975
Landmark Trials in Endocrine Adjuvant Therapy for
Breast Carcinoma
William Gradishar, M.o.
Feinberg School of Medicine, Northwestern Uni-
versity, Chicago, Illinois.
Dr. Gradishar has served as a consultant to Astra-
Z.eneca, Novartis, and Pfizer.
Address for reprints: William Gradishar, M.D., Feinberg
Schad of Medicine, Northwestern University, 676 Nortl1
St Oair St, Suite 850, Chicago, IL 60611; Fax: (312)
695-6189; E-mail: w-gradishar@northwestem.edu
Received 29 July 2005; revision received 6 Sep-
tember 2005; accepted 15 November 2005.
2006 American Cancer Society
DOl 10.1 002/cncr.21707
Published online 24 January 2006 in Wiley lnterScience (www.interscience.wiley.com).
The review summarizes the outcomes of seTeral landmark trials involving aro-
matase inhihilors that helped rormulate current therapeutic approaches recom-
mended by the American Society of Clinical Oncology for breast carcinoma treat-
ment. Ca11cer 2006;106:975-81. (C) 200fi 1\ merican r:ancer Snciely.
KEYWORDS: breast carcinoma, endocrine adjuvant therapy, tamoxifen, aromatase
inhibitors, clinical trials.
T amoxifen vvas the mainstay of adjuvant endocrine therapy for
women with hormone-sensitive breast carcinoma for nearly three
decades, but its limited efficacy span and side-effect profile prompted
the devdopment of other therapeutic agent~. Aromatase inhibitors
such as anastrozole, letrozole, and exemestane block estrogen con-
version and have demonstrated greater benefit for disease-free sur-
vival (DFS) than tamoxifen. Several landmark trials have supported
the use of aromatase inhibitors for the treatment of breast carcinoma
in postmenopausal women, leading the American Society of Clinical
Oncology to recommend their standard use.
Some two-thirds of breast carcinoma tumors are hormone-recep-
tor-positive, 1.2 and approximately 60-70% respond to antiestrogen
therapy with tamoxifen, the gold standard of endocrine adjuvant
therapy worldwide for over 20 years. The third-generation aromatase
inhibitors anastrozole, letrozole, and exemestane suppress estrogen
production by blocking the aromatase enzyme and thereby impeding
androgen conversion to estrogen.~ In the US. most postmenopausal
women with newly diagnosed hormone-sensitive breast carcinoma
are treated with aromatase inhibitors because of their superior effi-
cacy compared with that of tamoxifen, which has been demonstrated
by several trials. This review summarizes the outcomes of several
landmark trials that helped formulate current therapeutic approaches
for breast carcinoma treatment.
Landmark Trials with Tamoxifen in Breast Carcinoma Therapy
Approved in 1986, the use of tamoxifen expanded from treatment of
metastatic disease to first-line therapy for early-stage breast carci-
noma to preventative use in some patients.3 The 1983 Nolvadex
Adjuvant Trial Organization (NATO) results supported the benefits of
using tamoxifen as monotherapy for node-negative breast carcinoma
in over 1100 postmenopausal women.M when patients were random-
ized to either tamoxifen lU mg twice a day or no additional therapy
after definitive surgery for up to 5 years, significantly fewer breast
carcinoma recurrences occurred in subjects receiving tamoxifen. The
Early Rreast Cancer Trialists' Collaborative Group (ERCTCG) study of
976 CANCER March 1, 2006/ Volume 106 I Number 5
20,000 women with early breast carcinoma who re-
cl:!ived tamoxifen found that 5 yean; of adjuvant ta-
moxifen therapy provided propot1ional DFS reduc-
tions of 47%.5 6 However, tamoxifen is associated with
infrequent but potentially severe side effects; the in-
cidence of endometrial cancer quadrupled in women
taking tamoxifen for 5 years.
A recent study found that more than 50% of re-
currences occur after 5 years of tamoxifen treat-
ment,56 and when the 5-year and 10-year relapse-free
survival rates were calculated for patients who had
received standard adjuvant therapy, it was evident
that a large number of these patients still had a sub-
stantial risk of breast carcinoma recurrence and would
benefit from additional risk reduction. 7 The B-14 Na-
tional Surgical Adjuvant Breast and Bowel Project
(B-14 NSABP), a randomized, placebo-controlled clin-
ical assessment of 4127 women, showed that individ-
uals with estrogen-receptor-positive breast carcinoma
and negative axillary lymph nodes had a statistically
significant increase in DFS after 5 years of tamoxifen
therapy.8 When these subjects undenvent rerandom-
ization to placebo or to a longer period of tamoxifen
treatment, they showed no further benefit from the
drug. After 7 years of followup, patients in the placebo
group demonstrated a slight advantage in DFS (82%)
compared with tho:.-;e who continued tu H!ceive ta-
moxifen (78%) (P = 0.03), leading researchers to con-
dude that additional tamuxifen use is not warranted.9
Extending tamoxifen use beyond 5 years resulted in
pour tolerability and exacerbation of the drug's side
effects.
Currently, the Adjuvant Tamoxifen: Longer
Against Shorter (ATlAS) trial 10 and the Adjuvant Ta-
moxifen Treatment, Offer More? (ATTOMJ trial 11 are
follmving women who had tamoxifen treatment for up
to a decade after their initial tamoxifen therapy. Tn the
ATLAS trial. women are randomized to receive 5 or 10
years of adjuvant tamoxifen therapy, 11 whereas in the
ATTOM trial women who discontinue tamoxifen ther-
apy after at least 2 years of treatment (but as many as
5 or more years) are randomized to receive either an
additional 5 years of treatment with tamoxifen or no
additional therapy. 11 Until the results of these two
long-term trials are available, research suggests stop-
ping tamoxifen after 5 years of treatment, but consid-
ering the current use of aromatase inhibitors, the re-
sults of these trials may prove to be irrelevant.
Adjuvant Aromatase Inhibitor Therapy
Several large trials of third-generation aromatase in-
hibitors (anastrozole, letrozole, and exemestane) have
demonstrated efficacy that is as good as or better than
that of tamoxifen and provide a different, somewhat
more manageable side-effect profile. Adverse effects
observed with the arumatase inhibitors generally in-
clude fewer incidences of endometrial cancer, cere-
brovascular events, hut flush~s. and vaginal problems,
but more musculoskeletal disorders and fractures.
H.esults from the Arimidex, Tamoxifen Alone or in
Combination (ATAC) trial demonstrated that anastro-
zole is effective and well tolerated in the treatment of
postmenopausal women with hormone-responsive
early breast carcinoma after a median followup of 33
months.u The ATAC trial was the first adjuvant breast
carcinoma trial evaluating an aromatase inhibitor to
complete recruitment and to have results published at
a median followup of greater than 5 years. However,
the study population included women 'i'Vith unknown
estrogen-receptor I progesterone-receptor status and
one-third of the ATAC patients participated in a trial
arm (anastrozole + tamoxifen) that was stopped after
47 months of treatment. After a median followup of 68
months, patients treated with anastrozole had a sig-
nificantly better outcome for DFS than patients
treated with tamoxifen (hazards ratio [HR], 0.87; 95%
confidence interval [CIJ, 0.78-0.97) (P = O.Ol).n A
significant reduction in distant metastasis in the in-
tent-to-treat population (14%} occurred, but no signif-
icant outcome advantage was seen for distant metas-
tasis in the hormune-ret:eptur-pusitive population.
Fut1hermore, there was a trend showing that the ben-
efits of anastrozule therapy are maintained regardless
of the type of chemotherapy given, 14 but patients re-
ceiving chemotherapy and node-positive patients did
not experience any significant benefit in Dl'S when
taking anastrozole and no survival advantage for anas-
trozole over tarnoxlfen has been demonstrated thus
farY: Hot flushes and arthralgias were the most com-
mon adverse events. Ischemic cardiovascular disease,
angina pectoris, and hypercholesterolemia were ob-
served more often in patients taking anastrozole (4. 1%
vs. 3.4%). but the outcomes of these events were not
specifically reported.n 1 " All groups had similar overall
quality-of-life impacts, showing gradual improvement
over time. 11i
BIG 1-98 is a large (N = BO10) Phase III multina-
tional, double-blind, randomized clinical trial ofletro-
zole, conducted independently by the International
Breast Cancer Study Group. 17 Women recruited early
to the trial (n = 1835) were randomized to receive
letrozole (2.5 mg/ day) or tamoxifen (20 mg/ day). A
further 6193 women were randomized to the four-arm
section that includes 5 years of letrozole, 5 years of
tamoxifen, 2 years of letrozole followed by 3 years of
tamoxifen, or 2 years of tamoxifen followed by 3 years
of letrozole. Letrozole reduced the overall risk of dis-
ease recurrence by 19% (P = 0.003); the risk was re-

duced by 30% in patients receiving chemotherapy and
by 29% in tho.sl:! vvith nod!:!-po.sitiw di.s!:!a.sl:!. Th~ risk of
distant metastases was reduced by 27%, -..vhereas the
risk of death was reduced by 14% (P = 0.16). Results of
the BIG 1-98 trial suggest that letrozole may provide
higher efficacy for breast carcinoma patients, particu-
larly for patients at increased risk of recurrence. Ta-
moxifen therapy was associated '"r:ith higher inci-
dences of thromboembolic events and vaginal
bleeding, whereas a greater number of bone fractures,
NCI CTC (version 2) Grade 3-5 cardiovascular events,
and mild elevations in cholesterol were reported \vith
letrozole. With respect to lipids, the BIG l-98 trial is
the only trial to do such an analysis; because many
other trials did not investigate lipid profiles in a sys-
tematic manner, the long-term relevance of these mild
elevations is unknov.'fl at this point. Data from the
sequential arms are exp ected in 2008.
The Intergroup Exemestane Study (IE$) evaluated
the sequencing of tamoxifen with exemestane during
the first 5 years after surgery. Hl. 1 ~' The IES study com-
pared 5 years of tamoxifen treatment with 2-3 years of
tamoxifen therapy followed by 2-3 years of treatment
with exemestane. 1A, HJ Randomization to continued
treatment with tamoxifen or to exemestane occurred
after 2-3 years of tamo:xifen only. The investigators
found that sequential therapy with tamuxift:!n fulluwed
by exemestane demonstrated a 32% significant im-
provement in DFS compared with 5 years uf treatment
with tamoxifen alone and produced a significant 50%
reduction in contralateral breast carcinoma. 18 19 This
trial may also show a survival advantage because it is
trending in that direction. Adverse events experienced
by patients receiving exemestane included diarrhea
and arthralgia, whereas patients receiving tamoxifen
exp erienced more gynecologic syrnpton1s, vaginal
bleeding, and muscle cramps. Cardiovascular disease
was reported at a higher frequency for patients taking
exemestane (42.6% vs. 39.2%; P = 0.11) as was the
incidence of myocardial infarction (0.9% vs. 0.4%; P
18 19
= 0.23, NS).
Data from the Arimidex-Nolvadex CARNO 95) and
the Austrian Breast Cancer Study Group (ABCSG 8)
trials were combined to assess if switching from ta-
moxifen to anastrozole after 2 years is more effective
than tamoxifen alone for a full 5 years after surgery. 20
These trials were similar in design hut did have differ-
ences in tamoxifen dosage, patient age, and tumor
grades. One hundred percent of patients h ad hor-
mone-receptor-positive breast carcinoma, received
primary surgery, and exposure to tamo:xifen for 2
years; none of the patients had received chemother-
apy. Preliminaty analysis of 2176 patients in ABC:SG 8
<.md 947 in ARNO 95 at 26-month followup found the
Endocrine Adjuvant Therapy for Breast CA/Gradishar 977
hazard ratio for recurrence-free survival with anastro-
zole ver.su::; tamuxifen to b~ 0.59 (P < 0.0018).20 The
authors conclude that changing from anastrozole after
2 years oftamoxifen tt'eatment resulted in significantly
better distant recurrence-free survival. More fractures
occurred in women who S'\vitched to anastrozole.
Complete results and data analysis from these two
trials have not been published.
The MA-17 trial investigated extended adjuvant
therapy with letrozole after 5 years of tamoxifen treat-
ment after surgery. 21 22 The MA-17 trial, atl interna-
tional study independently coordinated by the Na-
tional Cancer Institute of Canada clinical trial groups,
investigated whether late-intervention treatment
could reduce the potential risk of late cancer recur-
rence. Breast carcinoma patients who previously re-
ceived 5 years of tamoxifen treatment were random-
ized to letrozole treatment or to placebo for a m edian
followup period of 2.4 years.21 Results indicate that
letrozole treatment after standard tamoxifen therapy
significantly improved DFS, with an estimated 4-year
DFS that was significantly higher in the letrozole arm
(93% vs. 87%, respectively; P = 0.001). Letrozole pro-
duced a significant reduction in contralateral breast
carcinoma (39%) and a reduced risk of distant metas-
tases (40%). An updated atlalysis confirmed the DFS
benefit and demonstrated a significant improvement
in distant DFS as well as a significant survival gain in
(39%) in the node-positive subgroup. 22' 23 Patients re-
ceiving letrozole had more frequent hot flushes, ar-
thritis, arthralgias, and myalgias.
Comparison of Trials
In the absence of head-to-head trials, some insights
about the various therapeutic options for breast car-
cinoma treatment today may be gained from a com-
parative review of these trials (Table l). Time of ran-
domization or preselection of patients is similar in the
BIG 1-98 and ATAC trials, in that patients are enrolled
in the study at the beginning of their endocrine ther-
apy. Patients in IES and !viA-17 in the meanwhile had
received tamoxifen for several years and were free of
disease before randomization to an aromatase inhib-
itor or placebo in these trials. Patients in the BIG 1-98
trial underwent randomization after surgery to 5 years
of tan1oxifen treatment or 5 years of letrozole treat-
ment. For trials assessing therapy sequencing. the IES
study did not randomize patients after surgery hut
randomized only patients who were disease-free at
2-3 years after tamoxifen treatment, whereas the
MA-17 trial protocol randomized patients after 5 yea1s
of tamo:xifen to an additional 5 years of treatment with
letrozole or placebo. Thus, the inconsistent applica-
978 CANCER March 1, 2006 I Volume 106 I Number 5

TABLE 1
Comparison of Landmark Trials of Endocrine Adjuvant Therapy for Breast Carcinoma

ATAC BJG 198 IES ARNO/ABCSG MA-17

Population Postmenopausal women; afrer Postmenopausal wom~n Postmenopausal women 100%HR+ patients Postmenopausal women
primary with EBC, ER + and/ with EBC, ER + and/ with primary BC:
SUigcry/chemotherapy or PgR+ nr PgR+ ER- aud/nr PgR+;
(where given); candidalc8 cnmplcLcd lS-~ yrs
fnr adjuvant hormonal adjuvant TAM
therapy therapy postsurgery
Size (IV~ 9366" 8010 4724 3224 (A RCSG 2262; 5l8i
AR\"0, 9G:L:
Handumization Handomiz~d tu reLtivt .~NA, Pirst 1835 r;mdomiztd lliseasdree <lith 2 \U 3 Pust primal")- llandomized to rective
TAM, or ANA - TAMb tu LET (2.5 mgl d) or ~rs TAM rhtrapy; surge1y + 2 yrs LET or platebu fur 5
TA.vl 120 mgldi: randomized w TAM nM ~Ts; re-randomized
another 6193 women or EX to complete 5 randomized to 3 after 5 yrs extended
randomized to 5 )T> yn of adjuvant yrs TAM or ANA therapy to 5 yrs LET
LET; 5 yrs T.:\.vl; 2 yrs therapy or placebo
LET/3 yrs TAM; or 3
yr> TA.vl 12 yrs LET
Primary endpoint DFS: time to earliest DEi: time from DFS: time from EFS: loco-rc~onal DFS: time from
(DFS 0r EFS) occurr~ncc of local or randomization to the randomization to BC recurrences, randomization to
distant recurrence, new first recurrence of the rccurrcnc~. CLBC dislanl recurrence of primary
primary BC. or deaLh [rom invasiv~ breast (second primary), or metastases, disease On Lhe breasL,
any cause carcinoma; intercurrent d~aths CLBC, with chest wall, or nodal
development of a (from any cau~~. Jeath1 not or metastatic sites) or
new invasive breast priur tu RC induded u ~velopmem uf new
carcinoma in th~ recurr~m:~l primary CLllC"
contralateral br~ast;
development of any
second malignancy;
or death from any
cause.
Secondary end Time w recUirence (including OS, S)'Stemic DFS (time OS, incidence of CLBC, Distant recurrence- OS, quality of life, long-
points new contralarerallltmors, from randomization long-term free survival and term safety,
but not padcm.~ who died tn systemic safcty/tnlcrahilil)', tolcrahility incidence of ClllC,
from non-llC cause~ hcforc recurrence. and substudic~ and
recurrence), incidence 01' meta~tases, second invcstigatin~ Uterine phatmacogcnomics
new primary CUlC, distant primary tumor'1 or thickening, R\fl), and
recurrence, OS death from any bone metaboliom,
cause:, Safe[V and patiem -a>sess~d
quality uf life
Folluwup 68 munt:hs Zj.8 mos 30.5 and 3i.4 mos 28 mus 30 mus
DFS !%1 !3%, p =0.01 19%, p =0.003 32a;,, p >0.001" 40%. p =0 0013 420:., p =0.00004
AIAC BIG l-98 JES AHN 0 IAliCSG MA-17
DDFS l"'ol 14%, p =0.04!TT 16%, p = 27w,, P =0.0012 11R:0.66/ P=0.0004 39%, p =0.0067~ 40"0, p =0.002
0.0611R+
Mortality 3%, P =O.i 14Wo, P =0.16 1200, P =0.37r Not reported 24"0. p =0.25; 39%
reduction iNode-positive
pati~m,),P = 0.04

ATAC: ;\rimilb, Tam>xif~n Alon~ or in C<Jmbination; IES: lmergrnup b:~m~stan~ Stltdy; AR)IO: Arimid~x-Nolmdtx; ,1J.lC~G: Amtrian Brmt Canr1r :itUU)' l.iroup: EBC: early breast can,er; ER : estn>gtnreepwr
pl}sitiv~; PgR+: pn>gcstcHnc-r~c,ptor p!>sitivc; honnronc-mcptorpu.litlvc; TAVT: tamif,n: nc: brca.sr cann,r: AI\.~: anastnJ7.<.1c; l.ET: lcno?.(.k; FXE: cxcmcstanc; DFS: disra.'''fr<'t' suf\il'ai.: F.FS: event-free survival;
GLEG: wntr~lah,ml brta;t rarrinom:1; OS: 0V!'T:ill ourviv~l; BMD. bunc mimral density DDFS: distant dista;c-frc, suf\il:d; ITT: inknt w trtat.
"Data rcportrcl on 6000+ patients at 68 months,
"This arm was dropped after 47 month& of fol!owup.
'" Secondary cancer. death without recurrence, and diagnoJiJ of Cl.RD not included as el'eJltS in this anal)~i>.
1
' Exl: luding basal cell rarcinoma and squamous cell carcinoma of !kin.
Dara r~porred on ar :\7.~ months.
t IMa lfportfd on at 30.& months.
g Dara presented bv R. Jakesz at the 2004 SAJlCS m~~ting.

tion of measurement variables prevents direct com-
pari::;un::; of the::;e trial ue::;ign::; ami result::;.
The trials also varied in their definitions of DFS.
The MA-17 trial did not include secondary cancer and
death without a recurrence or a diagnosis of contralat-
eral breast carcinoma as events in their analysis. The
ATAC trial defines DFS as the time-to-the-earliest-
occurrence of local or distant recurrence, new primary
breast carcinoma, or death from any cause, whereas
the BIG I-98 trial describes DPS as the time from
randomization to the first recurrence of the invasive
breast carcinoma, development of a new invasive
breast carcinoma in the contralateral breast, develop-
ment of any second malignancy, or death from any
cause. Thus, DFS in the ATAC trial does not include
secondary cancers, but DFS in the BIG 1-98 trial does,
and is, therefore, more inclusive of events.
The benefit derived from aromatase inhibitors in
patients previously treated with chemotherapy or in
particular subsets of patients (i.e., node-positive} re-
mains controversial. The IES and BIG 1-98 studies
evaluated these subsets of patients and data will be
forthcoming. The ATAC trial did not show any signif-
icant improvement for the node-positive population,
and whereas anastrozole did provide benefits over
tamoxifen for patients who were pretreated with che-
motherapy, it did not demonstrate a significant im-
provement in DFS in these patients, although this may
be demonstrated with Iunger fullowup. 1 3.14 For distant
DFS in the ATAC trial, anastrozole reduced the risk of
distant metastases by 14% (HR = 0.86, P = 0.04),
"Whereas the BIG 1-98 trial demonstrated almost twice
the reduction in distant metastases.
The quality, robustness, and consistency of data
in these trials appear to vary as well. Subgroup anal-
yses reveal inconsistencies in efficacy between the
aromatase inhibitors. The BTG 1-98 trial demonstrated
significant benefit in the node-positive population,
but at 33-month followup the ATAC trial showed that
only the node-negative patients significantly benefited
from treatment, which is difficult to explain because
node-negative disease should recur later than node-
positive cancer. Furthermore, the ATAC trial showed a
beneficial effect of anastrozole mainly in patients with
estrogen-receptor-positive and progesterone-recep-
tor-negative tumors, whereas in the BIG 1-98 study, all
estrogen-receptor-positive patients had a similar risk
reduction associated with letrozole, irrespective of
progesterone-receptor status. 21 In ATAC, anastrozole
showed significant time-to-recurrence benefit only in
the node-negative patients, who have a better prog-
nosis and who tend to have breast carcinoma recur-
rence later in the disease course.
When evaluating results of these large trials, safety
Endocrine Adjuvant Therapy for Breast CA/Gradishar 979
assessments and reporting of adverse events must be
dosely ::;<.:rutinized. ln the BIG 1-98 trial, the overall
incidence of cardiovascular adverse events was similar
in the two group~. Fewer patients re<.:eiving letruzole
experienced Grade 3-5 venous thromboembolic
events but slightly more experienced Grade 3-5 car-
diac events. In the MA-17 trial, however, letrozole
demonstrated no increase in cardiovascular events
compared with placebo. The IES trial also found an
increased risk of cardiovascular and coronary heart
disease, whereas the cardiac data from the ATAC trial
is not readily available. Thus, reporting of adverse
events also varies in these trials and may not be di-
rectly comparable.
Unresolved Issues
All trials of aromatase inhibitors show a reduction in
the relative risk of recurrence of breast carcinoma that
ranges from 13-43%, and studies comparing aro-
matase inhibitors to tamoxifen therapy demonstrate a
reduction in the relative risk of contralateral breast
carcinoma ranging from 39-So%, as well as an abso-
lute gain in DFS of 2.4-6% (Table 1). Whereas these
aromatase inhibitors are superior to tamoxifen, there
are some distinctions between them. Data from a di-
rectly comparative trial has suggested that some sub-
groups of women experience an increased btmd1t
from letrozole but not from anastrozole in the second-
line treatment of advanced breast carcinoma. How-
ever, this was an open-label trial, and half of t11e
patients in this study had unknown estrogen-receptor
status; in those who had known estrogen-receptor-
status disease, the efficacy endpoints were similar.25
However, considering the size of the estrogen-recep-
tor/progesterone-receptor status-unknown subgroup
(n = 340), the well-distributed demographics between
the trial arms and the high probability that a tumor of
undetermined hormone-receptor status would be
positive, it is unlikely that the increase in response rate
achieved with letrozole was due to a statistical imbal-
ance of estrogen-receptor /progesterone-receptor sta-
tus in favor of letrozole. 2 1i Moreover, studies of letro-
zole compared with tamoxifen in the first-line setting
also demonstrate the high efficacy of letrozole in the
estrogen-receptor /pro gestemne-receptor status-un-
known tumors. 25
Letrozole produces the highest level of aromatase
inhibition,27 and this mavin fact offer enhanced ben-
efit to certain patients. 211 .More trials directly compar-
ing aromatase inhibitors and more mature data from
the IES, ARNO/ABCSG, and BIG l-98 trials are needed
to provide more complete comparisons among these
agents. Questions about the optimal duration of treat-
ment and the ideal therapeutic sequence for aru-
980 CANCER March 1, 2006/ Volume 106 I Number 5
matase inhibitor therapy in breast carcinoma are be-
ing u1.h.lr~ss~d by the rerandomizatiun of MA-17
patients and by the sequential arms of BIG 1-98, re-
spectively. The Tamoxifen, Exemestane Adjuvant Mul-
tinational trial (TEAM) that randomizes patients to
tamoxifen or exemestane was also amended to evalu-
ate sequential therapy as well.
Revised Guidelines Include Outcomes From Aromatase
Inhibitor Trials
With several large clinical trials now demonstrating
that aromatase inhibitors produce better long-term
clinical results for women with breast carcinoma. phy-
sicians have new therapeutic options. The American
Society of Clinical Oncology CASCO) Technology As-
sessment Panel recommends that optimal adjuvant
hormonal therapy for postmenopausal women with
receptor-positive breast carcinoma should include an
aromatase inhibitor as initial therapy or after tamox-
ifen treatment. 23 Specifically, the panel supports at
least 2.5 years of extended adjuvant letrozole therapy
for patients who have completed tamoxifen therapy.
However, they do caution that the long-term side ef-
fects of aromatase inhibitors such as osteoporosis re-
main unclear.~::; Whereas the 2005 St. Gallen Interna-
tional Conference on Primaty Therapy of Early Breast
CanL.:er guidelines have nut been published yet, this
committee panel also recommends an aromatase in-
hibitor as adjuvant therapy for must postmenopausal
women with endocrine-responsive breast carcino-
ma.z9
Conclusions
Tamoxifen was the gold standard in breast carcinoma
therapy, but several landmark studies have found aro-
matase inhibitors to be superior. The ASCO guidelines
consensus now recommends that every postmeno-
pausal woman \N:ith estrogen-receptor/progesterone-
receptor- positive disease receive an aromatase inhib-
itor as part of her adjuvant therapy regimen.
Although there arc some limitations to making
indirect comparisons between the trials, they may
help with the decision-making process. Results from
BIG 1-98 and ATAC demonstrate the benefit of receiv-
ing anastrozole or letrozole as initial adjuvant treat-
ment. The outcomes of the IES and ARNO/ABCSG
trials support the safety and efficacy of anastrozole
and exemestane as sequential therapy in this patient
population. The BIG l-98 trial will define optimal ad-
juvant therapy by determining if letrozole is more
effective when given as initial adjuvant therapy or as
sequential therapy. The MA-17 trial is the first to dem-
onstrate that late intervention can reduce the recur-
rence of breast carcinoma and save lives, particularly
for women with node-positive cancer or distant me-
tastases. Results from MA-17 have altered the current
treatment paradigms for the management of breast
carcinoma by offering an extension of adjuvant ther-
apy beyond the previous 5-year protocol. Overall, re-
sults from all of the landmark trials of aromatase in-
hibitors recommend that physicians consider
aromatase inhibitors as options for the sustained
health of women treated for breast carcinoma.
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