 15-year survival: An overview of the randomisedtrials. Lancet 365:1687-1717, 2005

62. Fisher B, Anderson S, Tan-Chiu E, et al:Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer:Findings from National Surgical Adjuvant Breast andBowel Project B-23. J Clin Oncol 19:931-942, 2001

63. Paik S, Shak S, Tang G, et al: A multigeneassay to predict recurrence of tamoxifen-treated,node-negative breast cancer. N Engl J Med 351:2817-2826, 2004

64. Dowsett M, Cuzick J, Wale C, et al: Risk ofdistant recurrence using oncotype DX in postmeno-pausal primary breast cancer patients treated withanastrozole or tamoxifen: A Trans ATAC study.Presented at the 31st Annual San Antonio BreastCancer Symposium, San Antonio, TX, December10-14, 2008 (abstr 53)

65. Viale G, Regan MM, Dell’Orto P, et al: Cen-tral review of ER, PgR and HER2 in BIG 1-98evaluating letrozole vs letrozole followed by tamox-ifen vs tamoxifen followed by letrozole as adjuvantendocrine therapy for postmenopausal women withhormone receptor-positive breast cancer. CancerRes Treat 69:504s, 2009 (suppl; abstr 76)

66. Giordano SH, Perkins GH, Broglio K, et al:Adjuvant systemic therapy for male breast carci-noma. Cancer 104:2359-2364, 2005

67. Technology Evaluation Center (Blue CrossBlue Shield Association): CYP2D6 Pharmacogenom-ics of Tamoxifen Treatment, 2008. http://www.bcbs.com/blueresources/tec/vols/23/23_01.pdf

68. Albain K, Barlow WE, Shak S, et al: Prognos-tic and predictive value of the 21-gene recurrencescore assay in postmenopausal, node-positive, ER-positive breast cancer (S8814,INT0100). Presentedat the 30th Annual San Antonio Breast CancerSymposium, San Antonio, TX, December 13-16,2007 (abstr 10)

69. Borges S, Desta Z, Li L, et al: Quantitativeeffect of CYP2D6 genotype and inhibitors on tamox-ifen metabolism: Implication for optimization ofbreast cancer treatment. Clin Pharmacol Ther 80:61-74, 2006

70. Goetz MP, Knox SK, Suman VJ, et al: Theimpact of cytochrome P450 2D6 metabolism inwomen receiving adjuvant tamoxifen. Breast CancerRes Treat 101:113-121, 2007

71. Goetz MP, Rae JM, Suman VJ, et al: Phar-macogenetics of tamoxifen biotransformation is as-sociated with clinical outcomes of efficacy and hotflashes. J Clin Oncol 23:9312-9318, 2005

72. Gonzalez-Santiago S, Zarate R, Haba-Rodríguez J, et al: CYP2D6*4 polymorphism asblood predictive biomarker of breast cancer relapse

Burstein et al



in patients receiving adjuvant tamoxifen. J Clin On-col 25:25s, 2007 (suppl; abstr 590)

73. Schroth W, Goetz MP, Hamann U, et al:Association between CYP2D6 polymorphisms andoutcomes among women with early stage breastcancer treated with tamoxifen. JAMA 302:1429-1436, 2009

74. Cella D, Fallowfield L, Barker P, et al: Qualityof life of postmenopausal women in the ATAC(“Arimidex”, tamoxifen, alone or in combination) trialafter completion of 5 years’ adjuvant treatment forearly breast cancer. Breast Cancer Res Treat 100:273-284, 2006

75. Fallowfield L, Cella D, Cuzick J, et al: Qualityof life of postmenopausal women in the Arimidex,Tamoxifen, Alone or in Combination (ATAC) Adju-vant Breast Cancer Trial. J Clin Oncol 22:4261-4271,2004

76. Fallowfield LJ, Bliss JM, Porter LS, et al:Quality of life in the intergroup exemestane study: Arandomized trial of exemestane versus continuedtamoxifen after 2 to 3 years of tamoxifen in post-menopausal women with primary breast cancer.J Clin Oncol 24:910-917, 2006

77. Whelan TJ, Goss PE, Ingle JN, et al: Assess-ment of quality of life in MA.17: A randomized,placebo-controlled trial of letrozole after 5 years oftamoxifen in postmenopausal women. J Clin Oncol23:6931-6940, 2005

78. Osborne CK: Tamoxifen in the treatment ofbreast cancer. N Engl J Med 339:1609-1618, 1998

79. Rabaglio M, Sun Z, Price KN, et al: Bonefractures among postmenopausal patients withendocrine-responsive early breast cancer treatedwith 5 years of letrozole or tamoxifen in the BIG 1-98trial. Ann Oncol 20:1489-1498, 2009

80. Brufsky A, Harker WG, Beck JT, et al:Zoledronic acid inhibits adjuvant letrozole-inducedbone loss in postmenopausal women with earlybreast cancer. J Clin Oncol 25:829-836, 2007

81. Bundred NJ, Campbell ID, Davidson N, et al:Effective inhibition of aromatase inhibitor-associatedbone loss by zoledronic acid in postmenopausalwomen with early breast cancer receiving adjuvantletrozole: ZO-FAST Study results. Cancer 112:1001-1010, 2008

82. Hillner BE, Ingle JN, Chlebowski RT, et al:American Society of Clinical Oncology 2003 updateon the role of bisphosphonates and bone healthissues in women with breast cancer. J Clin Oncol21:4042-4057, 2003

83. Burstein HJ, Winer EP: Aromatase inhibitorsand arthralgias: A new frontier in symptom manage-ment for breast cancer survivors. J Clin Oncol 25:3797-3799, 2007

84. Crew KD, Greenlee H, Capodice J, et al:Prevalence of joint symptoms in postmenopausalwomen taking aromatase inhibitors for early-stagebreast cancer. J Clin Oncol 25:3877-3883, 2007

85. Henry NL, Giles JT, Ang D, et al: Prospectivecharacterization of musculoskeletal symptoms inearly stage breast cancer patients treated with aro-matase inhibitors. Breast Cancer Res Treat 111:365-372, 2008

86. Sestak I, Sapunar F, Cuzick J: Aromataseinhibitor-induced carpal tunnel syndrome: Results

from the ATAC trial. J Clin Oncol 27:4961-4965,2009

87. Goss PE, Ingle JN, Martino S, et al: Out-comes of women who were premenopausal atdiagnosis of early stage breast cancer in the NCICCTG MA.17 trial. Cancer Res Treat 69:487s, 2009(suppl; abstr 13)

88. Burstein HJ, Mayer E, Patridge AH, et al:Inadvertent use of aromatase inhibitors in patientswith breast cancer with residual ovarian function:Cases and lessons. Clin Breast Cancer 7:158-161,2006

89. Smith IE, Dowsett M, Yap YS, et al: Adjuvantaromatase inhibitors for early breast cancer afterchemotherapy-induced amenorrhoea: Caution andsuggested guidelines. J Clin Oncol 24:2444-2447,2006

90. Harris L, Fritsche H, Mennel R, et al: Amer-ican Society of Clinical Oncology 2007 update ofrecommendations for the use of tumor markers inbreast cancer. J Clin Oncol 25:5287-5312, 2007

91. Haynes RB, Ackloo E, Sahota N, et al: Inter-ventions for enhancing medication adherence. Co-chrane Database Syst Rev 2: CD000011, 2008

92. Adjuvant! Online. http://www.adjuvantonline.com

93. Ravdin PM: A computer program to assist inmaking breast cancer adjuvant therapy decisions.Semin Oncol 23:43-50, 1996 (suppl 1)

94. Barron TI, Connolly R, Bennett K, et al: Earlydiscontinuation of tamoxifen: A lesson for oncolo-gists. Cancer 109:832-839, 2007

95. Partridge AH, Wang PS, Winer EP, et al:Nonadherence to adjuvant tamoxifen therapy inwomen with primary breast cancer. J Clin Oncol21:602-606, 2003

96. Owusu C, Buist DS, Field TS, et al: Predic-tors of tamoxifen discontinuation among olderwomen with estrogen receptor-positive breast can-cer. J Clin Oncol 26:549-555, 2008

97. Chlebowski RT, Geller ML: Adherence toendocrine therapy for breast cancer. Oncology 71:1-9, 2006

98. Partridge AH, LaFountain A, Mayer E, et al:Adherence to initial adjuvant anastrozole therapyamong women with early-stage breast cancer. J ClinOncol 26:556-562, 2008

99. Horne R, Weinman J: Patients’ beliefs aboutprescribed medicines and their role in adherence totreatment in chronic physical illness. J PsychosomRes 47:555-567, 1999

100. Demissie S, Silliman RA, Lash TL: Adjuvanttamoxifen: Predictors of use, side effects, and dis-continuation in older women. J Clin Oncol 19:322-328, 2001

101. Kahn KL, Schneider EC, Malin JL, et al:Patient centered experiences in breast cancer: Pre-dicting long-term adherence to tamoxifen use. MedCare 45:431-439, 2007

102. Schrag D, Hanger M: Medical oncologists’views on communicating with patients about chem-otherapy costs: A pilot survey. J Clin Oncol 25:233-237, 2007

103. Meropol NJ, Schrag D, Smith TJ, et al: Amer-ican Society of Clinical Oncology guidance state-ment: The cost of cancer care. J Clin Oncol 27:3868-3874, 2009

104. U.S. Cancer Statistics Working Group.United States Cancer Statistics: 1999-2002, Inci-dence and Mortality Web-based Report. U.S. De-partment of Health and Human Services, Centersfor Disease Control and Prevention, and NationalCancer Institute Atlanta, 2005. http://apps.nccd.cdc.gov/uscs/

105. American Cancer Society. Cancer Factsand Figures for African Americans 2005-2006.Atlanta, 2005. http://www.cancer.org/downloads/STT/CAFF2005AACorrPWSecured.pdf

106. Mead H, Cartwright-Smith L, Jones K, et al:Racial and Ethnic Disparities in U.S. Health Care: AChartbook. New York, NY, The CommonwealthFund, 2008

107. Ries LA, Eisner MP, Kossary CL, et al: SEERCancer Statistics Review, 1973-1997. National Can-cer Institute. Bethesda, MD, 2000. http://seer.cancer.gov/csr/1973_1997/

108. Smedley BD, Stith AY, Nelson AR: UnequalTreatment: Confronting Racial and Ethnic Disparitiesin Health Care. Washington, DC, National Acade-mies Press, 2003

109. Bickell NA, Wang JJ, Oluwole S, et al:Missed opportunities: Racial disparities in adjuvantbreast cancer treatment. J Clin Oncol 24:1357-1362,2006

110. Kimmick G, Anderson R, Camacho F, et al:Adjuvant hormonal therapy use among insured, low-income women with breast cancer. J Clin Oncol27:3445-3451, 2009

111. Baum M, Budzar AU, Cuzick J, et al: Anas-trozole alone or in combination with tamoxifen ver-sus tamoxifen alone for adjuvant treatment ofpostmenopausal women with early breast cancer:First results of the ATAC randomised trial. Lancet359:2131-2139, 2002

112. Boccardo F, Rubagotti A, Amoroso D, et al:Anastrozole appears to be superior to tamoxifen inwomen already receiving adjuvant tamoxifen treat-ment. Breast Cancer Res Treat 82, 2003 (abstr 3)

113. Coombes RC, Hall E, Gibson LJ, et al: Arandomized trial of exemestane after two to threeyears of tamoxifen therapy in postmenopausalwomen with primary breast cancer. N Engl J Med350:1081-1092, 2004

114. Jakesz R, Jonat W, Gnant M, et al: Switchingof postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2years’ adjuvant tamoxifen: combined results ofABCSG trial 8 and ARNO 95 trial. Lancet 366:455-462, 2005

115. Goss PE, Ingle JN, Martino S, et al: A ran-domized trial of letrozole in postmenopausal womenafter five years of tamoxifen therapy for early-stagebreast cancer. N Engl J Med 349:1793-1802, 2003

116. Jakesz R, Samonigg H, Greil R, et al: Ex-tended adjuvant treatment with anastrozole: Resultsfrom the Austrian Breast and Colorectal CancerStudy Group Trial 6a (ABCSG-6a). J Clin Oncol23:10s, 2005 (suppl; abstr 527)

117. Mamounas EP, Jeong JH, Wickerham L, etal: Benefit from exemestane (EXE) as extendedadjuvant therapy after 5 years of tamoxifen (TAM):Intent-to-treat analysis of NSABP B-33. Breast Can-cer Res Treat 100:A49, 2006 (suppl 1)

■ ■ ■




Acknowledgment

The Update Committee thanks Kaitlin Einhaus; Karen Hagerty; Christina H. Jagielski; Carol Palackdharry; Richard Theriault, DO; LindaVahdat, MD; Robert Langdon, MD; and Sandra Swain, MD; the external reviewers for the Journal of Clinical Oncology; and the AmericanSociety of Clinical Oncology Board of Directors and Clinical Practice Guideline Committee for their thoughtful reviews of earlier drafts.

Appendix

Search Strategy for MEDLINE (PUBMED)

(Breast neoplasms[mesh] NOT (“Breast Neoplasms, Male”[Mesh] OR “Phyllodes Tumor”[Mesh] OR “Carcinoma, Ductal, Breast-”[Mesh]) OR (“Breast”[Mesh] AND (“Carcinoma”[Mesh] OR “Adenocarcinoma”[Mesh] OR “Neoplasms”[Mesh]))) OR ((breast[tiab]OR mammary[tiab]) AND (cancer[tiab] OR cancers[tiab] OR tumor[tiab] OR tumors[tiab] OR tumour[tiab] OR tumours[tiab] ORmalignan*[tiab] OR carcinoma[tiab] OR carcinomas[tiab] OR adenocarcinoma[tiab] OR adenocarcinomas[tiab])) AND

((“Aromatase Inhibitors”[Mesh] OR aromatase inhibitors[nm] OR “aromatase inhibitor”[TIAB] OR “aromatase inhibitors”[TIAB] OR “aromatase inhibition”[TIAB] OR “anastrozole”[Substance Name] OR anastrozole [tiab] OR arimedex[tiab] OR “letrozo-le”[Substance Name] OR “letrozole”[tiab] OR femara[tiab] OR aromasil[tiab]OR exemestane [Substance Name] OR “exemestane-”[tiab] OR aromasin[tiab] OR aromasine[TIAB] OR Tamoxifen[Mesh] OR Tamoxifen[substance name] OR “Tamoxifen”[tiab] ORnovaldex [tiab]) NOT (aminoglutethimide[mesh] OR aminoglutethimide[tiab])) AND

(((randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized controlled trials[mh] OR clinical trial[pt] OR“clinical trial”[tiab] OR “clinical trials”[tiab] OR clinical trials as topic[mh] OR controlled clinical trials as topic[mh] OR randomizedcontrolled trials as topic[mh] OR clinical trials, phase II as topic[mh] OR clinical trials, phase III as topic[mh] OR clinical trials, phase IVas topic[mh] OR clinical trial, phase II[pt] OR clinical trial, phase III[pt] OR clinical trial, phase IV[pt] OR random allocation[mh] OR“random allocation”[tiab] OR “randomly allocated”[tiab] OR double-blind method[mh] OR single-blind method[mh]) OR ((random-[tiab] OR randomly[tiab] OR randomized[tiab] OR randomised[tiab] OR randomization[tiab] OR randomisation[tiab]) AND (clini-cal[tiab] OR control[tiab] OR controlled[tiab] or control groups[mh])) OR ((single[tiab] OR single-[tiab] OR double[tiab] ORdouble-[tiab] OR triple[tiab] OR triple-[tiab] OR multi[tiab] OR multi-[tiab]OR evaluator[tiab] OR assessor[tiab] OR interviewer-[tiab]) AND (mask[tiab] OR masked[tiab] OR masking[tiab] OR blind[tiab] OR blinded[tiab] OR blinding[tiab])) OR ((placebos[mh]OR placebo[tiab] OR placebos[tiab] OR random[tiab] OR randomly[tiab] OR randomized[tiab] OR randomised[tiab] OR randomiza-tion[tiab] OR randomization[tiab]) AND (research design[mh] OR “comparative study”[tiab] OR comparative study[pt] OR evaluationstudies as topic[mh:noexp] OR evaluation studies[pt] OR “evaluation study”[tiab] OR “evaluation studies”[tiab] OR validation studiesas topic[mh] OR follow-up studies[mh] OR “follow-up study”[tiab] OR “follow up study”[tiab] OR “follow-up studies”[tiab] OR“follow up studies”[tiab] OR prospective studies[mh] OR prospective[tiab] OR epidemiologic research design[mh] OR epidemiologicmethods[mh] OR epidemiologic study characteristics as topic[mh] OR epidemiologic studies[mh] OR intervention studies[mh] ORcross-over studies[mh]))) NOT (clinical trial, phase I[pt] OR clinical trials, phase I as topic[mh]) NOT (animals[mh] NOT hu-mans[mh])) AND English[la]

Table A1. Update Committee Members

Member Affiliation

Harold J. Burstein, MD, PhD, Co-Chair Dana-Farber Cancer InstituteJennifer J. Griggs, MD, MPH, Co-Chair University of Michigan Comprehensive Cancer CenterHolly Anderson, RN, BSN, Patient Representative Breast Cancer Coalition of RochesterDiana Rowden, MS, Patient Representative Susan G. Komen for the CureThomas A. Buchholz, MD M. D. Anderson Cancer CenterNancy E. Davidson, MD University of Pittsburgh Cancer InstituteKaren A. Gelmon, MD British Columbia Cancer AgencySharon Hermes Giordano, MD M. D. Anderson Cancer CenterClifford Hudis, MD Memorial Sloan-Kettering Cancer CenterJennifer Malin, MD, PhD Greater Los Angeles Veterans Affairs Healthcare SystemEleftherios P. Mamounas, MD Aultman Health FoundationAlexander J. Solky, MD Interlakes Oncology and HematologyMaryFran R. Sowers, PhD University of MichiganVered Stearns, MD Johns Hopkins School of MedicineEric P. Winer, MD Dana-Farber Cancer Institute

Burstein et al



Table A2. Time to Recurrence

Trial


Range(months)


Time to Recurrence Events

HR 95% CI P

AI Comparator


PrimaryATAC20 ITT 100 3,125 3,116 538 645 0.81 0.73 to 0.91 � .001

SequentialTEAM56 EXE/TAM v EXE ITT 61 4,868 4,898 10.9 10.2 0.94 0.83 to 1.06 .293IES13 55.7 0-89.7 2,352 2,372 265 325 0.7 0.58 to 0.83� NRN-SAS BC-038 42 3.2-60 347 349 15 4.3 27 7.7 0.54 0.29 to 1.02†‡ .06‡ARNO 9533 30.1 � 12 to � 84 489 490 36 7.4 47 9.6 NR NR

ExtendedMA.1725 64 2,583 2,587 136 5.3 190 7.3 NR NRNSABP B-3336 30 783 779 17 2.2 37 4.7 0.44 NR§ .004

NOTE. Percent calculated as number of events divided by number of patients observed.Abbreviations: AI, aromatase inhibitor; HR, hazard ratio; ATAC, Arimidex, Tamoxifen, Alone or in Combination (trial); ITT, intent to treat; TEAM, Tamoxifen

Exemestane Adjuvant Multinational (trial); EXE, exemestane; TAM, tamoxifen; IES, Intergroup Exemestane Study; N-SAS, National Surgical Adjuvant Study (Group);ARNO, Arimidex-Nolvadex (trial); NR, not reported; NSABP, National Surgical Adjuvant Breast and Bowel Project.

�Disease recurrence.†Relapse-free survival.‡Two different sets of values reported on abstract and poster; table reflects poster (abstract: aromatase inhibitor, N � 15 �4.3%�; comparator: N � 28 �NR�; hazard

ratio, 0.52; 95% CI, 0.28 to 0.98; P � .02).§Relapse-free survival follow-up for all TEAM patients is 33 months (data beyond that point censored).




Table A3. Disease-Free Survival Subset Analyses

Trial


Range(months)


Disease-Free Survival Events

HR 95% CI P

AI Comparator


PrimaryATAC20,60(Goss PE, et al: J Natl

Cancer Inst 97:1262-1271, 2005)ANA v TAM ITT 100 0-126 3,125 3,116 817 26.1 887 28.5 0.90 0.82 to 0.99 .025Hormone receptor–positive 100 0-126 2,618 2,598 618 23.6 702 27.0 0.85 0.76 to 0.94 .003ANA v TAM ITT 68 Total: 9,366 402 12.9 498 16.0 0.79 0.70 to 0.90� � .001Node-positive 68 NR NR NR 0.84 0.70 to 1.00 NRNode-negative 68 NR NR NR 0.68 0.55 to 0.84 NRNode-unknown 68 NR NR NR 0.48 0.23 to 1.00 NRER-positive/PR-positive 68 Total: 5,719 191 10 222 12 0.84 0.69 to 1.02� .07ER-positive/PR-negative 68 Total: 1,372 50 11 102 24 0.43 0.31 to 0.61� � .001ER-negative/PR-positive 68 Total: 220 17 27 25 33 0.79 0.43 to 1.47� .5ER-negative/PR-negative 68 Total: 703 66 28 79 32 0.90 0.65 to 1.25� .5ER-positive/PR-unknown 68 Total: 518 22 13 20 11 1.29 0.71 to 2.37� .4ER- and PR-unknown 68 Total: 743 46 19 47 19 0.96 0.64 to 1.44� .8

BIG 1-9841,44,49 LET v TAM 76 2,463 2,459 509 20.7 565 23.0 0.88 0.78 to 0.99 .03Node-negative or node-unknown 71 1,376 1,404 200 14.5 227 16.2 0.89 0.74 to 1.08 NR†Node-positive 71 1,050 1,017 303 28.9 332 32.6 0.83 0.71 to 0.98 NRERBB2-negative 51 1,648 1,646 178 1.08 240 14.6 0.72 0.59 to 0.87 NRERBB2-positive 51 134 105 27 20.1 32 30.5 0.62 0.37 to 1.03 NRLow Ki-67 51 730 703 56 7.7 66 9.4 0.81 0.57 to 1.15 .09 (for interaction

between lowand high Ki-67)

High Ki-67 51 631 621 66 10.5 115 18.5 0.53 0.39 to 0.72ER-positive/PR-positive 25.8 2,542 2,513 179 7 208 8.3 0.84 0.49 to 1.03 .09†ER-positive/PR-negative 25.8 808 823 89 11 107 13 0.83 0.62 to 1.10 .18†ER-positive/PR-unknown 25.8 579 575 70 12.1 92 16 0.72 0.53 to 0.98 .04†

SequentialBIG 1-9841 TAM/LET v LET 71 1,548 1,546 259 16.7 248 16.0 1.05 0.84 to 1.32‡ NR

Node-negative or node-unknown 71 894 886 100 11.2 102 11.5 0.96 0.67 to 1.38 NRNode-positive 71 635 645 154 24.2 145 22.5 1.13 0.84 to 1.52 NRLET/TAM v LET 71 1,540 1,546 236 15.3 248 16.0 0.96 0.76 to 1.21‡ NRNode-negative or node-unknown 71 920 886 101 102 0.97 0.67 to 1.39 NRNode-positive 71 611 645 135 145 0.98 0.72 to 1.59 NR

IES13 ITT 55.7 0-89.7 2,352 2,372 354 455 0.76 0.66 to 0.88 � .001Node-negative 55.7 0-89.7 1,217 1,230 NR NR 0.74 0.58 to 0.94 NRNode-positive 55.7 0-89.7 1,050 1,039 NR NR 0.72 0.61 to 0.86 NRER-positive/ER-unknown 55.7 0-89.7 2,296 2,306 339 14.8 439 19.0 0.75 0.65 to 0.87 � .001ER and PR high NR NR NR NR NR 0.686 NR

ExtendedMA.1725 ITT§ 64 16-95 2,583 2,587 164 6.3 235 9.1 0.68 0.55 to 0.83 � .001

Node-positive 64 1,174 1,194 91.7 DFS at4 years

87.8 DFS at4 years

0.74 0.58 to 0.94 .01

Node-negative 64 1,295 1,281 97.0 DFS at4 years

94.6 DFS at4 years

0.51 0.35 to 0.75 � .001

ITT§ 30 2,583 2,587 92 3.6 155 6.0 0.58 0.45 to 0.76 � .001ER-positive/PR-positive 30 1,907 1,902 60 3.0 117 6.0 0.49 0.36 to 0.67 NRER-positive/PR-negative 30 309 327 19 6.0 17 5.0 1.21 0.63 to 2.34 NRER-negative/PR-positive 30 100 100 4 4.0 5 5.0 0.56 0.15 to 2.12 NR

NSABP B-3336 30 783 779 37 4.7 52 6.7 0.68 .07Node-positive 30 Total: 755 NR NR 0.5 0.30 to 0.86 .01Node-negative 30 Total: 807 NR NR 1.13 NR .74ER-positive and PR-positive 30 Total: 1,266 NR NR 0.7 NR .15ER-positive or PR-positive 30 Total: 248 NR NR 0.52 NR .17


to treat; NR, not reported; ER. estrogen receptor; PR, progesterone receptor; BIG, Breast International Group; LET, letrozole; IES, Intergroup Exemestane Study;DFS, disease-free survival; NSABP, National Surgical Adjuvant Breast and Bowel Project.

�Time to recurrence.†Relapse-free survival, local and distant recurrence, contralateral breast cancer, and death without recurrence.‡99% CIs used to account for multiple comparisons.§Seventeen patients omitted from ITT analysis.

Burstein et al



Table A4. Adverse Cardiovascular (cardiovascular deaths, ischemic cardiac disease, hypertension, high cholesterol) Effects

Trial

MedianFollow-Up(months) Arm

No. ofPatients

Cardiovascular Events

All CardiacEvents

Grades3 to 5

CardiacEvents

CardiovascularDeaths

AllIschemicCardiacDisease

Grades3 to 5

IschemicCardiacDisease

Any GradeHypertension

HighCholesterol

No. % No. % No. % No. % No. % No. % No. %

ATAC (Howell A, et al:Lancet 365:60-62, 2005;Buzdar et al: LancetOncol 7:633-643, 2006) 68 ANA 3,092 49 2 127 4.10 402 13 278 9

TAM 3,094 46 1 104 3.40 349 11 108 3OR NR 1.23 1.18 2.7395% CI NR 0.95 to 1.60 0.69 to 1.44 2.02 to 3.69P NR .1 .04 � .001

BIG 1-9814,35,40 30.1 LET 3,975 140 5.7 96 2.4 54 2.2 45 1.1 150 3.8 43.60�

TAM 3,988 127 5.2 57 1.4 45 1.8 29 0.7 135 3.4 19.20RR NR 1.68 NR 1.55 1.11 NRP .45 .001 .42 .06 .37

ABCSG-829 75 TAM/ANA 1,469 127 6.5TAM 1,453 130 6.0P .479

ITA9 (Boccardo F, et al: J ClinOncol 23:5138-5147,2005)

64 ANA 223 17 7.6† 19 9.3�

TAM 225 14 6.2 6 4.0P .6 .04

TEAM56 61 TAM/EXE 4,814 60 1.2‡ 215 4.5 134 2.8EXE 4,852 77 1.6 293 6.0 227 4.7P .183 .001 � .001

IES13 55.7 EXE 2,320 382 16.5§ 23 1 14 � 1 185 8.0 185 8 830 35.8 166 7.2TAM 2,338 350 15.0 18 � 1 13 � 1 162 6.9 162 6.9 772 33.0 141 6.0P .16 NR NR .17 .17 .05 .12

ARNO 9533 30.1 ANA 445 9 2.0TAM 452 4 0.9

N-SAS BC-038 42 TAM/ANA 347 0.6¶TAM 349 0.9

MA.1724 30 LET 2,572 5.80 16.00Placebo 2,577 5.60 16.00P .76 .79

Abbreviations: ATAC, Arimidex, Tamoxifen, Alone or in Combination (trial); ANA, anastrozole; TAM, tamoxifen; OR, odds ratio; NR, not reported; BIG, BreastInternational Group; LET, letrozole; RR, risk ratio; ABCSG, Austrian Breast and Colorectal Cancer Study Group; ITA, Italian Tamoxifen Anastrozole (trial); TEAM,Tamoxifen Exemestane Adjuvant Multinational (trial); EXE, exemestane; IES, Intergroup Exemestane Study; ARNO, Arimidex-Nolvadex (trial); N-SAS, NationalSurgical Adjuvant Study (Group).

�Lipid metabolism disorder.†Cardiovascular disease.‡Myocardial ischemia/infarction.§Excludes venous thromboembolic events.¶Heart disease.




Table A5. Adverse Cardiovascular (ischemic cerebrovascular, stroke, or TIA thrombosis) Effects

Trial


No. ofPatients

Cardiovascular Events

All IschemicCerebrovascular

EventsGrades 3 to 5Stroke or TIA

All VenousThrombosis

Events

Grades 3 to5 Venous

ThrombosisEvents

No. % No. % No. % No. %

ATAC20 (Howell A, et al:Lancet 365:60-62, 2005;Arimidex, Tamoxifen,Alone or in CombinationTrialists’ Group,et al: Lancet Oncol7:633-643, 2006) 68 ANA 3,092 62 2 20 0.16� 87 2.80

TAM 3,094 88 2.8 34 0.28 140 4.50OR 0.70 NR 0.6195% CI 0.50 to 0.97 NR 0.46 to 0.80P .03 NR � .001

BIG 1-9840 30.1 LET 3,975 47 1.2 68 1.7 35 0.9TAM 3,988 49 1.2 154 3.9 92 2.3RR 1 0.44 0.38P 0.99 � .001 � .001

ABCSG-1222 47.8 ANA � GOS 453 0TAM � GOS 451 0

ABCSG-829 75 TAM/ANA 1,469 44 2.3†TAM 1,453 47 2.2P .833

TEAM56 61 TAM/EXE 4,814 35 0.7 97 2.0EXE 4,852 51 1.1 45 0.9P .112 � .001

IES13 55.7 EXE 2,320 28 1.2 7 � 1TAM 2,338 54 2.3 19 � 1P .004 NR

ARNO 9533 30.1 ANA 445 3 0.7TAM 452 1 0.2

N-SAS BC-038 42 TAM/ANA 347 0.3TAM 349 0.0

Abbreviations: TIA, transient ischemic attack; ATAC, Arimidex, Tamoxifen, Alone or in Combination (trial); ANA, anastrozole; TAM, tamoxifen; OR, odds ratio; NR,not reported; BIG, Breast International Group; LET, letrozole; RR, risk ratio; ABCSG, Austrian Breast and Colorectal Cancer Study Group; GOS, goserelin; TEAM,Tamoxifen Exemestane Adjuvant Multinational (trial); EXE, exemestane; IES, Intergroup Exemestane Study; ARNO, Arimidex-Nolvadex (trial); N-SAS, NationalSurgical Adjuvant Study (Group).

�Cerebrovascular accidents.†Embolism, thromboses.

Burstein et al



Table A6. Adverse Musculoskeletal Effects

Trial


No. ofPatients

Musculoskeletal Events

Bone PainMusculoskeletal

Pain Arthralgia OsteoporosisFracture

Rate Decreasein HipBMD

Decreasein

LumbarSpineBMDNo. % No. % No. % No. % No. %

ATAC17,20 (Howell A, et al:Lancet 365:60-62,2005; Arimidex,Tamoxifen, Alone or inCombination Trialists’Group, et al: LancetOncol 7:633-643, 2006) 68 ANA 3,092 132 4a 1,100 35.6 325 11b 375 12.1 �7.24c � 6.08c

TAM 3,094 235 8 911 29.4 226 7 234 7.6 0.74 �2.77OR 0.54 1.32 1.49 1.55 NR NR95% CI 0.41 to 0.72 1.19 to 1.47 1.18 to 1.88 1.25 to 1.77 NR NRP � .001 � .001 � .001 � .001 NR NR

BIG 1-9814,35 30.1 LET 3,975 196 8TAM 3,988 132 5.4P � .001

ABCSG-1222 47.8 ANA � GOS 451 128 28.3 112 4.7 1 0.2 �7.8%d

TAM � GOS 453 94 20.8 52 11.5 1 0.2 �4.5%ABCSG-829 75 TAM/ANA 1,469 223 11.4e 69 3.5

TAM 1,453 179 8.2 35 1.6P � .001 � .001

ITA9 64 ANA 223 22 9.9f

TAM 225 15 6.7P .2

TEAM56 61 TAM/EXE 4,814 302 6.3g 961 20.0 259 5.4 170 3.5EXE 4,852 188 3.9 1,140 23.5 478 9.9 249 5.1P � .001 � .001 � .001 � .001

IES12,13 55.7 EXE 2,320 488 21.0 432 18.6 169 7.3 100 4.3 �2.799 �3.726TAM 2,338 376 16.1 275 11.8 128 5.5 73 3.1 �1.011 �0.412P � .001 � .001 .01 .03 NR NR

N-SAS BC-038 42 TAM/ANA 347 50.4TAM 349 31.8

ARNO 9533 30.1 ANA 445 52 11.7h 13 2.9 10 2.2TAM 452 22 4.9 4 0.9 10 2.2

ABCSG-6a30 62.3 ANA 387 86 18.3i

Placebo 469 95 24.5OR 1.5595% CI 1.11 to 2.17P .009

NSABP B-3336 30 EXE 799 0.50j 1.00j 28Placebo 799 0.70 0.50 20P NR NR .33

MA.1724 (Goss PE, et al:J Natl Cancer Inst 97:1262-1271, 2005) 30 LET 2,572 5 15k 25 8.10 5.30 �3.60%l �5.35%l

Placebo 2,577 6 12 21 6 4.60 �0.71% �0.70%P .67 .004 � .001 .003 .25 .044 .008

Abbreviations: BMD, bone mineral density; ATAC, Arimidex, Tamoxifen, Alone or in Combination (trial); ANA, anastrozole; TAM, tamoxifen; OR, odds ratio; NR, notreported; BIG, Breast International Group; LET, letrozole; ABCSG, Austrian Breast and Colorectal Cancer Study Group; GOS, goserelin; ITA, Italian TamoxifenAnastrozole (trial); TEAM, Tamoxifen Exemestane Adjuvant Multinational (trial); EXE, exemestane; IES, Intergroup Exemestane Study; N-SAS, National SurgicalAdjuvant Study (Group); ARNO, Arimidex-Nolvadex (trial); NSABP, National Surgical Adjuvant Breast and Bowel Project.

aMuscle cramps.bOsteoporosis or osteopenia.cChange in BMD from baseline to year 5.dChanges at 60 months.eBone or joint disorder.fIncludes both musculoskeletal disorders and bone fractures.gMuscle cramps/disorders.hBoth arthralgia and bone pain.iGrades 1 to 4 only.jGrades 3 and 4 only.kMuscle pain.lBMD from 24 months: N (LET) � 122; N (placebo) � 104 cases only.




Table A7. Adverse Gynecologic Effects

Trial


No. ofPatients

Gynecologic Events

GynecologicDisorders Vaginal Bleeding

VaginalDischarge

EndometrialBiopsy

EndometrialCancer

UterinePolyps

No. % No. % No. % No. % No. % No. %

ATAC (Howell A, et al: Lancet365:60-62, 2005) 68 ANA 3,092 95 3a 167 5.4 109 3.5 5 0.2

TAM 3,094 324 10 317 10.2 408 13.2 17 0.8OR 0.27 0.50 0.24 0.2995% CI 0.20 to 0.37 0.41 to 0.61 0.19 to 0.30 0.11 to 0.80P � .001 � .001 � .001 .02

BIG 1-985,35 25.8 LET 3,975 3.3 2.3 6 0.1TAM 3,988 6.6 9.1 15 0.3P � .001 � .001 NR

ABCSG-1222 47.8 ANA � GOS 453 1 0.2TAM � GOS 451 5 1.1

ABCSG-829 75 TAM/ANA 442 22.6TAM 681 31.2P � .001

ITA9 64 ANA 223 16 7.2b

TAM 225 9 4.0P .1

TEAM56 61 TAM/EXE 4,814 94 2.0c 243 5.0 402 8.4 187 3.9 d 17 0.4EXE 4,852 64 1.3 114 2.3 123 2.5 20 0.4 7 0.1P .017 � .001 � .001 � .001 .040

IES5,13 55.7 EXE 2,320 91 4.6 65 2.8 1 � 0.1e 5 0.2 24 1.2f

TAM 2,338 131 6.5 91 3.9 20 0.9 11 0.5 65 (3.2)P .008 .04 � .001 NR � .001

N-SAS BC-038 42 TAM/ANA 347 9.2g 16.1 0TAM 349 8.0 24.4 0.3

ARNO 9533 30.1 ANA 445 7 1.6 8 1.8e 0 4 0.9TAM 452 9 2.0 39 8.6 2 0.4 15 3.3

ABCSG-6a30 62.3 ANA 387 3 0.8h 23 59Placbeo 469 1 0.2 13 2.8OR 3.84 2.3495% CI 1.40 to 37.06 1.17 to 4.68P .245 .017

MA.175 (Goss PE, et al:J Natl Cancer Inst 97:1262-1271, 2005) 30 LET 2,572 145 6.0 4

Placebo 2,577 196 8.0 11P .005 .12

Abbreviations: ATAC, Arimidex, Tamoxifen, Alone or in Combination (trial); ANA, anastrozole; TAM, tamoxifen; OR, odds ratio; BIG, Breast International Group; LET,letrozole; NR, not reported; ABCSG, Austrian Breast and Colorectal Cancer Study Group; GOS, goserelin; ITA, Italian Tamoxifen Anastrozole (trial); TEAM, TamoxifenExemestane Adjuvant Multinational (trial); EXE, exemestane; IES, Intergroup Exemestane Study; N-SAS, National Surgical Adjuvant Study (Group); ARNO,Arimidex-Nolvadex (trial).

aGynecologic events.bGynecologic symptoms.cOther vulvovaginal disorders.dEndometrial abnormalities.eEndometrial hyperplasia.fUterine fibroids or polyps.gGenital bleeding.hGrades 1 and 2 only.

Burstein et al



Table A8. Adverse Climacteric Effects

Trial


No. ofPatients

Climacteric Symptoms

Hot FlashesFatigue/Asthenia

MoodDisturbance

DecreasedLibido

Nauseaand

Vomiting HeadacheCognitiveDisorder

GISymptoms

No. % No. % No. % No. % No. % No. % No. % No. %

ATAC (Howell A, et al:Lancet 365:60-62,2005; Arimidex,Tamoxifen, Aloneor in CombinationTrialists’ Group, etal: Lancet Oncol7:633-643, 2006) 68 ANA 3,092 1,104 35.7 575 18.6 597 19.3 39 1 393 12.7 265 9a

TAM 3,094 1,264 40.9 544 17.6 554 17.9 12 � 1 384 12.4 216 7OR 0.80 1.07 1.10 3.28 1.03 1.2595% CI 0.73 to 0.89 0.94 to 1.22 0.97 to 1.25 1.4 to 7.7 0.88 to 1.19 0.98 to 1.60P � .001 .3 .2 � .001 .7 .02

BIG 1-9835 25.8 LET 3,975 33.5TAM 3,988 38P � .001

ABCSG- 1222 47.8 ANA � GOS 453 25 5.5 93 20.5 97 21.4b 32 7.1 63 13.9 3 0.7TAM � GOS 451 28 6.2 70 15.5 70 15.5 23 5.1 59 13.1 0

ABCSG-829 75 ANA/TAM 1,469 80 4.1c 67 3.4TAM 1,453 51 2.3 82 3.8P .001 .616

ITA9 64 ANA 223 4 1.8 26 11.7d

TAM 225 0 15 6.6P .045 .07

TEAM56 61 TAM/EXE 4,814 2,127 44.2EXE 4,852 1,812 37.3P � .001

IES13,18 55.7 EXE 2,320 957 41.3 526 22.7 228 9.8e 50.6 225 9.7 416 17.9 97 4.2a

TAM 2,338 903 38.6 522 22.3 205 8.8 56.9 248 10.6 363 15.5 51 2.2P .07 .78 .21 .30 .03 � .001

N-SAS BC-038 42 TAM/ANA 347 36.3 26.5 20.5f 18.2TAM 349 44.7 25.5 18.1 16.0

ARNO 9533 30.1 ANA 445 29 6.5TAM 452 29 6.4

ABCSG-6a30 62.3 ANA 387 151 39.0g 41 10.6h 32 8.3 16 4.1a

Placebo 469 105 22.4 20 4.3 11 2.3 12 2.6OR 2.44 2.82 3.97 1.7395% CI 1.80 to 3.31 1.62 to 4.90 1.97 to 7.9 0.81 to 3.70P � .001 � .001 � .001 .159

NSABP B-3336 30 EXE 799 0.90i

Placebo 799 0.50P NR

MA.174 (Goss PE, etal: J Natl CancerInst 97:1262-1271, 2005) 30 LET 2,572 1,486 58 999 39 272 16j

Placebo 2,577 1,383 54 998 39 249 15P .003 .95 NR

Abbreviations: ATAC, Arimidex, Tamoxifen, Alone or in Combination (trial); ANA, anastrozole; TAM, tamoxifen; OR, odds ratio; BIG, Breast International Group; LET,letrozole; ABCSG, Austrian Breast and Colorectal Cancer Study Group; GOS, goserelin; ITA, Italian Tamoxifen Anastrozole (trial); TEAM, Tamoxifen ExemestaneAdjuvant Multinational (trial); EXE, exemestane; IES, Intergroup Exemestane Study; N-SAS, National Surgical Adjuvant Study (Group); ARNO, Arimidex-Nolvadex(trial); NSABP, National Surgical Adjuvant Breast and Bowel Project; NR, not reported.

aDiarrhea.bDepression or sleep disturbance.cNeurologic or psychiatric disorder.dGI complaints.eDepression.fMood fluctuations.gGrade 1 only.hGrades 1 to 4.iGrade 3 or 4 toxicity.jSubset analysis: N (LET) � 1,813; N (placebo) � 1,799.




Potentially relevant publicationsidentified by electronic searching

and screened for retrieval(n = 484)

Excluded(n = 432)

Other articles recommended by panel members or identified by hand-searching

(n = 13)

Articles retrieved in full copyfor detailed evaluation

(n = 52)

Articles that met selectioncriteria for data extraction

(n = 49)

Excluded(n = 0)

Articles that met selectioncriteria for data extraction

(n = 13)

Excluded(n = 3)

Articles included fordata extraction

(n = 62)

Fig A1. Quorum diagram. Inclusion and exclusion of publications identified for this systematic review.

Burstein et al



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