Nej Mo A 0810818

The n e w e ng l a n d j o u r na l of m e dic i n e
original article
Letrozole Therapy Alone or in Sequence with

Tamoxifen in Women with Breast Cancer
The BIG 1-98 Collaborative Group*
A bs t r ac t
Background
The members of the writing committee The aromatase inhibitor letrozole, as compared with tamoxifen, improves disease-
(Henning Mouridsen, M.D., chair, Anita free survival among postmenopausal women with receptor-positive early breast can-
Giobbie-Hurder, M.S., Aron Goldhirsch,
M.D., Beat Thrlimann, M.D., Robert cer. It is unknown whether sequential treatment with tamoxifen and letrozole is
Paridaens, M.D., Ian Smith, M.D., Louis superior to letrozole therapy alone.
Mauriac, M.D., John F. Forbes, F.R.A.C.S.,
M.S., Karen N. Price, B.S., Meredith M.
Regan, Sc.D., Richard D. Gelber, Ph.D.,
Methods
and Alan S. Coates, M.D.) assume full re- In this randomized, phase 3, double-blind trial of the treatment of hormone-recep-
sponsibility for the overall content and torpositive breast cancer in postmenopausal women, we randomly assigned wom-
integrity of the article. The affiliations of
the members of the writing committee en to receive 5 years of tamoxifen monotherapy, 5 years of letrozole monotherapy,
are listed in the Appendix. Address re- or 2 years of treatment with one agent followed by 3 years of treatment with the
print requests to the International Breast other. We compared the sequential treatments with letrozole monotherapy among
Cancer Study Group (IBCSG) Coordinat-
ing Center, Effingerstr. 40, 3008 Bern, 6182 women and also report a protocol-specified updated analysis of letrozole ver-
Switzerland, or at ibcsg18_BIG1-98@ sus tamoxifen monotherapy in 4922 women.
fstrf.org.
*Members of the Breast International

Results
Group (BIG) 1-98 Collaborative Group At a median follow-up of 71 months after randomization, disease-free survival was
are listed in Section 1 in the Supplemen- not significantly improved with either sequential treatment as compared with letro-
tary Appendix, available with the full
text of this article at NEJM.org. zole alone (hazard ratio for tamoxifen followed by letrozole, 1.05; 99% confidence
interval [CI], 0.84 to 1.32; hazard ratio for letrozole followed by tamoxifen, 0.96;
N Engl J Med 2009;361:766-76. 99% CI, 0.76 to 1.21). There were more early relapses among women who were as-
Copyright 2009 Massachusetts Medical Society.
signed to tamoxifen followed by letrozole than among those who were assigned to
letrozole alone. The updated analysis of monotherapy showed that there was a non-
significant difference in overall survival between women assigned to treatment with
letrozole and those assigned to treatment with tamoxifen (hazard ratio for letro-
zole, 0.87; 95% CI, 0.75 to 1.02; P=0.08). The rate of adverse events was as expected
on the basis of previous reports of letrozole and tamoxifen therapy.
Conclusions
Among postmenopausal women with endocrine-responsive breast cancer, sequen-
tial treatment with letrozole and tamoxifen, as compared with letrozole monotherapy,
did not improve disease-free survival. The difference in overall survival with letro-
zole monotherapy and tamoxifen monotherapy was not statistically significant.
(ClinicalTrials.gov number, NCT00004205.)
766 n engl j med 361;8 nejm.org august 20, 2009
The New England Journal of Medicine

Downloaded from nejm.org by LITBANG PPDS on January 5, 2017. For personal use only. No other uses without permission.
Copyright 2009 Massachusetts Medical Society. All rights reserved.
Letrozole Alone or in Sequence as Adjuvant Ther apy
F
or decades, the standard adjuvant letrozole (Femara, Novartis), 2.5 mg daily, or only
endocrine therapy for postmenopausal wom- tamoxifen, 20 mg daily, for 5 years; however, from
en with hormone-receptorpositive early April 1999 through May 2003, women were ran-
breast cancer was tamoxifen, taken for 5 years, domly assigned to one of four study treatments:
a treatment that improved disease-free survival only tamoxifen for 5 years, only letrozole for
and reduced the number of deaths from breast 5 years, letrozole for 2 years followed by tamoxifen
cancer.1 More recently, reports from the Breast for 3 years, or tamoxifen for 2 years followed by
International Group (BIG) 1-98 trial2,3 and the letrozole for 3 years (Fig. 1).
Arimidex, Tamoxifen, Alone or in Combina- The primary end point was disease-free surviv-
tion trial (ATAC; ClinicalTrials.gov number, al, defined as the time from randomization to the
NCT00849030)4,5 showed that 5 years of adjuvant first of any of the following events (hereinafter
therapy with an aromatase inhibitor alone improved called primary-end-point events): recurrence of the
disease-free survival as compared with 5 years of disease at a local, regional, or distant site; a new
tamoxifen therapy; other large studies showed that invasive cancer in the contralateral breast; any sec-
switching to an aromatase inhibitor after initial ond (nonbreast) cancer; or death without a previ-
treatment with tamoxifen improved survival.6-12 ous cancer event. Other end points included time
A meta-analysis13 of trials of initial and sequen- to the recurrence of breast cancer (including inva-
tial strategies supported the recommendation in sive contralateral breast cancer but not consider-
guidelines that an aromatase inhibitor should be ing second [nonbreast] cancers and with censoring
included in adjuvant therapy for postmenopausal of deaths that were not associated with a previous
women with endocrine-responsive early breast cancer event); time to distant recurrence, defined
cancer.14-16 as the time from randomization to the recurrence
In the BIG 1-98 study, we compared mono- of breast cancer at a distant site; and overall sur-
therapy with tamoxifen, monotherapy with an aro- vival.
matase inhibitor, and two sequential treatments: The 2005 results,2 which showed the superior-
tamoxifen followed by an aromatase inhibitor (for ity of letrozole over tamoxifen, led to the recom-
which models predicting contradictory outcomes mendation by the data and safety monitoring
have been published17,18) and an aromatase inhibi- committee of the International Breast Cancer
tor followed by tamoxifen. Initial results from the Study Group (IBCSG), and a decision by the BIG
BIG 1-98 trial showed that the aromatase inhibi- 1-98 steering committee, to inform women in the
tor letrozole given alone, as compared with ta- tamoxifen-monotherapy group of their treatment,
moxifen given alone, reduced the risk of recurrent thereby allowing informed decisions to be made
disease, especially at distant sites.2 In this report, about their future care. An amendment of the pro-
we present the results of the comparison of each tocol in April 2005 allowed for the provision of
sequential treatment with letrozole monotherapy. letrozole to any patient assigned to tamoxifen
We also present a protocol-defined updated analy monotherapy who was free of disease, was receiv-
sis of the comparison between 5 years of mono- ing tamoxifen, and wished to cross over to letro-
therapy with tamoxifen and 5 years of monothera- zole (selective crossover). With respect to the three
py with letrozole. groups whose treatment regimens included letro-
zole, the double-blind nature of the study remained
Me thods in effect.
Study Design Study Procedures

The trial design has been described previous- Clinical assessments were performed at baseline,
ly.2,3,19 Briefly, the BIG 1-98 trial is a randomized, every 6 months for the first 5 years, and yearly
phase 3, double-blind trial involving postmeno- thereafter. Six-month supplies of study drugs that
pausal women with estrogen-receptorpositive or were identical in appearance and packaging were
progesterone-receptorpositive early breast cancer. dispensed at each semiannual study visit for 5 years.
Initially, from March 1998 through March 2000, Hematologic and blood chemical measurements
women were randomly assigned to receive only and bilateral mammographic studies were per-
n engl j med 361;8 nejm.org august 20, 2009 767

2-Group Option
Randomization A Tamoxifen (N=911)

and Enrollment
19982000
(N=1828) B Letrozole (N=917)
Stratification according to institution

and according to whether chemo-
therapy was neither given nor
Surgery planned, was completed before 4-Group Option
randomization, or was planned
N=8010
to be given concurrently with
endocrine therapy A Tamoxifen (N=1548)
Randomization B Letrozole (N=1546)

and Enrollment
19992003
Tamoxifen Letrozole
(N=6182) C
(N=1548)
Letrozole Tamoxifen
D
(N=1540)
0 1 2 3 4 5
Years
Figure 1. Design of the Trial.

The numbers shown are for the intention-to-treat population, which excludes 18 enrolled women who did not receive a study treatment
and who withdrew consent for use of their data (47 other women who refused study treatment did not withdraw consent for the use of
ICM
AUTHOR: Mouridsen (Price) RETAKE 1st
their data and are included). The sequential-therapy analyses include 6182 women randomly assigned
2nd to one of four treatment groups
FIGURE: 1 of 4
(four-group randomization option only). The REG F
updated monotherapy analyses include 4922 women
3rd randomly assigned to letrozole mono-
therapy or tamoxifen monotherapy as part ofCASE Revised
either the two-group or the four-group randomization option.
EMail Line 4-C SIZE
ARTIST: ts H/T H/T
Enon 39p6
Combo
formed at baseline and were repeated as medically
AUTHOR, PLEASE NOTE:sible for the decision to submit it for publication.
indicated. Adverse events,Figure
including
has beenaredrawn
cerebrovas-
and type has The
beenethics
reset. committee and relevant health authori-
Please check carefully.
cular accident or transient ischemic attack, cardiac ties at each participating institution approved the
ischemic infarction,JOB: 36108 requiring percutane- study
angina ISSUE:protocol.
8-20-09 All women gave written informed
ous transluminal coronary angioplasty, angina consent. The data and safety monitoring commit-
requiring coronary-artery bypass grafting, any tee received safety data semiannually throughout
thromboembolic event, other cardiovascular events, the trial and reviewed three predefined interim
hypercholesterolemia (usually assessed when the efficacy analyses and the final efficacy analysis.
patient was not fasting), bone fracture, vaginal Novartis, the manufacturer of letrozole, distrib-
bleeding, nausea, vomiting, hot flashes, and night uted the study drugs and provided financial sup-
sweats, were listed on the case-report forms and port but imposed no restrictions on the inves-
graded according to the Common Toxicity Crite- tigators with respect to trial data. The IBCSG
ria (version 2) of the National Cancer Institute at Statistical Center had full access to the trial da-
each study visit. Other adverse events were record- tabase (which included all data related to the
ed in free-text format on the case-report forms. trial, except for study-treatment assignment) and
Serious adverse events were reported promptly, in to the study-treatment-assignment database, but
accordance with regulatory requirements. the IBCSG Data Management Center had access
The IBCSG was responsible for the design and to the trial database only. The manuscript was
coordination of the study, the collection and man- prepared by the members of the writing commit-
agement of the data, the medical review, the tee, who made the final decisions about the con-
analysis of the data, and the reporting of the re- tent. Members of the steering committee (in-
sults. The members of the trial steering commit- cluding a minority representation from Novartis)
tee (see Section 1 in the Supplementary Appendix, reviewed the article and suggested changes. The
available with the full text of this article at NEJM. chair of the writing committee vouches for the
org) reviewed the manuscript and were respon- accuracy and completeness of the data. The data

were analyzed by statisticians at the IBCSG Sta- results of the other three pairwise treatment com-
tistical Center. parisons specified in the amendment of April
The final efficacy analysis of the sequential 2005.)
treatments was reviewed by the data and safety Analyses were performed according to the in-
monitoring committee in October 2008 and re- tention-to-treat principle. KaplanMeier20 esti-
leased to the steering committee when a protocol- mates of the time-to-event end points were cal-
defined number of primary-end-point events had culated. A Cox proportional-hazards regression
occurred. At the same time, the planned 10-year analysis21 (stratified according to chemotherapy
efficacy update of the monotherapy treatments use, on the basis of the randomization stratum
was performed. [Fig. 1]) was used to estimate P values and haz-
ard ratios, with 99% confidence intervals to ac-
Statistical Analysis count for the five comparisons described in the
The evaluation of sequential treatments involved amendment of April 2005. We used cumulative-
only the women who participated in the four-group incidence estimates22 to control for competing
randomization option. To ensure adequate power, risks. The significance of differences in the inci-
statistical considerations were based on primary- dence of adverse events among the four treatment
end-point events that occurred after the fifth groups was assessed with the use of Fishers exact
6-month supply of study medication was dispensed test; these analyses were not adjusted for mul-
that is, after the agents were changed in the tiple comparisons.
sequential treatments (approximately 2 years after The study protocol specified that an updated
randomization). The objective was to assess the analysis of the comparison of letrozole mono-
superiority of switching endocrine agents as com- therapy with tamoxifen monotherapy be performed
pared with continuing the initial agent. For each 10 years after the beginning of the trial. We there-
of the two pairwise comparisons (tamoxifen fol- fore updated the previous analysis3 of the 4922
lowed by letrozole vs. tamoxifen and letrozole fol- women who were assigned to one of the two
lowed by tamoxifen vs. letrozole), we calculated monotherapy groups either as part of the two-
that at least 331 primary-end-point events after group or as part of the four-group randomization
the switch in treatment would be needed for the option. For this analysis, the Cox models were
study to have 80% power to detect a 29% reduc- stratified both according to chemotherapy use and
tion in the risk of a primary-end-point event after according to randomization option, and 95% con-
the switch. (Section 2 in the Supplementary Ap- fidence intervals were calculated. Among the 2459
pendix shows the results of the treatment com- women assigned to tamoxifen monotherapy, 619
parisons evaluated after the time of the switch in (25.2%) selectively crossed over to letrozole before
treatment.) a primary-end-point event occurred, and follow-up
In 2005, on the basis of emerging data from the after the crossover accounted for 7.2% of total
BIG 1-98 trial and other trials, the data and safety patient-years of follow-up. Women who selectively
monitoring committee recommended that the crossed over were more likely to have node-posi-
steering committee revise the statistical-analysis tive disease than those who continued to receive
plan to include five additional pairwise treatment tamoxifen (46.9% vs. 29.0%). Crossovers occurred
comparisons, with analyses starting from the time between 3 and 5 years after the start of therapy,
of randomization. An amendment activated in and the average duration of letrozole therapy after
April 2005, before any evaluation of results for the crossover was 18 months. In addition to intention-
sequential-treatment groups was performed, spec- to-treat analyses, exploratory analyses were per-
ifies the comparisons, which include the two that formed in which data were censored at the time
are most clinically relevant: comparisons of each of crossover.
sequential treatment with 5 years of letrozole
monotherapy. These comparisons are the main R e sult s
focus of this report. Post hoc power calculations
showed that if the true reduction in the risk of a Analysis of Sequential Treatment
primary-end-point event was at least 26.7%, there Clinical Characteristics
was an 80% chance that the 99% confidence in- A total of 8028 women were enrolled in the BIG
terval would exclude a hazard ratio of 1.00. (Sec- 1-98 trial; 18 withdrew consent and did not re-
tion 3 in the Supplementary Appendix shows the ceive treatment, leaving an intention-to-treat pop-

ulation of 8010 (Fig. 1). The sequential-treatment ference in the outcome between women who were
analyses were performed on the basis of the 6182 assigned to letrozole alone and those who were
women in the intention-to-treat population who assigned to letrozole followed by tamoxifen, re-
were randomly assigned to a treatment group as gardless of nodal status (Fig. 3B and 3D).
part of the four-group option. This cohort includ-
ed 3604 women (58.3%) with node-negative dis- Safety
ease, 3480 (56.3%) in whom the primary tumor Section 4 in the Supplementary Appendix shows
was less than 2 cm, 3782 (61.2%) who underwent the adverse events that occurred among women
breast-conserving surgery, and 4596 (74.3%) who who were randomly assigned to a treatment group
received no adjuvant or neoadjuvant chemotherapy. as part of the four-group option, according to time
The median age at randomization was 61 years (years 1 and 2, 3 through 5, and overall) and
(range, 38 to 89). Clinical characteristics were Common Toxicity Criteria grade (any grade and
well balanced across the four treatment groups grade 3 to 5, on a scale of 1 to 5, with higher
(data not shown). The median follow-up period numbers indicating worse toxic effects). There was
for the sequential-treatment analyses was 71 a higher incidence of thromboembolic events
months. The database for this report was locked among women who were assigned to one of the
on July 2, 2008. regimens that included tamoxifen than among
those who were assigned to letrozole monother-
Efficacy apy (4.1 to 4.9% vs. 2.4%, P<0.001). There were
Figure 2 shows the hazard ratios, with 99% con- similar rates of stroke and transient cerebral ische
fidence intervals, for the comparisons of each of mic attack between women who were assigned
the sequential treatments with letrozole mono- to one of the regimens that included tamoxifen
therapy with respect to the study end points. and those who were not (1.7 to 1.9% and 1.4%,
Differences between the treatment groups were respectively; P=0.74). The incidence of cardiac
not significant. The KaplanMeier estimates of events of any type or grade was similar between
the percentage of patients who remained disease- women who were assigned to one of the regimens
free at 5 years after randomization were 87.9% that included letrozole and women who were as-
in the group that was assigned to letrozole alone, signed to tamoxifen monotherapy (6.1 to 7.0% and
87.6% in the group that was assigned to letrozole 5.7%, respectively; P=0.45). The incidence of hy-
followed by tamoxifen, and 86.2% in the group percholesterolemia (predominantly mild) was lower
that was assigned to tamoxifen followed by letro- among women who were assigned to tamoxifen
zole. The estimated 5-year rate of disease-free sur- monotherapy than among those who were assigned
vival for women in the tamoxifen-monotherapy to one of the regimens that included letrozole
group was 84.6% on the basis of the intention-to- (29.9% vs. 41.4 to 53.2%, P<0.001).
treat analysis in which 612 of the 1548 women in Vaginal bleeding was reported in 9.9% of the
the tamoxifen-monotherapy group (39.5%) crossed women who were assigned to tamoxifen mono-
over to letrozole. Section 3 of the Supplementary therapy, 5.1% of those who were assigned to letro-
Appendix shows the KaplanMeier curves for dis- zole monotherapy, and 6.4 to 7.5% of those who
ease-free survival in all four groups, the sites of were assigned to sequential therapy (P<0.001). Hot
first primary-end-point events, and the hazard ra- flashes and night sweats occurred in all groups
tios for the five pairwise comparisons. but were more frequent among women who were
Figure 3 shows the cumulative incidence of the assigned to one of the regimens that included
recurrence of breast cancer among women in each tamoxifen than among women assigned to letro-
of the two sequential-regimen groups as compared zole monotherapy (hot flashes: 41.7 to 44.0% of
with the letrozole-monotherapy group, with sec- women vs. 37.7%, P=0.003; night sweats: 17.8 to
ond, nonbreast primary cancers and deaths with- 19.4% vs. 15.6%, P=0.04). Arthralgia, myalgia, or
out a recurrence of breast cancer considered as both were more frequent among women assigned
competing events. The risk of a recurrence of to one of the regimens that included letrozole than
breast cancer with tamoxifen followed by letro- among women assigned to tamoxifen monother-
zole did not differ significantly from the risk with apy (31.9 to 34.7% of women vs. 30.1%, P=0.05),
letrozole alone (Fig. 3A and 3C). There was no dif- and the excess incidence among women in the

A TamoxifenLetrozole vs. Letrozole Estimated Percentage

of Patients without
End Point No. of Patients Hazard Ratio (99% CI) No. of Events an Event at 5 Yr
Tamoxifen Tamoxifen Tamoxifen
Letrozole Letrozole Letrozole Letrozole Letrozole Letrozole
All patients 1548 1546
Disease-free survival 1.05 (0.841.32) 259 248 86.2 87.9
Overall survival 1.13 (0.831.53) 154 137 92.4 93.4
Time to distant recurrence 1.22 (0.881.69) 141 116 92.3 94.2
Node negative, including Nx 894 886
Node positive 635 645
0.50 0.75 1.00 1.25 1.50
TamoxifenLetrozole Letrozole
Better Better
B LetrozoleTamoxifen vs. Letrozole Estimated Percentage

of Patients without
End Point No. of Patients Hazard Ratio (99% CI) No. of Events an Event at 5 Yr
Letrozole Letrozole Letrozole
Tamoxifen Letrozole Tamoxifen Letrozole Tamoxifen Letrozole
All patients 1540 1546
Node negative, including Nx 920 886
Node positive 611 645
0.50 0.75 1.00 1.25 1.50
LetrozoleTamoxifen Letrozole
Better Better
Figure 2. Results of Cox Proportional-Hazards Analyses of Disease-free Survival, Overall Survival, and Time to Distant Recurrence,
with Tamoxifen Followed by Letrozole as Compared
ICM
with Letrozole
AUTHOR: Monotherapy
Mouridsen (Price) and with Letrozole
RETAKE 1st Followed by Tamoxifen
as Compared with Letrozole Monotherapy. REG F FIGURE: 2 of 4 2nd
3rd
The events related to the end points are as follows:
CASE for disease-free survival, recurrence of the disease at a local, regional, or distant site;
Revised
a new invasive cancer in the contralateral breast;
EMail any second (nonbreast)
Line cancer;
4-C or death without
SIZE a previous cancer event; for overall
survival, death; and for time to distant recurrence, ARTIST: ts of cancer
recurrence H/Tat a distant
H/T site.36p6The models were stratified according to chemo-
Enon
Combo error of the hazard ratio. As specified in the protocol, 99%
therapy use. The size of the boxes is inversely proportional to the standard
AUTHOR, PLEASE
confidence intervals are shown to account for multiple comparisons. NOTE:of the percentage of patients without an event at 5 years
Estimates
are KaplanMeier estimates. Results of tests for Figure has been redrawn and type has been reset.
interactions between treatment
and nodal status were not significant. Nx denotes 0
positive axillary lymph nodes with 1 to 7 nodes examined.
JOB: 36108 ISSUE: 08-20-09
sequential regimens was seen during the periods women assigned to letrozole monotherapy and
when the women were receiving letrozole (Sec- lowest among women assigned to tamoxifen
tion 4 in the Supplementary Appendix). monotherapy (P=0.02). The incidence of fractures
The incidence of fractures was highest among among women assigned to tamoxifen followed by

A B
20 20
Tamoxifenletrozole Letrozoletamoxifen
Letrozole Letrozole
Breast-Cancer Recurrence (%)

15 15
9.1
10 10 7.3
4.1
5 7.3 5 7.3
2.5
2.5 2.5
0 0
0 1 2 3 4 5 6 0 1 2 3 4 5 6
Years since Randomization Years since Randomization
C D
20 20
Tamoxifenletrozole Letrozoletamoxifen
Letrozole Letrozole
14.7

15 15 12.5
Node positive
12.4 Node positive 12.4
10 7.9 10
4.7 4.9 4.7

3.9
5 5
1.3 3.9
3.5 1.5 3.5
0.9 Node negative 0.9 Node negative
0 0
0 1 2 3 4 5 6 0 1 2 3 4 5 6
Years since Randomization Years since Randomization
Figure 3. Cumulative Incidence of the Recurrence of Breast Cancer.

ICM
Results are shown for letrozole monotherapy as compared with tamoxifen followed2nd by letrozole (Panels A and C)
REG F FIGURE: 3 of 4
and for letrozole monotherapy as compared with letrozole followed by tamoxifen (Panels 3rd B and D). Both overall re-
sults (Panels A and B) and results CASE
according to nodal status (Panels C andRevised D) are shown. The results are from a
EMail Line 4-C SIZE
competing-risk analysis in which second, nonbreast
ARTIST: ts cancers and deaths without a previous cancer event were con-
H/T H/T
sidered as competing risks. The numbers
Enon of women with aCombo first recurrence of 33p9
breast cancer were as follows for the
group assigned to letrozole monotherapy, the group assigned to tamoxifen followed by letrozole, and the group as-
AUTHOR, PLEASE NOTE:
signed to letrozole followed by tamoxifen,
Figurerespectively: localand
has been redrawn recurrence, 12,reset.
type has been 14, and 17 women; cancer in the con-
tralateral breast, 18, 19, and 16; regional recurrence, 7, 3,check
Please andcarefully.
6; distant recurrence, 112, 130, and 105; and recur-
rence at an unknown site, 0, 3, and 0. Second, nonbreast cancers (64, 65, and 59 in the three groups, respectively)
and deaths without a previous cancer event (35, 25, and 33, respectively)
JOB: 36108 were08-20-09
ISSUE: also recorded as first primary-end-
point events.
letrozole was similar to that among women as- deaths without a recurrence of breast cancer and
signed to letrozole alone (9.4% and 9.8%, respec- of second (nonbreast) primary cancers, except for
tively), and the incidence of fractures in the group endometrial cancers, of which there were 13 cases
assigned to letrozole followed by tamoxifen was in the group assigned to tamoxifen monotherapy,
similar to that among women assigned to tamox- 2 cases in the group assigned to letrozole mono-
ifen alone (7.5% and 7.3%, respectively). Among therapy, and 4 cases in each sequential group
the four groups, there was a similar number of (P=0.01).

Updated Analysis of Monotherapy involved lymph nodes, large tumors, or vascular

The median follow-up period for the analysis that invasion. A similar pattern was seen in the cur-
included women assigned to letrozole or tamox- rent analysis of the sequential-treatment cohort.
ifen monotherapy in both randomization options There was a nonsignificant increase in the risk of
was 76 months. In the updated intention-to-treat early relapse among women with node-positive
analyses comparing letrozole monotherapy with disease who were assigned to tamoxifen followed
tamoxifen monotherapy, there were 509 primary- by letrozole (Fig. 3C). Since the interactions be-
end-point events in the letrozole group versus 565 tween treatment group and nodal status were not
events in the tamoxifen group (P=0.03). The time significant, caution is required in the interpreta-
to distant recurrence also differed significantly in tion of these subgroup analyses.24
favor of letrozole (P=0.05) (Fig. 4). The 5-year over- The present analysis shows that treatment with
all survival was 91.8% in the letrozole group and letrozole for 2 years followed by tamoxifen yield-
90.9% in the tamoxifen group (hazard ratio, 0.87; ed outcomes similar to those seen with letrozole
95% confidence interval, 0.75 to 1.02; P=0.08) monotherapy. It is possible that part of this ef-
(Fig. 4). The censored analyses (Fig. 4) suggested fect is a carryover benefit of the initial letrozole
that there was more benefit with letrozole for each therapy, similar to that observed after cessation
end point, but these analyses were subject to bi- of anastrozole in the ATAC study.4 The follow-up
ases, some of which may have favored letrozole. of the BIG 1-98 trial is ongoing; the follow-up data
The difference in the incidence of adverse events that are currently available (median, 6 years) indi-
between the monotherapy groups changed little cate that, after 2 years of adjuvant therapy with
from that previously reported3 (data not shown). letrozole, a switch to tamoxifen to complete 5 years
Eighty-seven deaths without prior cancer events of therapy would be acceptable, if cessation of
were recorded in each monotherapy group. Sec- letrozole is required for any reason.
tion 5 in the Supplementary Appendix gives fur- Previous analyses of the BIG 1-98 trial have
ther details on the types of first primary-end-point shown that, as compared with tamoxifen alone,
events and the selective crossover. letrozole monotherapy significantly reduces the
risk of recurrence of disease, especially at distant
Discussion sites.2,3 The updated intention-to-treat analysis of
monotherapy confirms these observations and
The main purpose of the BIG 1-98 trial was to com- shows a nonsignificant difference between letro-
pare an aromatase inhibitor (letrozole) with ta- zole monotherapy and tamoxifen monotherapy
moxifen as adjuvant therapy in postmenopausal with respect to overall survival (P=0.08). Our belief
women with endocrine-responsive early breast can- that this result underestimates the survival ben-
cer. We report here analyses of letrozole mono- efit that would have accrued if there had been no
therapy as compared with sequential treatment crossover to letrozole is based on evidence from
with tamoxifen and letrozole; in addition, we in- independent trials that have shown a survival ben-
vestigated whether letrozole monotherapy prolongs efit from switching to an aromatase inhibitor after
overall survival as compared with tamoxifen mono- initial treatment with tamoxifen.11,13 The censored
therapy. The limitations of the study include the analysis of overall survival, which suggests an even
selective crossover to letrozole among women as- greater advantage of letrozole over tamoxifen than
signed to tamoxifen monotherapy and the inabil- that seen in the intention-to-treat analysis (Fig. 4),
ity, after a median follow-up period of 6 years, to may be an overestimate, particularly since women
assess the influence of a potential carryover ef- who had recurrent disease were not candidates for
fect of letrozole on the results. crossover (see Section 5 in the Supplementary Ap-
In the analyses of sequential treatments, nei- pendix). Thus, it is likely that the best estimate
ther tamoxifen followed by letrozole nor letrozole of the survival benefit with letrozole if there had
followed by tamoxifen showed superiority over been no selective crossover lies somewhere be-
letrozole alone. A previous analysis of the trial tween these two extremes.
data23 showed that the frequency of relapses After 5 years of adjuvant endocrine therapy, re-
within 2 years after randomization was signifi- lapses continue to occur in women with endocrine-
cantly reduced with letrozole as compared with responsive early breast cancer. Other trials have
tamoxifen, especially among women with many shown the value of extended therapy with an aro-

A All Patients
Estimated Percentage of Patients
End Point No. of Events Hazard Ratio (95% CI) without an Event at 5 Yr
Letrozole Tamoxifen
(N=2463) (N=2459) Letrozole Tamoxifen
Disease-free survival
Intention-to-treat 509 565 0.88 (0.780.99) 85.6 82.6
Censored 509 544 0.84 (0.740.95) 85.6 82.2
Overall survival
Censored 303 338 0.81 (0.690.94) 91.8 90.2
Time to distant recurrence
Censored 257 292 0.81 (0.680.96) 92.4 89.8
0.50 0.75 1.00 1.25 1.50
Letrozole Tamoxifen
Better Better
B Node-Negative Patients
Letrozole Tamoxifen
Censored 200 218 0.87 (0.721.05) 90.3 88.4
Overall survival
Censored 107 116 0.88 (0.681.15) 95.2 94.6
Censored 70 80 0.84 (0.611.16) 96.7 95.4
0.50 0.75 1.00 1.25 1.50
Letrozole Tamoxifen
Better Better
C Node-Positive Patients
Letrozole Tamoxifen
Censored 303 320 0.78 (0.670.91) 79.5 73.1
Overall survival
Censored 191 218 0.73 (0.600.89) 87.7 83.9
Censored 185 210 0.75 (0.620.92) 86.7 81.6
0.50 0.75 1.00 1.25 1.50
Letrozole Tamoxifen
Better Better
ICM
FIGURE: 4 of 4 2nd
REG F
3rd
CASE Revised
EMail Line 4-C SIZE
ARTIST: ts H/T H/T
Enon 36p6
Combo
774 n engl j medPLEASE
AUTHOR, 361;8 NOTE:
nejm.org august 20, 2009
Figure has been redrawn and type has been reset.
JOB: 36108
Copyright ISSUE: 08-20-09
2009 Massachusetts Medical Society. All rights reserved.
monotherapy and the sequential-therapy groups

Figure 4 (facing page). Results of Cox Proportional-
Hazards Analyses of Disease-free Survival, Overall Sur- are reassuring. There were no unexpected life-
vival, and Time to Distant Recurrence, with Letrozole threatening adverse events in any group. The
Monotherapy as Compared with Tamoxifen Monothera- safety and efficacy results add to the information
py among Women Assigned to the Single-Agent Treat- that supports the use of adjuvant endocrine ther-
ment Groups.
apy with letrozole in postmenopausal women with
Results are shown for the total cohort and according to
endocrine-responsive early breast cancer and pro-
nodal status. Results of the intention-to-treat and cen-
sored analyses are presented. The events related to the vide additional treatment options for such women.
end points are as follows: for disease-free survival, re- Supported by Novartis. The International Breast Cancer Study
currence of the disease at a local, regional, or distant Group (IBCSG), which coordinated the study, is also supported by
site; a new invasive cancer in the contralateral breast; the Swedish Cancer Society, the Cancer Council Australia, the
any second (nonbreast) cancer; or death without a pre- Australian New Zealand Breast Cancer Trials Group, the Frontier
vious cancer event; for overall survival, death; and for Science and Technology Research Foundation, the Swiss Group
time to distant recurrence, recurrence of cancer at a for Clinical Cancer Research, the National Cancer Institute (CA-
75362), Cancer Research Switzerland and Oncosuisse, and the
distant site. The models were stratified according to
Foundation for Clinical Cancer Research of Eastern Switzerland.
study cohort (two-group or four-group randomization Dr. Mouridsen reports receiving consulting and lecture fees
option) and chemotherapy use. The size of the boxes is from Novartis; Dr. Thrlimann, owning stock in Novartis; Dr.
inversely proportional to the standard error of the haz- Mauriac, receiving consulting fees from Novartis and AstraZen-
ard ratio. Estimates of the percentage of patients with- eca and grant support from AstraZeneca; Dr. Forbes, receiving
out an event at 5 years are KaplanMeier estimates. consulting fees from Eli Lilly, Novartis, and AstraZeneca and
The results of tests for interactions between treatment lecture fees from AstraZeneca; Dr. Smith, receiving consulting
and nodal status were not significant. The intention-to- and lecture fees from Novartis; and Dr. Goldhirsch, receiving
treat analysis included all women and all follow-up consulting and lecture fees from Novartis, AstraZeneca, and
Pfizer. Novartis contracted with the IBCSG for provision of ser-
time and events according to treatment assignment.
vices related to the conduct and management of the trial. Drs.
The exploratory censored analysis was identical except Goldhirsch, Coates, and Gelber are responsible for the scientific
that it excluded (i.e., censored) events and follow-up management of the IBCSG. No other potential conflict of inter-
beyond the time of selective crossover among women est relevant to this article was reported.
randomly assigned to tamoxifen. Both analyses were We thank the women, physicians, nurses, and data managers
subject to potential biases that may have influenced who participated in this clinical trial; the secretariat of the
the estimated magnitude of the benefit with letrozole Breast International Group (BIG); the BIG groups, including the
as compared with tamoxifen. IBCSG, with participating centers from Australia and New Zea-
land (members of the Australian New Zealand Breast Cancer
Trials Group), Brazil, Chile (members of the Chilean Coopera-
tive Group for Oncologic Research), Hungary, Italy, Peru, Slove-
matase inhibitor after 5 years of adjuvant therapy nia, South Africa, Sweden (members of the West Swedish Breast
with tamoxifen.25,26 The ongoing Study of Letro- Cancer Study Group), Switzerland (members of the Swiss Group
zole Extension (SOLE; NCT00553410)27 is explor- for Clinical Cancer Research), and United Kingdom; the Danish
Breast Cancer Cooperative Group; the French Group (Federation
ing this concept in more detail and is adding an Nationale des Centres de Lutte contre le Cancer); and the North
evaluation of intermittent letrozole as extended Yorkshire Group; and independent centers and groups from Ar-
adjuvant therapy.28,29 gentina, Australia, Belgium, Canada, Chile, Czech Republic,
Germany, Hungary, Italy, the Netherlands, New Zealand, Po-
The adverse-event profile and the number of land, Portugal, Russia, South Africa, Spain, Switzerland, Turkey,
deaths without a previous cancer event in the United Kingdom, and Uruguay.
Appendix
The affiliations of the Writing Committee are as follows: Danish Breast Cancer Group, Rigshospitalet, Vejle Hospital, Copenhagen
(H.M.); the International Breast Cancer Study Group (IBCSG) Statistical Center, DanaFarber Cancer Institute (A.G.-H., K.N.P., M.M.R.,
R.D.G.), Harvard School of Public Health and Harvard Medical School (M.M.R., R.D.G.), and Frontier Science and Technology Research
Foundation (K.N.P., R.D.G.) all in Boston; the European Institute of Oncology, Milan (A.G.); the Oncology Institute of Southern
Switzerland, Bellinzona (A.G.), the Breast Center, Kantonsspital, St. Gallen (B.T.), and the Swiss Group for Clinical Cancer Research,
Bern (B.T.) all in Switzerland; the Department of Medical Oncology, University Hospital Gasthuisberg, Catholic University of Leuven,
Leuven, Belgium (R.P.); the Royal Marsden Hospital, London, and the Royal Marsden National Health Service Trust, Sutton, Surrey
both in the United Kingdom (I.S.); Fdration Nationale des Centres de Lutte contre le Cancer, Institut Bergoni, Bordeaux, France
(L.M.); and the Australian New Zealand Breast Cancer Trials Group, University of Newcastle, Calvary Mater Newcastle, Newcastle, NSW
(J.F.F.), and the University of Sydney, Sydney (A.S.C.) both in Australia.

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The n e w e ng l a n d j o u r na l of m e dic i n e

Letrozole Therapy Alone or in Sequence with

*Members of the Breast International

766 n engl j med 361;8 nejm.org august 20, 2009

The New England Journal of Medicine

Study Design Study Procedures

n engl j med 361;8 nejm.org august 20, 2009 767

Randomization A Tamoxifen (N=911)

Stratification according to institution

Randomization B Letrozole (N=1546)

Figure 1. Design of the Trial.

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The New England Journal of Medicine

A TamoxifenLetrozole vs. Letrozole Estimated Percentage

0.50 0.75 1.00 1.25 1.50

B LetrozoleTamoxifen vs. Letrozole Estimated Percentage

0.50 0.75 1.00 1.25 1.50

n engl j med 361;8 nejm.org august 20, 2009 771

Breast-Cancer Recurrence (%)

Breast-Cancer Recurrence (%)

Breast-Cancer Recurrence (%)

4.7 4.9 4.7

Figure 3. Cumulative Incidence of the Recurrence of Breast Cancer.

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Updated Analysis of Monotherapy involved lymph nodes, large tumors, or vascular

n engl j med 361;8 nejm.org august 20, 2009 773

monotherapy and the sequential-therapy groups

n engl j med 361;8 nejm.org august 20, 2009 775

776 n engl j med 361;8 nejm.org august 20, 2009

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