Adjuvant Targeted Therapy in EarlyBreast CancerJohn Mackey, MD1, Deanna McLeod, BSc2, Joseph Ragaz, MD3, Karen Gelmon, MD4, Sunil Verma, MD5,

Kathleen Pritchard, MD5, Kara Laing, MD6, Louise Provencher, MD7,

and Lauren F. Charbonneau, RPh, BSc(Pharm)5

For this review, the authors appraised the evidence for adjuvant trastuzumab therapy in early breast can-

cer. There was level 1 evidence to support the routine use of 1 year of adjuvant trastuzumab in conjunction

with chemotherapy for women with human epidermal growth factor receptor 2 (HER-2)-positive early

breast cancer. The relative benefits of concurrent versus sequential administration remained unclear; how-

ever concurrent administration permitted the earliest possible intervention with trastuzumab with possible

superiority. There was evidence to support the use of trastuzumab in both lymph node-positive and high-

risk lymph node-negative patients, and preliminary data suggested that all patient subgroups that were eli-

gible for the trials benefit equally from trastuzumab. Adjuvant trastuzumab was associated with a risk of

cardiotoxicity, the long-term impact of which remains largely unknown. Routine cardiac risk assessment

considering left ventricular ejection fraction, age, and prior history of cardiac events is recommended along

with the selection of trastuzumab-based regimens that minimize cardiotoxicity. Trastuzumab acquisition

costs for 1 year of therapy were the largest component of treatment costs. Cancer 2009;115:1154–68.

VC 2009 American Cancer Society.

KEY WORDS: breast neoplasms, drug therapy, trastuzumab, therapeutic use, monoclonal antibodies,

adjuvant chemotherapy, erbB-2 receptor, antineoplastic agents, humans.

Increased knowledge of the biologic diversity of breast cancer has been accompanied by increasedefforts to individualize breast cancer treatment based on the underlying molecular features of each tumor.Approximately 15% to 20% of early breast cancers have amplification of the human epidermal receptor-2(HER-2) gene, with resultant overexpression of the HER-2 protein.1-3 HER-2 belongs to a family of 4transmembrane receptor tyrosine kinases that mediate the growth, differentiation, and survival of cells.4-6

Tumors that over express this protein are imbued with more aggressive qualities, including enhancedgrowth and proliferation, increased invasive and metastatic capability, and stimulation of angiogenesis.4,6

Individual trials, population-based studies, and retrospective analyses also have shown that HER-2 overex-pression is associated with poorly differentiated, high-grade tumors and lymph node involvement.4,6 Until

Received: June 24, 2008; Revised: September 12, 2008; Accepted: September 19, 2008

Published online: January 21, 2009, VC 2009 American Cancer Society

DOI: 10.1002/cncr.24114, www.interscience.wiley.com

Corresponding author: John Mackey, MD, Cross Cancer Centre, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, Canada; Fax: (780)

432-8221; johnmack@cancerboard.ab.ca

1Cross Cancer Center, Edmonton. Alberta, Canada; 2Kaleidoscope Strategic, Toronto, Ontario, Canada; 3McGill University, Montreal, Quebec, Canada;4British Columbia Cancer Agency, British Columbia, Canada; 5Sunnybrook Odette Cancer Center, Toronto, Ontario, Canada; 6Cancer Care Program,

Dr. H. Bliss Murphy Cancer Center, St. John’s, Newfoundland, Canada; 7Deschenes-Fabia Center for Breast Disease, Quebec, Canada

We thank Kaleidoscope Strategic Inc., for the information management services required for developing this review.

1154 Cancer March 15, 2009

Review Article

recently, patients who had breast cancer with HER-2overexpression (HER-2-positive breast cancer) faced amarkedly poorer prognosis than patients who had breastcancer without HER-2 overexpression (HER-2 negativebreast cancer).4,6 A promising recent addition to the adju-vant treatment arsenal is trastuzumab (Herceptin; Genen-tech, South San Francisco, Calif), a new agent biologicallytargeted against the HER-2 protein that has demonstratedthe ability to mitigate the prognostic disadvantage ofHER-2 expression.

Trastuzumab is a humanized monoclonal antibody

that targets the extracellular domain of the HER-2 pro-

tein. Trastuzumab activates antibody-dependent, cell-

mediated cytotoxicity and disrupts the signal transduction

process through interference with receptor dimerization,

downstream effectors, and receptor internalization and

degradation.5 Trastuzumab was tested formally in combi-

nation with chemotherapy for the first-line treatment of

metastatic breast cancer and demonstrated both improved

response rate and improved survival compared with

chemotherapy alone in patients with HER-2-positive

breast cancer.7 Although the risk of cardiotoxicity

increased with the addition of trastuzumab to chemother-

apy, otherwise, trastuzumab was well tolerated. These

results triggered several prospective clinical trials to test

the efficacy of adjuvant trastuzumab in early breast cancer.

In the current review, we have appraised the evidence for

adjuvant trastuzumab therapy in early breast cancer,

considered treatment costs, and reviewed select quality-

of-life factors as a means of navigating the landscape of

available and emerging treatment options.

Search Strategy and Study Overview

Published clinical trials of for early breast cancer were

identified in a search of the PubMed database through to

April 2007 using the terms ‘adjuvant or postoperative,’

‘trastuzumab,’ and ‘breast cancer.’ In addition, conference

proceedings from the American Society of Clinical

Oncology (ASCO) (2003-2007), the San Antonio Breast

Cancer Symposium (2003-2007), and the European

Society of Clinical Oncology (2004-2006) were searched

manually for studies that met the eligibility criteria.

Results presented at symposia were considered an impor-

tant source of current clinical information, and, whenever

available, data from presentations were used to supple-

ment published abstract information. Studies were eligi-

ble for inclusion if they reported efficacy results from

prospective, randomized controlled trials; if they were

published in the English language, and if they investigated

the use of adjuvant trastuzumab therapy in patients with

early breast cancer. Six prospective clinical trials met the

eligibility criteria of this review.

Study Findings

Efficacy

The largest of the adjuvant trastuzumab trials is the

Herceptin Adjuvant (HERA) trial,8,9 which an interna-

tional randomized study investigating the use of trastuzu-

mab in HER-2-positive patients who have completed

locoregional therapy and a minimum of 4 courses of

chemotherapy. In total, 5102 women with HER-2-posi-

tive breast cancer were assigned randomly within 6 weeks

of completing primary therapy to 1 of 3 groups: 1)

women who underwent observation alone; 2) women

who were treated with adjuvant trastuzumab (8 mg/kg

load followed by 6 mg/kg every 3 weeks) for 1 year; and 3)

women who were treated with adjuvant trastuzumab at

the same dose and schedule for 2 years. The baseline char-

acteristics of the patients in the HERA trial are summar-

ized in Table 1. It is noteworthy that just over half (57%)

of the women in this trial had lymph node-positive

disease, less than one-third (26%) had received prior

adjuvant anthracycline and taxane therapy, and an

additional 11% received neoadjuvant chemotherapy.

At a median follow-up of 23.5 months, 1 year of

trastuzumab therapy resulted in significant reductions in

the risk of recurrence (hazards ratio [HR], 0.64; 95% con-

fidence interval [95% CI], 0.54�0.76 [P < .0001]) and,

despite a 51% crossover rate, the risk of death was signifi-

cantly reduced (HR, 0.66; 95% CI, 0.47�0.91 [P ¼.0115]) (Table 2) compared with observation.9 When

considering the clinical application of sequentially admin-

istering trastuzumab after chemotherapy as in the HERA

trial (chemo-trastuzumab sequences), it is important to

consider the following: 1) a potential further benefit may

exist from the concurrent administration of chemotherapy

and trastuzumab10-14 that was not explored in the trial; 2)

significant losses in patient follow-up (5.7% experimental

arm and 3.4% observation arm) and a high rate of patient

Adjuvant Trastuzumab for Breast Cancer/Mackey et al

Cancer March 15, 2009 1155

Table

1.PatientCharacteristics,T

umorCharacteristics,andPriorChemoth

erapy

StudyGroup

HERA:Piccart-

Gebhart

2005,8

Smith20079

N9831/B

-31

Analysis:Perez

200713

BCIRG

006:Slamon200612

PACS-04(Trastuzu

mab

Subgroup):Spielm

ann

200719

FinHer(Trastuzu

mab

Subgroup):

Joenssu200611

Variable

CTfiTrfor

1y,n51703

CT,

n51698

ACfiP/Tr,

n51989

ACfiP,

n51979

ACfiD/Tr,

n51074

CB/D

/Tr,

n51075

ACfiD,

n51073

FEC

orEDfiTr,

n5260

FEC

orED,

n5268

DorV/Trfi

FEC,

n5116

DorVfiFEC,

n5116

AdjuvantATtherapy,

%26

26

100

100

100

0100

50

50

50

50

Horm

onetherapy:ER/PgR-positive

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Age<50y,

%52

52

51

50

52

54

52

48(M

ed)

49(M

ed)

51(M

ed)

50(M

ed)

Horm

one-receptorpositive,%

50

50

50

50

54

54

54

58

61

50(ERþ)/

39(PgRþ)

44(ERþ)/

29(PgRþ)

Lymphnodestatus,%

NeoadjuvantCT

11

10

NA

NA

NA

NA

NA

NA

NA

NA

NA

High-risklymphnodenegative

32

33

77

29

29

29

00

10

22

No.ofpositivelymphnodes

1-3

29

29

53

52

38

39

38

60

56

55

50

‡428

28

40

40

33

33

33

40

44

34

28

Tumorsize,%

£2cm

39

40

38

40

38

40

41

30(<

2cm)

35(<

2cm)

40

30

2.125cm

45

43

52

51

55

54

53

70(�

2cm)

65(�

2cm)

59(>

2cm)

71(>

2cm)

>5cm

46

97

76

6

Trastuzu

mabinitiatedbasedon

norm

alcardiacfunction

Atcompletionof

RTandCT

Atcompletion

ofAC

AtcompletionofAC

forAC!

Dandafter

surgery

forCB/D

/Tr

AtcompletionofRTandCT

Aftersurgery

HERA

indicatestheHerceptinAdjuvanttrial;N9831,NorthCentralCancerTreatm

entGrouptrialN9831;B-31,NationalSurgicalAdjuvantBreastandBowelProjecttrialB-31;BCIRG

006,BreastCancerInter-

nationalResearchGrouptrial006;PACS-04,Protocole

Adjuvantdansle

CancerduSein;FinHer,FinlandHerceptinstudy;CT,

chemotherapy;Tr,trastuzu

mab;AC,doxorubicin

andcyclophosphamide;P,

pacli-

taxel;D,docetaxel;CB,carboplatin;FEC,fluorouracil,

epirubicin,and

cyclophosphamide;ED,epirubicin

and

docetaxel;V,

vinorelbine;AT,

anthracyclin

e-taxane;ER,estrogen

receptor;

PgR,progesterone

receptor;Med,median;þ,positive;NA,notapplicable;RT,

radiotherapy.

Review Article

1156 Cancer March 15, 2009

Table

2.Disease-freeSurvivalandOverallSurvival

StudyGroup

HERA:Smith

20079

N9831/B

-31Anal-

ysis:Perez200713

BCIRG

006:Slamon

200612

PACS-04(Trastuzu

mab

Subgroup):Spielm

ann

200719

FinHer(Trastuzu

mab

Subgroup):Joenssu

200611

Variable

CTfiTrfor1y,

n51703

CT,

n51698

ACfiP/Tr,

n51989

ACfiP,

n51979

ACfiD/Tr,

n51074

CB/D

/Tr,

n51075

ACfiD,

n51073

FEC

orEDfiTr,

n5260

FEC

orED,

n5268

DorV/Trfi

FEC,

n5116

DorVfiFEC,

n5116

Medianfollo

w-up,y

23

34

3

Disease-freesurvival,%

3-Y

80.6

74.3

87.9

77.6

87

86

81

80.9

77.9

89.3*,y

77.6y

4-Y

NA

NA

85.9

73.1

83

82

77

72.7

73.2

NAy

NAy

HR

[95%

CI]

0.64[0.54�0.76]

0.48[0.41�0.57]

AC!D/TrvsAC!D,

0.61[0.48�0.76]/CB/D

/Trvs

AC!D,0.67[0.54�0.83]

0.86[0.61�1.22]

0.42[0.21�0.83]y

P<.0001z

<.00001§

<.0001/.0003

.41

.01y

Overallsurvival,%

3-Y

92.4

89.7

94.6

92.7

97

95

93

95.7

96.5

96.3

89.7

4-Y

NA

NA

92.6

89.4

92

91

86

91.5

93.0

NR

NR

HR

[95%

CI]

0.66[0.47�0.91]

0.65[0.51�0.84]

AC!D/TrvsAC!D,

0.59[0.42�0.85]/CB/D

/Trvs

AC!D,0.66[0.47�0.93]

1.27[0.68�2.38]

0.41[0.16�1.08]

P.0115k

.0007

.004/<

.017

NR

.07

HERAindicatestheHerceptinAdjuvanttrial;N9831,NorthCentralCancerTreatm

entGrouptrialN9831;B-31,NationalSurgicalAdjuvantBreastandBowelProjecttrialB-31;BCIRG

006,BreastCancerInterna-

tionalResearchGroup

trial006;PACS-04,_____;FinHer,Finland

Herceptinstudy;CT,

chemotherapy;Tr,trastuzu

mab;AC,doxorubicin

and

cyclophosphamide;P,

paclitaxel;D,docetaxel;CB,carboplatin;

FEC,fluorouracil,

epirubicin,andcyclophosphamide;ED,epirubicin

anddocetaxel;V,

vinorelbine;NA,notapplicable;HR,haza

rdratio;95%

CI,95%

confidenceinterval;RFS,recurrence-freesurvival;NR,not

reported.

*P<.0087.

yRecurrence-freesurvival.

zCensoredanalysis:HR,0.63;95%

CI,0.53�0.75(P

<.0001).

§TheHR

wasadjustedforlymphnodes,receptorstatus,paclitaxelschedule,andprotocol.

||Censoredanalysis:HR,0.63;95%

CI,0.45�0.87(P

¼.0051).

Adjuvant Trastuzumab for Breast Cancer/Mackey et al

Cancer March 15, 2009 1157

crossover (51%) may affect outcomes, particularly overall

survival; and 3) the prior chemotherapy in this trial may

be considered suboptimal. In addition, women were

randomized after they completed chemotherapy, which

may have resulted in a more favorable cohort, because

those with early recurrences were omitted and were not el-

igible for enrollment.

The 5 subsequent adjuvant trastuzumab trials investi-

gated the administration of trastuzumab in conjunction

with prescribed chemotherapy, whereby trastuzumab was

administered either as a chemo-trastuzumab sequence or

concurrently with the taxane component of the prescribed

regimen (concurrent trastuzumab-taxane regimens) in

women with HER-2-positive tumors. The North Central

Cancer Treatment Group trial (N9831)10,13,15 and the

National Surgical Adjuvant Breast and Bowel Project trial

(B-31)10 are multicenter, open-label, randomized controlled

trials that were designed to explore the benefits of adding

trastuzumab to an adjuvant combination of doxorubicin

and cyclophosphamide (AC) followed by paclitaxel.

In the N9831 trial,10 women with lymph node-posi-

tive and high-risk lymph node-negative breast cancer were

assigned randomly to 1 of 3 arms: 1) women who received

AC then weekly paclitaxel (AC!P), 2) women who

received the same AC!P with weekly trastuzumab (4

mg/kg load followed by 2 mg/kg per week) administered

concurrently beginning with the first dose of paclitaxel

and continuing for 1 year (AC!P/Tr), 3) and women

who received the same AC!P followed sequentially, after

the completion of paclitaxel, by 1 year of weekly trastuzu-

mab therapy at the same dose and schedule as the other 2

arms (AC!P!Tr).

In the B-31 trial,10 only lymph node-positive

patients were eligible. Enrolled women were assigned to 1

of 2 arms: 1) AC followed by paclitaxel administered ev-

ery 3 weeks (AC!P), and 2) the same AC!P with

weekly trastuzumab administered concurrently beginning

with the first cycle of paclitaxel and continuing for 1 year

(AC!P/Tr). Because the N9831 and B-31 trials had

somewhat similar control and treatment arms, a joint

analysis (N9831/B-31 Analysis) comparing the concur-

rent trastuzumab-taxane arms (AC!P/Tr) with the con-

trol arms (AC!P) of the 2 trials was conducted. The

primary endpoint of the N9831/B-31 Analysis was dis-

ease-free survival (DFS). A subset of 3968 women quali-

fied for inclusion in the joint analysis, of whom 93% had

lymph node-positive disease (Table 1) and approximately

57% had received weekly paclitaxel.13

At a median follow-up of 2.9 years, despite a 21%

crossover rate,13 AC!P/Tr produced significant reduc-

tions in the risk of both recurrence (HR, 0.48; 95% CI,

0.41�0.57 [P< .00001]) and death (HR, 0.65; 95% CI,

0.51�0.84 [P ¼ .0007]) compared with AC!P (Table

2).13 These data confirm the findings of the HERA trial.

When considering these findings, it is important to

remember the following: 1) the joint analysis of 2 distinct

trials with different treatment and statistical approaches is

unorthodox; 2) the standards for validation and source

verification used in these trials were less rigorous than

those used in the HERA trial and the Breast Cancer Inter-

national Research Group 006 (BCIRG 006) trial; 3) a

small percentage of patients who were treated on the study

were identified as HER-2 negative at central review13,16;

and 4) AC!P may be considered suboptimal adjuvant

therapy.3,17

The BCIRG 006 trial is an international, multicen-

ter, open-label, randomized controlled study12,18 that was

designed to assess the benefits of adding trastuzumab to an

anthracycline/docetaxel-based or a nonanthracycline, doce-

taxel, and carboplatin-based adjuvant chemotherapy regi-

men in patients with HER-2-positive breast cancer. In

total, 3222 women were assigned randomly to 1 of 3 treat-

ment arms: 1) women who received a combination of AC

followed by docetaxel administered every 3 weeks

(AC!D); 2) women who received AC!D with concur-

rent, weekly trastuzumab beginning with docetaxel (4 mg/

kg load followed by 2 mg/kg weekly) for the duration of

chemotherapy followed by trastuzumab administered every

3 weeks for a total therapy duration of 1 year (AC!D/Tr);

and 3) women who received a combination of carboplatin,

docetaxel, and weekly trastuzumab followed by trastuzu-

mab administered every 3 weeks for a total therapy dura-

tion of 1 year (CB/D/Tr). Patient characteristics were well

balanced across study arms, and approximately 71% of

patients had lymph node-positive disease (Table 1).12

At a median follow-up of 36 months, both the

AC!D/Tr regimen and the CB/D/Tr regimen, com-

pared with AC!D, produced significant reductions in

the risk of both recurrence (HR, 0.61; 95% CI,

0.48�0.76 [P < .0001]; and HR, 0.67; 95% CI,

0.54�0.83 [P ¼ .0003], respectively) and death (HR,

0.59; 95% CI, 0.42�0.85 [P ¼ .004]; and HR, 0.66;

Review Article

1158 Cancer March 15, 2009

95%CI, 0.47�0.93 [P¼ .017], respectively) (Table 2).12

When considering these study results, it is important to

note that: 1) the results of the BCIRG 006 trial have not

yet been published or peer reviewed, and 2) the nonan-

thracycline CB/D regimen is not an established adjuvant

regimen for breast cancer.

The Protocole Adjuvant dans le Cancer du Sein

(PACS) 04 study is a multicenter, open-label, random-

ized controlled trial.19 It is the first study designed to

evaluate the benefits of a chemo-trastuzumab sequence

following a prescribed escalated-dose epirubicin or epi-

rubicin-taxane regimen. In total, 3010 women with axil-

lary lymph node-positive breast cancer were assigned

randomly to 1 of 2 arms: 1) a combination of epirubicin

and docetaxel (ED), or 2) a combination of escalated-

dose epirubicin, fluorouracil and cyclophosphamide

(FEC100). Once their HER-2 status was determined,

women with HER-2-positive tumors (n ¼ 528) imme-

diately underwent a second randomization to 1 year of

trastuzumab administered every 3 weeks (8 mg/kg load

followed by 6 mg/kg every 3 weeks) or observation. As

in the HERA trial, trastuzumab therapy was initiated af-

ter the completion of both chemotherapy and radiother-

apy. Baseline characteristics of the patients with HER-

2-positive disease were well balanced (Table 1).19

At a median follow-up of 4 years, the PACS-04

study has the longest follow-up of trastuzumab trials

reported to date. Results from the first randomization

comparing concomitant ED with FEC100 have yet to be

reported; however results of the second randomization

failed to demonstrate a significant reduction in the risk of

recurrence (HR, 0.86; 95% CI, 0.61�1.22 [P ¼ .41]) or

death (HR, 1.27; 95% CI, 0.68�2.38 [P value not

reported]) for chemo-trastuzumab sequences compared

with observation (Table 2). When considering these find-

ings, it is important to note that: 1) the study may have

been underpowered because of the small sample size; 2) as

in the HERA trial, the sequential approach may have pre-

cluded a potential benefit from the concurrent adminis-

tration of chemotherapy and trastuzumab10-14; 3) in

contrast to the HERA trial population, a large proportion

of patients in the PACS-04 trial received optimal chemo-

therapy, which may explain the reduced incremental ben-

efit of trastuzumab observed in the PACS-04 relative to

the HERA trial; and 4) the PACS-04 results have not

been published or peer reviewed.

The Finland Herceptin (FinHer) study is a multi-

center, open-label, randomized controlled trial11 that was

designed to assess the benefits of docetaxel administered

every 3 weeks (D) or weekly vinorelbine (V) followed by

fluorouracil, epirubicin, and cyclophosphamide (FEC) in

1010 women with axillary lymph node-positive or high-

risk, lymph node-negative breast cancer. The study also

assigned 232 women with HER-2-positive tumors to

receive 9 cycles of weekly trastuzumab (4 mg/kg load fol-

lowed by 2 mg/kg weekly) administered concurrently

with either docetaxel, or vinorelbine, or no further treat-

ment. Baseline characteristics of the patients were bal-

anced with the exception of axillary lymph node

metastases, which were somewhat more frequent in the

trastuzumab group than in the observation group (89% vs

78%, respectively) (Table 1).11

At a median follow-up of 3 years, as in the 4 larger

trastuzumab trials, fewer events of recurrence were evident

for women who received trastuzumab (HR, 0.42; 95%

CI, 0.21�0.83 [P ¼ .01]) compared with women who

did not (Table 2), although overall survival reached only

borderline significance, most likely because of the small

sample size (HR, 0.41; 95% CI, 0.16�1.08 [P ¼ .07])

(Table 2).11 Although the short 9-week course of trastuzu-

mab therapy (short-course trastuzumab therapy) proved

beneficial, caution should be used when interpreting these

findings, because: 1) the sample size of the HER-2-posi-

tive patient population was small; 2) the study prescribed

lower than standard doses of both anthracyclines and tax-

anes; and 3) although there was a trend toward improved

overall survival with the addition of trastuzumab, the

findings were not statistically significant.

Safety

Noncardiac adverse events

Trastuzumab is associated with few grade 3 or 4

adverse effects. Small but significant increases in severe

adverse events were reported with trastuzumab compared

with observation (11% vs 6%; P < .0001) in the HERA

trial.9 However, the addition of trastuzumab to chemo-

therapy did not result in clinically significant increases

in the incidence of adverse events compared with controls

in the FinHer trial,11 the N9831/B-31 Analysis,10 or the

AC!D/Tr arm of the BCIRG 006 trial.12 The CB/D/Tr

regimen was the only treatment that produced less severe

toxicity compared with controls.12

Adjuvant Trastuzumab for Breast Cancer/Mackey et al

Cancer March 15, 2009 1159

Cardiotoxicity

Because both anthracyclines and trastuzumab are

cardiotoxic,20-22 significant measures were undertaken to

mitigate cardiac risk in all trials. These include appropri-

ate eligibility criteria, cardiac screening and monitoring,

and strict criteria for the initiation and discontinuation

of trastuzumab therapy.8-12,19

Chemo-trastuzumab sequences were explored in 3

of the 6 trials: the HERA trial, the sequential arm of the

N9831 trial, and the PACS-04 trial. The reported car-

diac data captured differing components of therapy

across trials. Because patients in the HERA and PACS-

04 trials were randomized after the completion of chem-

otherapy, the reported cardiotoxicity data from these

trials reflects trastuzumab-induced cardiotoxicity exclu-

sively, because patients with compromised cardiac

capacity after chemotherapy were excluded from the

trastuzumab portion of the trial. In the N9831 trial,

although patients were randomized before they received

chemotherapy, the trial reports cumulative post-AC car-

diotoxicity, which may not fully capture the anthracy-

cline-induced cardiotoxicity of the AC portion of

chemotherapy.

Furthermore, the rigor of cardiac screening in the 3

trials differed considerably: Patients in the HERA trial

had a more favorable cardiac profile (left ventricular

ejection fraction [LVEF] >55% after chemotherapy and

locoregional therapy) relative to patients in both the

PACS-04 trial (LVEF �55% or between 50% and 55%

with cardiologist approval) and the N9831 trial (LVEF

>50%).

Chemo-trastuzumab sequences were associated with

increases in cardiotoxicity in all 3 trials. Patients in the

HERA trial experienced a small but significantly greater

degree of cardiotoxicity with trastuzumab compared with

observation, including a confirmed, significant decrease

in LVEF (3.04% vs 0.53%; P < .0001), symptomatic

congestive heart failure (CHF) (2.15% vs 0.12%; P <

.0001), and severe CHF (0.60% vs 0%; P< .0001); thus,

4.3% of patients were unable to complete trastuzumab

therapy for cardiac reasons.9,23 Patients in the PACS-04

trial also experienced increased cardiotoxicity with the

addition of trastuzumab, resulting in increases in severe

CHF (1.7% vs 0.4%) and a higher rate of discontinuation

due to cardiotoxicity (17.9%) (Table 3).19 Finally, when

sequential trastuzumab was added to the AC!P arm of

the N9831 trial, increases in cardiac events once again

were apparent (2.8% vs 0.3%).24

Concurrent trastuzumab-taxane regimens were

explored in 3 of the 6 trials.10,12,15 In all 3 studies, only

patients who had an LVEF>50% after the completion of

AC therapy were eligible for trastuzumab therapy, result-

ing in a small proportion of enrolled patients in all 3 trials

being denied trastuzumab therapy (N9831/B31 Analysis,

6.7% of patients; BCIRG 006 trial, 2% of patients). Car-

diotoxicity was evident in all 3 trials. The addition of tras-

tuzumab to paclitaxel after the completion of AC resulted

in an increase in cumulative cardiac events (either events

from cardiac causes or New York Heart Association

[NYHA] class III or IV CHF) compared with controls in

both the N9831 and B31 trials (3-year cumulative cardiac

events [N9831], 3.3% vs 0.3%; 5-year cumulative cardiac

events [B31], 3.8% vs 0.9%).24,25 Furthermore, 15% of

patients in the N9831 trial and 19% of patients in the

B31 trial were unable to complete trastuzumab therapy

for cardiac reasons.26,27 Increased cardiotoxicity also was

apparent in the AC!D/Tr arm of the BCIRG 006 com-

pared with controls (>10% relative LVEF decline; 18.1%

vs 10.1%, respectively; P < .0001; NYHA grade 3 or 4

CHF, 1.9% vs 0.4%, respectively)12; and, similar to the

other concurrent trastuzumab-taxane trials, 8.3% of

patients who received AC!D/Tr were unable to com-

plete therapy because of trastuzumab-mediated cardiotox-

icity (unpublished data).

The nonanthracycline-containing, concurrent tras-

tuzumab-taxane regimen (CB/D/Tr) of the BCIRG 006

trial and the short-course trastuzumab regimen of the

FinHer trial were the least cardiotoxic. At 3 years, no

increase in cardiotoxicity was apparent for CB/D/Tr com-

pared with controls (>10% relative LVEF decline, 8.6%

vs 10.1%; grade 3/4 CHF, 0.4% vs 0.4%) in the BCIRG

006 trial (Table 3),12 and none of the 4 patients who

experienced cardiac infarction or failure in the FinHer

trial had received trastuzumab (Table 3).11

DISCUSSION

There is overwhelming evidence to support the overall

benefits of adding adjuvant trastuzumab to chemotherapy

in women with HER-2-positive cancer despite the risk of

developing clinically significant cardiac toxicity. Although

the benefit of adjuvant trastuzumab is clear, many

Review Article

1160 Cancer March 15, 2009

Table

3.Card

iacSafety

StudyGroup

N9831/B

-31Analysis:Perez2008,24Rastogi

2007,25Perez2005,26Tan-C

hiu

200527

HERA:Suter200723

ACfiP/Tr

ACfiP

BCIRG

006:Slamon200512*

PACS04:

Spielm

ann200719

FinHer:Joensuu

200611

Variable

CTfiTr

CTfi

Observation

N9831

B-31

N9831

B-31

ACfiD/Tr

CB/

D/Tr

Control

FEC

orEDfiTr

FEC

orED

Dor

V/Trfi

FEC

Dor

VfiFEC

Sample

size,no.ofpatients

1678

1708

579y

947

670z

898

1068

1056

1050

260

268

115

116

Trastuzumabdiscontinuedbecauseofcardiacproblems

Percentageofpatients

4.3

NA

15.4

26

1927

NA

NA

8.3*

3.6*

NA

17.9

NA

NR

NA

Medianfollo

w-up,y

23

Decreasesin

LVEF�15%

points

from

baseline

Percentageofpatients

7.0§

2.1§

17.3

26|

NR

6.7

26|

NR

18.1

12¶

8.6

12¶

10.1

12¶

NR

NR

3.5#

6.0

zz

P<.0001

.5

Medianfollo

w-up,y

22

33

33

33

Severe

CHF

Percentageofpatients

(no.)

0.6

0.0

3.3

24**

3.8

(n¼35)25yy

0.3

24**

0.9

(n¼6)25yy

1.9

(n¼20)zz

12

0.4

(n¼4)zz

12

0.4

(n¼4)zz

12

1.7

(n¼4)

0.4

(n¼1)

0.0

(n¼0)§§

NR

Medianfollo

w-up,y

22

3.75

53.75

53

33

44

3

Cardiacdeath

Percentageofpatients

(no.)

0.0

(n¼0)

0.06(n¼1)

0.2

(n¼1)25

0.0

(n¼0)25

0.2

(n¼1)24

0.1

(n¼1)25

0.0

(n¼0)12

0.0

(n¼0)12

0.0

(n¼0)12

0.0

(n¼0)

0.0

(n¼0)

0.0

(n¼0)

0.0

(n¼0)

Medianfollo

w-up,y

22

3.75

53.75

53

33

44

33

HERA

indicatestheHerceptinAdjuvanttrial;N9831,NorthCentralCancerTreatm

entGrouptrialN9831;B-31,NationalSurgicalAdjuvantBreastandBowelProjecttrialB-31;BCIRG

006,BreastCancerInternationalResearchGroup

trial006;PACS-04,Protocole

Adjuvantdansle

CancerduSein;FinHer,FinlandHerceptinstudy;CT,

chemotherapy;Tr,trastuzu

mab;AC,doxorubicin

andcyclophosphamide;P,

paclitaxel;D,docetaxel;CB,carboplatin;FEC,fluoroura-

cil,

epirubicin,andcyclophosphamide;ED,epirubicin

anddocetaxel;V,

vinorelbine;NA,notapplicable;LV

EF,

leftventricularejectionfraction;NR,notreported;CHF,

congestiveheartfailure.

*Unpublisheddata.

yAt3.75years,n¼570.

At3.75years,n¼664.

§Adecreasein

LVEF�10%

from

baselineto

anLV

EF<50%

atanytime.

|Thegreatestchangein

LVEF�15%

comparedwiththepre-A

Clevelatanytimepointin

thestudy.

¶Definedasa>10%

relativeLV

EFdecline.

#Definedas�1measurement(s)ofLV

EF<15%

ofthebaselinevalue.

**The3-yearcumulativeincidenceofcardiacevents.Acardiaceventwasdefinedasdeath

from

cardiaccausesorNew

York

HeartAssociationclassIIIorIV

CHF.

yyThe5-yearcumulativeincidenceofcardiacevents.A

cardiaceventwasdefined

asdeath

from

cardiaccauses,orNationalHeart

AssociationclassIIIorIV

CHF,

andanabsolute

dropin

LVEFonamutigated

acquisitionscanor

echocardiogram

of>10%

points

tobelow

55%

or>5%

andbelow

thelowerlim

itofnorm

alin

subpopulationsofpatients

elig

ible

fortrastuzu

mabtherapy.

zzGrade3or4CHF,

excludingarrhythmias.

§§Definedascardiacfailure

orcardiacinfarction.

questions remain related to the clinical application of

these findings.

Are There Patient Groups That Benefit

More or Less From Trastuzumab Therapy?

In light of the risks and costs associated with trastuzumab

therapy, the accurate identification of patients with HER-

2-positive tumors who preferentially may benefit from tras-

tuzumab therapy is imperative. Both fluorescent in situ

hybridization (FISH) and chromogenic in situ hybridiza-

tion, as well as immunohistochemistry testing with or with-

out FISH confirmation, have been used in the adjuvant

setting to assess HER-2 status.9-12 Central confirmation of

HER-2 status before enrolment was required in all studies

with the exception of an initial cohort of the N9831 trial

and all patients in the B-31 trials, which relied on testing in

approved local laboratories. Differences between local and

central HER-2 assessment and between immunohisto-

chemistry and FISH testing have been reported in the

N9831 and B-31 trials, revealing a proportion of patients

in both trials withHER-2-negative tumors at central review

(8.8% and 9.7, respectively).13,28 Unexpectedly, in addi-

tion to the benefits of trastuzumab among HER-2-positive

patients, exploratory subgroup analyses from both the

N9831 trial and the B-31 trial revealed a potential benefit

for trastuzumab among patients who tested negative for

HER-2 at central review.13,28 Discordance in HER-2 test-

ing and the possibility of heterogeneity in relative treatment

effect underscore the importance of continued research

into optimal HER-2 testing and the use of standardized

HER-2 testing in clinical practice.

Adjuvant trastuzumab trials enrolled significant pro-

portions of patients with lymph node-positive and high-

risk, lymph node-negative disease. Although low numbers

of very small T1a and T1b tumors were included in the

high-risk, lymph node-negative cohorts,9,12 nevertheless,

it is reasonable to consider the use of the aforementioned

trastuzumab regimens in all patients who have lymph

node-negative, HER-2-positive disease with a high-risk of

recurrence.

None of the trials that we reviewed were powered to

detect the effect of trastuzumab in patient subgroups at

the time of their interim analyses. However, an early look

at the forest plots of HRs for DFS in the HERA trial,9 the

BCIRG 006 trial,12 and the N9831/B-31 Analysis10,13

suggest that all eligible patient subgroups, regardless of

age, lymph node status, menopausal status, or hormone

status, benefited equally from trastuzumab.

BothHER-2/neu amplification and topoisomerase IIa

(Topo IIa) amplification are associated with a relative ben-

efit from anthracycline-containing regimens compared

with nonanthracycline-containing regimens.29-34 It has

been postulated that this benefit may relate to the physical

proximity on chromosome 17q of the HER-2 and Topo

IIa gene, because topoisomerase II is involved integrally in

the mechanism of action of the anthracyclines. Data from

the BCIRG 006 trial demonstrated that CB/D/Tr is

equivalent to AC!D/Tr in patients overall; however, in

the 35% of women with HER2-positive early breast can-

cer in whom the Topo IIa and HER-2 genes are coampli-

fied, CB/D/Tr and AC!D/Tr are equivalent to

AC!D.12 These data suggest that anthracycline-contain-

ing chemotherapy may not be required in HER-2-overex-

pressing women and/or that trastuzumab may not be

required in addition to an anthracycline-containing

regimen in women with HER-2/Topo IIa coamplified

tumors.

A meta-analysis of studies comparing higher dose

anthracycline-containing regimens with standard-dose

anthracycline-containing regimens suggested that women

with HER-2-positive tumors benefited from higher dose

chemotherapy compared with standard-dose chemother-

apy, whereas women with HER-2-negative tumors did

not.35 Similarly, a significant interaction between HER-2

status and taxane-containing versus nontaxane-containing

regimens have been reported.36,37 In Cancer and Leuke-

mia Group B trial 9344 trial, both women with HER-2-

positive tumors and women with HER-2-negative tumors

benefited from the addition of taxanes; however, those

with HER-2-positive tumors did so to a greater degree.

An analysis of the PACS-04 and BCIRG 006 clinical trial

populations designed to assess the benefits of HER-2 and

Topo IIa as predictors of response to trastuzumab cur-

rently is underway.

Should Trastuzumab Be Administered

Concurrently or Sequentially With

Chemotherapy?

Annualized DFS hazards rates for patients with HER-2-

positive early breast cancer who have not received

Review Article

1162 Cancer March 15, 2009

trastuzumab indicate an increased risk of recurrence

within 1 to 2 years, providing a rationale for the earliest

possible intervention with trastuzumab.9,13 Concurrent

trastuzumab-taxane regimens10-12 minimize postsurgery

trastuzuamb treatment delays (1�4 months), whereas

chemo-trastuzumab sequences administered in the HERA

trial (8 months) and the PACS-04 trial9,19 tend to incur

greater trastuzumab delays. At 3 years, all 4 concurrent

trastuzumab-taxane regimens10,12 resulted in improved

DFS compared with controls, and 2-year results from the

HERA trial demonstrated a similar improvement in DFS

for chemo-trastuzumab sequences compared with obser-

vation. However, at 4 years, outcomes for the PACS-04

trial did not indicate a benefit for aggressive anthracy-

cline-based regimens or anthracycline-taxane regimens

compared with controls (HR, 0.86; 95% CI, 0.61�1.22

[P ¼ .41]) despite a trend toward improved DFS during

the first 18 months (HR, 0.57; 95% CI, 0.30�1.09

[P value not reached]).19 This suggests a potential attenu-

ation of the benefit of trastuzumab with delayed

administration, which may indicate a cytostatic effect for

sequential trastuzumab administration, whereas concur-

rent use may result in a cytotoxic effect.

The N9831 trial is the only adjuvant trastuzumab

trial that was designed to directly compare the sequential

versus concurrent approaches.15 Although a sufficient

number of events are currently unavailable to complete

this analysis, initial data suggest that sequential trastuzu-

mab administration may result in inferior efficacy (DFS:

HR, 0.64; 95% CI, 0.46�0.91 [P ¼ .0114]) compared

with concurrent administration.15,24 Until the final

results of this analysis are available, the benefits of concur-

rent versus sequential administration remain unclear.

What Is the Optimal Duration of

Trastuzumab-based Therapy?

The balance of available evidence supports the use of

1-year of adjuvant trastuzumab therapy.8-10,12,13 The

HERA trial, which was designed to evaluate duration of

therapy, assessed the benefits of 2 years of therapy com-

pared with 1 year.9 Results from that trial, anticipated in

the fall of 2008, will provide insight into the risk-benefit

ratio for extended trastuzumab exposure; however, even

longer follow-up will be required to confirm the safety of

this treatment approach.

The use of short-course trastuzumab therapy has

clinical appeal because of the enhanced safety profile,

reduced cost, and improved quality of life of this

approach compared with 1 year of trastuzumab therapy.

The significant reductions in the risk of recurrence

observed with short-course trastuzumab therapy com-

pared with controls in the FinHer trial11 and the nonin-

feriority of short-course trastuzumab therapy relative

to 1 year of therapy in the randomized phase 2 E2198

pilot trial,38 although not powered to assess therapy

duration, support this approach. Nevertheless, evidence

from larger randomized clinical trials, such as the Syn-

ergism or Long Duration (SOLD) study and the Proto-

col of Herceptin Adjuvant with Reduced Exposure

(PHARE) trial, directly comparing short versus longer

durations of trastuzumab therapy is needed to establish

the noninferiority of this approach. Until mature study

findings from these trials are available, short-course

trastuzumab therapy should be reserved for instances in

which institutional budgetary restraints or patient

preference limit the administration of a full year of

trastuzumab therapy.

What Are the Implications of

Trastuzumab-related Cardiotoxicity?

Unlike anthracycline-mediated cardiotoxicity, some

degree of cardiac recovery appears to be possible with tras-

tuzumab-mediated cardiotoxicity. In the HERA trial,

heart failure treatment was recommended for all patients

with severe CHF. At a median follow-up of 1 year, of the

10 patients who had severe CHF at the last scheduled

assessment, 8 patients (80%) were asymptomatic, and 6

patients (60%) had an LVEF �55%.23 In the N9831

trial, at a median follow-up of 2 years, the majority of

patients who developed CHF improved on medical treat-

ment, and LVEFs>50% were observed in approximately

50% of patients who received sequential therapy and in

61% of patients who received concurrent therapy at 2

years.26 Finally, in the B-31 trial, with 5 years follow-up,

women who had confirmed CHF and at least 6 months of

follow-up usually were asymptomatic (85%). Although a

large proportion required medication (61%), approxi-

mately 66% of patients had an LVEF >50% on a follow-

up multigated acquisition (MUGA) scan.25

Adjuvant Trastuzumab for Breast Cancer/Mackey et al

Cancer March 15, 2009 1163

Which Patients Are at a Greater Risk

of Cardiotoxicity?

The ability to reliably predict a patient’s risk of developing

CHF is of great clinical importance. The HERA, N9831,

and B-31 trials conducted analyses to identify factors that

were correlated with an increased risk of cardiotoxicity

with adjuvant trastuzumab therapy. Lower screening

LVEFs,23-25 lower post-AC LVEFs,25 and age24,25 were

associated with significant increases in cardiotoxicity.

Other factors that were associated with increased cardio-

toxicity included higher doses of anthracyclines,23

increased body mass index,23 and the requirement for

hypertensive medications.24,25 Although the analyses of

potential risk factors are exploratory and were based on

small numbers, routine cardiac risk assessment is recom-

mended for all trastuzumab candidates, especially those at

an increased risk for cardiotoxicity.

Should Trastuzumab-based Therapy Be

Given Concurrently With Radiotherapy?

Preclinical data indicate that trastuzumab may exert a

radiosensitizing effect on HER-2-positive breast cancer

cells, although it is uncertain whether it has a similar effect

on normal cells.39,40 In the adjuvant studies that we

reviewed, trastuzumab was administered either concur-

rently with radiotherapy after the completion of chemo-

therapy10 or after the completion of both chemotherapy

and radiotherapy.9,19 When trastuzumab was adminis-

tered concurrently, left-sided tumors and radiation

therapy were not identified as cardiac risk factors,25 radio-

therapy was not observed to increase cardiac events or

radiation-related adverse events, and internal mammary

radiotherapy appeared to be feasible when the cardiac

dose was limited.39 These study findings support the con-

tinued practice of concurrent trastuzumab and radiother-

apy administration after the completion of chemotherapy

in conjunction with continued cardiac follow-up.

Should Trastuzumab-based Therapy Be

Given Concurrently With Endocrine

Therapy?

There is a strong rationale for the concurrent, early

administration of endocrine therapy and trastuzumab in

HER-2-positive and hormone receptor-positive breast

cancer because of preclinical evidence of cross talk

between HER-2 and estrogen receptor signaling path-

ways. Recent evidence from the first-line metastatic

breast cancer setting provides further support for this

approach.41 Women who received concurrent endocrine

therapy had a benefit from trastuzumab similar to the

benefit experienced by those who did not receive

endocrine therapy with no increase in toxicity.8,10-12,19

These findings support the continued practice of concur-

rent endocrine and trastuzumab administration after the

completion of chemotherapy in HER-2-positive and hor-

mone receptor-positive patients.

How Do Trastuzumab-based Regimens

Compare in Terms of Cost?

The administration of adjuvant trastuzumab therapy is

associated with considerable expense. In addition to the

cost of diagnostic testing, significant treatment costs

include acquisition costs, administration costs (nursing

and pharmacy time), and the costs of clinical cardiac mon-

itoring. Numerous cost-effectiveness studies suggest that

costs are comparable to other accepted and standard uses

of healthcare dollars42-46; nevertheless, factoring in treat-

ment costs when selecting from among safe and effective

treatment options improves the overall cost-benefit ratio

of the intervention. Selected treatment costs for chemo-

trastuzumab sequences and concurrent trastuzumab-tax-

ane regimens are summarized in Table 4.

Trastuzumab acquisition costs for 1 year of therapy

were the single greatest factor contributing to total treat-

ment costs (in U.S. dollars, between $41,459 and $43,023),

followed by cardiac monitoring by MUGA scan (between

$3675 and $4410). The administration costs associated

with 1 year of trastuzumab therapy administered every 3

weeks were significantly less than those associated with

weekly administration ($510 vs $1473). The inclusion of

taxanes increased total treatment costs. The short-course

trastuzumab regimen from the FinHer trial ($16,747) was

associated with the lowest total treatment cost.

Which Trastuzumab-based Regimen Is Most

Convenient for Patients?

The patient-related convenience of a regimen can have a

significant impact on a patient’s quality of life, especially

Review Article

1164 Cancer March 15, 2009

when patients live at a distance or have limited support

networks. Selected factors that affect the quality of life of

patients receiving either chemo-trastuzumab sequences or

concurrent trastuzumab-taxane regimens are summarized

in Table 5. Of the regimens that administered 1 year of

therapy, the concurrent trastuzumab-taxane regimens

resulted in shorter total treatment durations compared

with the chemo-trastuzumab sequences. The administra-

tion of both trastuzumab and paclitaxel every 3 weeks

resulted in significantly fewer patient visits compared with

weekly administration. Total clinic time was shortest for

nontaxane trastuzumab regimens and longest for regimens

that involved paclitaxel. The short-course trastuzumab

regimen of the FinHer study was considerably more con-

venient overall than all other regimens.

Ongoing Clinical Trials

Although many advances have been made in the use of ad-

juvant trastuzumab, our journey into the new frontier of

targeted therapy has only just begun. The HERA, N9831,

PHARE, and SOLD trials promise further insights into

the optimal use of trastuzumab in terms of sequencing,

treatment duration and chemo-trastuzumab combina-

tions. Large randomized trials exploring the benefits of

lapatinib used in conjunction with chemotherapy or tras-

tuzumab (the Adjuvant Lapatinib and/or Trastuzumab

Treatment Optimization or ALTTO trial and the Tykerb

Evaluation After Chemotherapy or TEACH trial) and the

effects of combining bevacizumab in combination

with adjuvant trastuzumab and chemotherapy (the

Table 4. Treatment Costs

Chemotherapy/TrastuzumabAdministration

ChemotherapyAcquisitionCosts (US$)*

TrastuzumabAcquisitionCosts (US$)

AdministrationCosts (US$)†

ClinicalMonitoringfor Duration ofTreatment(US$)‡

Total(US$)

Chemotherapy-trastuzumab sequencesAnthracycline, nontaxane (68%)

FEC10036 4098 43,023 790 — 47,911

Anthracycline, taxane (26%)

ED36 11,560 43,023 695 — 55,278

AC34fiP34 1084 43,023 786 3675 48,569

FEC10033fiD33 7757 43,023 742 3675 55,197

Concurrent trastuzumab-taxane regimensN9831

ACfiP/Tr (1 y) 1387 41,459 1996 4410 49,252

B-31

ACfiP/Tr (1 y) 1084 41,459 1749 4410 48,702

BCIRG 006

ACfiD/Tr (1 y) 7878 41,459 1013 4410 54,760

CB/D/Tr (1 y) 8568 41,459 1489 3675 55,191

FinHer

D/TrfiFEC 6967 7822 487 1470 16,747

FEC100 indicates escalated-dose fluorouracil, epirubicin (100 mg/m2/cycle), and cyclophosphamide; ED, epirubicin and docetaxel; AC, doxorubicin and cyclo-

phosphamide; P, paclitaxel; D, docetaxel; N9831, North Central Cancer Treatment Group trial N9831; Tr, trastuzumab; B-31, National Surgical Adjuvant Breast

and Bowel Project trial B-31; BCIRG 006, Breast Cancer International Research Group trial 006; CB, carboplatin; FinHer, Finland Herceptin study.

* Assumptions for cost calculations: cost/mg Medbuy Buying Group, March 2007 (Tr, $6.14; fluorouracil, $0.01; doxorubicin, $0.57; epirubicin, $4.00; D,

$11.42; P, $0.70; cyclophosphamide,$0.01; vincristine; $1.93; CB, $0.10); body surface area¼1.7 m2, weight¼65 kg; an area under the serum concentration-

time cure of 6¼600 mg; Canadian to US $ conversion factor (May 2008)¼$0.98.

yAssumptions for administration costs used nonnormalized complexity values from the Clinical Care Options Oncology website (available at: http://www.can-

cercare.on.ca; July 2007); complexity values for chemotherapy and trastuzumab additive: wage per minute and benefits for pharmacy and nursing¼$0.85;

administration costs were calculated by multiplying the complexity value per component by wage per minute by the number of cycles.

zWe assumed that a mutigated acquisition scan was obtained either at baseline or at the initiation of trastuzumab, either after the anthracycline-containing

component or at the initiation of trastuzumab, and every 3 months for the duration of trastuzumab therapy.

Adjuvant Trastuzumab for Breast Cancer/Mackey et al

Cancer March 15, 2009 1165

Bevacizumab and Trastuzumab Adjuvant Therapy in

HER-2-Positive Breast Cancer or BETH study) will

provide insight into the benefits of combining targeted

therapies.

In conclusion, the current review indicates that there

is level 1 evidence to support the routine use of 1 year of

adjuvant trastuzumab in conjunction with chemotherapy

in women who have early-stage, HER-2-positive breast

cancer. Because adjuvant trastuzumab is associated with a

risk of cardiotoxicity in the form of severe CHF, compro-

mised LVEF function, and potential for cardiovascular

disease, every effort should be made to preserve cardiac

function through routine cardiac risk assessment and the

selection of minimally cardiotoxic regimens.

Conflict of Interest Disclosures

Information support services for this review were funded throughan unrestricted educational grant administered through a thirdparty from Sanofi-Aventis.

Dr. Mackey has received honoraria for Continuing MedicalEducation speaking events from the following: Sanofi-Aventis,Roche Oncology, and GlaxoSmithKline Oncology.

Dr. Verma has served as a consultant and as a member of theadvisory board for GlaxoSmithKline, Roche Canada, and Sanofi-Aventis.

Over the past 3 years, Dr. Pritchard has been a consultant withSanofi-Avenits, AstraZeneca, Roche, Pfizer, Ortho-Biotech, YMBiosciences, Novartis, Abraxis, Amgen, and GlaxoSmithKline.She has received research funding either directly, or through percase funding for studies, or indirectly through the National Can-cer Institute of Canada Clinical Trials Group, contracted withpharmaceutical companies including AstraZeneca, YM Bioscien-ces, Bristol Myers-Squibb, Sanofi-Aventis, Amgen, Ortho-Bio-tech, Pfizer, Novartis, GlaxoSmithKline, and Ortho Biotech. Shealso has received honoraria or has been part of the Speaker’sBureau for Sanofi-Aventis, AstraZeneca, Pfizer, Roche, YMBiosciences, and Novartis and has provided paid expert testi-mony for Sanofi-Aventis, AstraZeneca, and GlaxoSmithKline.Dr. Pritchard also has been a member of the Advisory Commit-tee for Sanofi-Aventis, AstraZeneca, Ortho-Biotech, Roche,Pfizer, Novartis, YM Biosciences, and GlaxoSmithKline.

Dr. Laing has received honoraria from Sanofi-Aventis and Rocheand also has received travel grants to attend ASCO 2007 fromSanofi-Aventis.

Dr. Provencher is a member of the Canadian Advisory Boardsfor the pharmaceutical companies Roche and Sanofi-Aventis.

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Table 5. Factors That Influence Patient Convenience

Chemotherapy/TrastuzumabAdministration

Total TreatmentDuration, Months*

Total No. of Visits/Treatments

Total Clinic Time/Treatment, Hours†

Chemotherapy-trastuzumab sequencesAnthracycline, nontaxane (68%)

FEC10036 16.7 24 45

Anthracycline, taxane (26%)

ED36 16.7 24 48

AC34fiP34 19.5 22 60

FEC10033fiD33 16.3 24 45.1

Concurrent trastuzumab-taxane regimensN9831

ACfiP/Tr 14.9 68 172

B-31

ACfiP/Tr 14.9 48 132

BCIRG 006

ACfiD/Tr 15.3 30 66

CB/D/Tr 12.6 30 78

FinHer

D/TrfiFEC 4.2 12 28.5

FEC100 indicates escalated-dose fluorouracil, epirubicin (100 mg/m2/cycle), and cyclophosphamide; ED, epirubicin and docetaxel; AC, doxorubicin and cyclo-

phosphamide; P, paclitaxel; D, docetaxel; N9831, North Central Cancer Treatment Group trial N9831; Tr, trastuzumab; B-31, National Surgical Adjuvant Breast

and Bowel Project trial B-31; BCIRG 006, Breast Cancer International Research Group trial 006; CB, carboplatin; FinHer, Finland Herceptin study.

* For this analysis, the assumption was that 1 month¼4.3 weeks.

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Review Article

1166 Cancer March 15, 2009

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