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A Randomized Trial of Exemestane after Two to Three Years of Tamoxifen Therapy in Postmenopausal Women R. Charles Coombes, M.D., Ph.D., Emma Hall, Ph.D., Lorna J. Gibson, M.Phil., Robert Paridaens, M.D., Ph.D., Jacek Jassem, M.D., Ph.D., Thierry Delozier, M.D., Stephen E. Jones, M.D., Isabel Alvarez, M.D., Gianfilippo Bertelli, M.D., Olaf Ortmann, M.D., Ph.D., Alan S. Coates, M.D., Emilio Bajetta, M.D., David Dodwell, M.D., Robert E. Coleman, M.D., Lesley J. Fallowfield, D.Phil., Elizabeth Mickiewicz, M.D., Jorn Andersen, D.M.Sc., Per E. Lønning, M.D., Ph.D., Giorgio Cocconi, M.D., Ph.D., Alan Stewart, M.D., Nick Stuart, D.M., Claire F. Snowdon, M.Sc., Marina Carpentieri, Ph.D., Giorgio Massimini, M.D., and Judith M. Bliss, M.Sc., background
Tamoxifen, taken for five years, is the standard adjuvant treatment for postmenopausal From the Department of Cancer Medicine, Imperial College and Charing Cross Hospi- women with primary, estrogen-receptor–positive breast cancer. Despite this treatment, tal, London (R.C.C., L.J.G., C.F.S.); Institute however, some patients have a relapse.
of Cancer Research, Sutton (E.H., J.M.B.);South West Wales Cancer Institute, Swan- sea (G.B.); Cookridge Hospital, Leeds(D.D.); Cancer Research Centre, Weston We conducted a double-blind, randomized trial to test whether, after two to three years Park Hospital, Sheffield (R.E.C.); Psycho- of tamoxifen therapy, switching to exemestane was more effective than continuing ta- social Oncology Group, University of Sus-moxifen therapy for the remainder of the five years of treatment. The primary end point sex, Brighton (L.J.F.); Christie Hospital, Bangor, Gwynedd (N.S.) — all in the UnitedKingdom; Universitair Ziekenhuis, Leuven, Belgium (R.P.); Medical University ofGdansk, Gdansk, Poland (J.J.); Centre Of the 4742 patients enrolled, 2362 were randomly assigned to switch to exemestane, François Baclesse, Caen, France (T.D.); U.S.
and 2380 to continue to receive tamoxifen. After a median follow-up of 30.6 months, Oncology Research, Houston (S.E.J.); Hos- 449 first events (local or metastatic recurrence, contralateral breast cancer, or death) pital Donostia, San Sebastián, Spain (I.A.); University of Regensburg, Regensburg, Ger- were reported — 183 in the exemestane group and 266 in the tamoxifen group. The un- many (O.O.); University of Sydney, Sydney, adjusted hazard ratio in the exemestane group as compared with the tamoxifen group Australia (A.S.C.); Istituto Nazionale per was 0.68 (95 percent confidence interval, 0.56 to 0.82; P<0.001 by the log-rank test), lo Studio e la Cura dei Tumori, Milan, Italy (E.B.); Instituto Angel Roffo, Buenos Aires, representing a 32 percent reduction in risk and corresponding to an absolute benefit in Argentina (E.M.); Århus University Hospi- terms of disease-free survival of 4.7 percent (95 percent confidence interval, 2.6 to 6.8) tal, Århus, Denmark (J.A.); Haukeland Hos- at three years after randomization. Overall survival was not significantly different in the pital, University of Bergen, Bergen, Norway (P.E.L.); University Hospital, Parma, Italy two groups, with 93 deaths occurring in the exemestane group and 106 in the tamoxifen (G.C.); and Pharmacia Italia, Pfizer Group, group. Severe toxic effects of exemestane were rare. Contralateral breast cancer oc- Nerviano, Italy (M.C., G.M.). Address re- curred in 20 patients in the tamoxifen group and 9 in the exemestane group (P=0.04).
print requests to Dr. Coombes at the De-partment of Cancer Medicine, Imperial conclusions
College London, 6th Fl., Cyclotron Bldg.,Hammersmith Hospital, Du Cane Rd., Exemestane therapy after two to three years of tamoxifen therapy significantly improved London W12 0NN, United Kingdom.
disease-free survival as compared with the standard five years of tamoxifen treatment.
N Engl J Med 2004;350:1081-92.
Copyright 2004 Massachusetts Medical Society. Downloaded from www.nejm.org at CILEA BIBLIOSAN on December 11, 2007 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine dent in many cases, and reducing the estro- gen levels by means of ovariectomy can study design
cause regression of established disease,1 especially Our study is an international, intergroup, phase 3,if the tumor is rich in estrogen receptors.2 The selec- randomized, double-blind trial comparing the effi-tive estrogen-receptor modulator tamoxifen blocks cacy and safety of continued adjuvant tamoxifenthe action of estrogen by binding to one of the acti- therapy with the efficacy and safety of exemestanevating regions of the estrogen receptor.3,4 When giv- therapy in postmenopausal women with primaryen to women with estrogen-receptor–positive breast breast cancer who remain free of disease after re-cancer for five years after surgery, tamoxifen reduces ceiving adjuvant tamoxifen therapy for two to threethe risk of recurrence by 47 percent and the risk of years. Women were randomly assigned to receivedeath by 26 percent.5 The risk–benefit ratio of us- oral exemestane (25 mg) or tamoxifen (20 mg) dai-ing tamoxifen for longer than five years remains ly in order to complete a total of five years of adju-unclear,6,7 and trials addressing this question are vant endocrine treatment (Fig. 1). Randomizationongoing. International guidelines recommend that was performed with the use of permuted blockspatients should not receive adjuvant tamoxifen ther- and was stratified according to center.
apy for more than five years outside the context of The primary end point was disease-free survival, defined by the time from randomization to recur- Alternative endocrine therapy is often effective rence of breast cancer at any site, diagnosis of a sec- after disease has relapsed despite tamoxifen treat- ond primary breast cancer, or death from any cause.
ment, since at that point, estrogen receptors are still Secondary end points included overall survival, thepresent in most patients.9 Several trials have con- incidence of contralateral breast cancer, and long-firmed the superiority of aromatase inhibitors over term tolerability. For consistency and comparabilityprogestins in this setting.10,11 Aromatase is an en- with other reported trials,19 we also report breast-zyme that catalyzes the conversion of androgens to cancer–free survival, with censoring of deaths thatestrogens. There are two classes of third-generation occurred without a recurrence of breast cancer or aoral aromatase inhibitors: irreversible steroidal in- diagnosis of contralateral breast cancer. Resultsactivators, exemplified by exemestane,12,13 and re- from substudies assessing the quality of life, uterineversible nonsteroidal inhibitors, such as anastro- thickness, bone metabolism, and bone mineral den-zole and letrozole.14 Exemestane inhibits aromatization in vivo by The study was coordinated by the International about 98 percent.15 It is superior to megestrol ace- Collaborative Cancer Group (ICCG), Imperial Col-tate with respect to time to progression in advanced lege London, and conducted under the auspices ofbreast cancer14 and has antitumor effects in patients the Breast International Group (BIG). The trial waswho have no response to third-generation nonste- governed by a steering committee comprising rep-roidal aromatase inhibitors.16 Preliminary results resentatives from the ICCG, participating coopera-show that exemestane is superior to tamoxifen as tive groups, BIG, and the pharmaceutical-industryfirst-line therapy for metastatic disease.17 Theo- sponsor. Data for each cooperative group were col-retically, exemestane should not cause endometri- lected by the group’s data center and collated cen-al thickening or endometrial cancer, which are oc- trally by the ICCG Data Center. Central review andcasionally observed after tamoxifen therapy.18 querying and analysis of data were undertaken by The Intergroup Exemestane Study (IES) was de- the ICCG Data Center in collaboration with the In- signed to investigate whether exemestane, when stitute of Cancer Research, where the independentgiven to postmenopausal women who remained statisticians were based. The sponsor had no accessfree of recurrence after receiving adjuvant tamoxifen to the trial data base or interim analyses. The studytherapy for two to three years for primary breast can- was overseen by a data and safety monitoring com-cer, could prolong disease-free survival, as com- mittee that was independent of the ICCG Data Cen-pared with continued tamoxifen therapy. Here we ter, the steering committee, and the sponsor.
report the results of the second planned interim The institutional review board at each partici- analysis, which we are releasing in accordance with pating institution approved the study protocol, andthe recommendation of the independent data and all patients gave written informed consent. Ran-safety monitoring committee.
domization was performed by the data center for Downloaded from www.nejm.org at CILEA BIBLIOSAN on December 11, 2007 . Copyright 2004 Massachusetts Medical Society. All rights reserved. e x e m e s t a n e v e r s u s t a m o x i f e n a f t e r i n i t i a l t a m o x i f e n t h e r a p y f o r b r e a s t c a n c e r Figure 1. Trial Schema.
The percentage of patients who continue to receive treatment represents the percentage who are not known to have discon-
tinued their randomized treatment and who began initial tamoxifen therapy less than five years before December 31, 2003.
each cooperative group or through the ICCG Data Patients were required to have adequate hematolog-Center.
ic, renal, and liver function at the time of random-ization (defined as a normal blood count, a serum eligibility criteria
creatinine concentration less than 1.5 times the up- Patients were eligible if they had histologically per limit of normal, and a serum alanine amino-confirmed, completely resected unilateral invasive transferase concentration less than 2.5 times the up-breast carcinoma that was positive for estrogen re- per limit of normal).
ceptors (as determined by means of standard immu- The criteria for exclusion included the presence nostaining procedures) or that was of unknown re- of a tumor with known negative estrogen-receptorceptor status. Patients were postmenopausal (55 status; evidence of local relapse or a distant metas-years of age or older with amenorrhea for more tasis since the time of diagnosis; a clinically signif-than two years, or amenorrhea for more than one icant skeletal, cardiac, or endocrine disorder; andyear at the time of diagnosis) and had received ad- the use of hormone-replacement therapy within fourjuvant tamoxifen therapy for at least two years but weeks before randomization. Patients were also ex-not more than three years and one month. Most pa- cluded if they had clinical evidence of severe osteo-tients (95 percent) received tamoxifen at a dose of porosis or a history of a previous neoplasm other20 mg daily, but patients who received 30 mg daily than carcinoma in situ of the cervix or basal-cell skinwere eligible (and continued to receive the same carcinoma or if they were taking concomitant anti-dose if they were assigned to the tamoxifen group). coagulant agents, a selective estrogen-receptor Downloaded from www.nejm.org at CILEA BIBLIOSAN on December 11, 2007 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine modulator other than tamoxifen, or any other form Meier time-to-event curves are presented. Theof hormonal therapy.
groups were compared in terms of the incidence of The protocol required adequate treatment of pri- adverse effects with the use of chi-square tests. Be- mary disease, including postoperative radiotherapy cause of the early release of the efficacy results, datain patients who had been treated with breast-pre- on adverse events are provisional; the validation pro-serving surgery. Neoadjuvant chemotherapy was cess is ongoing. Here, we emphasize the adverse ef-permitted according to a consistent policy within fects for which there is a difference between groupseach center. Patients were required to have started with a P value of 0.01 or less.
chemotherapy within three months after diagnosisand to have begun receiving tamoxifen and radio- therapy within three months after the completionof chemotherapy.
study population
We recruited 4742 women from 37 countries and follow-up procedures
20 cooperative groups between February 1998 and Symptoms, side effects, findings on clinical exam- February 2003. Recruitment continued beyond theination, and the level of compliance with treatment target enrollment of 4400 in order to complete ac-were recorded at three-month intervals during the crual to the substudies on the effects on bone andfirst year after randomization, every six months dur- quality of life. The median follow-up was 30.6ing the second and third years, and annually there- months (interquartile range, 23.9 to 36.6). The twoafter. Hematologic and biochemical analyses and groups were balanced with regard to base-line char-mammography (if the local procedure permitted) acteristics (Table 1). A total of 192 patients were sub-were performed annually.
sequently found to be ineligible (16 because of pre-vious breast cancers, 31 because of previous other statistical analysis
cancers, 74 because they had undergone breast- Enrollment of 4400 patients was required in order conserving surgery but had not received radiother-
to detect an absolute difference of 3.6 percent in apy, 25 because they were of uncertain menopausal
disease-free survival three years after randomiza- status, 24 because they had known estrogen-recep-
tion (with 88 percent power and a two-sided level tor–negative tumors, 8 because they had used hor-
of significance of 4.3 percent after adjustment for mone-replacement therapy within four weeks be-
interim analyses). The a priori expectation was that fore randomization, and 14 for other reasons); these
the principal analysis would be conducted after 716 patients are included in all analyses on an intention-
end-point events had occurred. Three interim effi- to-treat basis.
cacy analyses were to be conducted, with the use of
O’Brien–Fleming stopping boundaries, after one efficacy
quarter, one half, and three quarters of the planned The second interim analysis, which was triggered
total number of events. Emerging trial data and in- by the reporting of 358 events, was presented to the
terim analyses were reviewed by the independent data and safety monitoring committee on Decem-
data and safety monitoring committee, whose terms ber 2, 2003, and included all data that had been re-
of reference dictated that their decisions be guided ceived relating to events and follow-up through
(but not mandated) by the above stopping rules.
June 30, 2003. At that meeting, the committee Analyses were performed according to the in- recommended that key efficacy data be released, tention-to-treat principle and included all patients because the O’Brien–Fleming stopping boundarywho underwent randomization. All data were cen- (P=0.004) had been exceeded. The steering com-sored on June 30, 2003, but the snapshot of data mittee agreed to the release at a meeting on Decem-used for the analysis of efficacy was updated to in- ber 3, 2003. This report constitutes a refined analysisclude all data received by the ICCG Data Center of that presented to the data and safety monitoringthrough December 31, 2003. Log-rank tests were committee.
used to compare the two groups. Two-sided P values A total of 449 first events were reported: 183 in and 95 percent confidence intervals are reported. the exemestane group and 266 in the tamoxifenCox proportional-hazards regression was used to group (Table 2). The unadjusted hazard ratio in theadjust for prespecified prognostic factors.20 Hazard exemestane group as compared with the tamoxifenratios of less than 1.0 favor exemestane. Kaplan– group was 0.68 (95 percent confidence interval, 0.56 Downloaded from www.nejm.org at CILEA BIBLIOSAN on December 11, 2007 . Copyright 2004 Massachusetts Medical Society. All rights reserved. e x e m e s t a n e v e r s u s t a m o x i f e n a f t e r i n i t i a l t a m o x i f e n t h e r a p y f o r b r e a s t c a n c e r Table 1. Base-Line Characteristics of the Patients and Tumors and Primary Treatment.*
Variable
Exemestane (N=2362)
Tamoxifen (N=2380)
Progesterone-receptor status unknown or missing Previous hormone-replacement therapy — no. (%) Duration of tamoxifen therapy at randomization — yr * Plus–minus values are means ±SD. Patients with missing data had no value reported for a given variable; for patients in the “unknown” category, data were reported as unknown.
† Data for positive and negative estrogen-receptor status include retrospectively ascertained status for some patients whose status was unknown at randomization.
Downloaded from www.nejm.org at CILEA BIBLIOSAN on December 11, 2007 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Table 2. End-Point Events.
Exemestane Group Tamoxifen Group All Patients
Variable
(N=2362)
(N=2380)
(N=4742)
Events included in analysis of disease-free survival* Recurrence, contralateral breast cancer, or intercurrent death * Data for distant recurrence and primary cancer in the contralateral breast include patients who also reported a local re- lapse. One patient in the exemestane group died of breast cancer after contralateral breast cancer had been reported and is also included in the analysis of distant-disease–free survival.
to 0.82; P=0.00005 by the log-rank test), which cor- tane group vs. 227 in the tamoxifen group). Survivalresponds to an absolute benefit of 4.7 percent (95 free of distant disease was also better in the exemes-percent confidence interval, 2.6 to 6.8) at three years tane group (hazard ratio, 0.66; 95 percent confi-(Fig. 2). Disease-free survival three years after ran- dence interval, 0.52 to 0.83; P=0.0004). A total ofdomization was 91.5 percent (95 percent confidence 199 patients have died (93 in the exemestane groupinterval, 90.0 to 92.7) in the exemestane group and and 106 in the tamoxifen group). There is no statis-86.8 percent (95 percent confidence interval, 85.1 tically significant difference in overall survival at thisto 88.3) in the tamoxifen group. In a subsidiary stage (hazard ratio, 0.88; 95 percent confidence in-analysis of breast-cancer–free survival in which terval, 0.67 to 1.16; P=0.37) (Fig. 2). The causes ofdeaths of patients who did not have a recurrence or death are listed in Table 2. Exemestane significantlycontralateral breast cancer were censored, the haz- reduced the risk of contralateral breast cancer (haz-ard ratio was 0.63 (95 percent confidence interval, ard ratio, 0.44; 95 percent confidence interval, 0.200.51 to 0.77; P=0.00001; 144 events in the exemes- to 0.98; P=0.04).
Downloaded from www.nejm.org at CILEA BIBLIOSAN on December 11, 2007 . Copyright 2004 Massachusetts Medical Society. All rights reserved. e x e m e s t a n e v e r s u s t a m o x i f e n a f t e r i n i t i a l t a m o x i f e n t h e r a p y f o r b r e a s t c a n c e r A Disease-free Survival
Patients Surviving Free of Disease (%)
Years after Randomization
No. of Events/No. at Risk
Exemestane
B Overall Survival
Patients Surviving (%)
Years after Randomization
No. of Events/No. at Risk
Exemestane
Figure 2. Kaplan–Meier Estimates of Disease-free Survival (Panel A) and Overall Survival (Panel B).
The hazard ratios are for the exemestane group as compared with the tamoxifen group. P values were determined by the
log-rank test. An additional six patients in the exemestane group and four patients in the tamoxifen group had a recur-
rence or a second primary cancer in the contralateral breast or died more than four years after randomization (Panel A);
an additional four patients in the exemestane group and two patients in the tamoxifen group died more than four years
after randomization (Panel B).
Adjusting for the prespecified prognostic fac- or use at any time of hormone-replacement thera- tors did not affect the hazard ratios (Table 3), and py (Fig. 3).
there was no evidence of heterogeneity among
subgroups defined according to estrogen-recep- adverse effects and safety
tor status, combined estrogen-receptor and pro- Exemestane was associated with a higher incidence
gesterone-receptor status, number of positive of arthralgia and diarrhea than tamoxifen, but gyne-
nodes, receipt or type of previous chemotherapy, cologic symptoms, vaginal bleeding, and muscle
Downloaded from www.nejm.org at CILEA BIBLIOSAN on December 11, 2007 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine apy because of adverse events, and another 164 Table 3. Hazard Ratios in the Exemestane Group as Compared
patients in the exemestane group and 116 in the ta- with the Tamoxifen Group.*
moxifen group refused to continue therapy. An ad- End Point
Unadjusted
Adjusted
ditional 63 patients in the exemestane group and 65 in the tamoxifen group have discontinued their randomly assigned treatment for other reasons, including protocol violations, or have been lost to follow-up. On the basis of the time since random- ization, 9 percent of patients are likely to be still re- * A Cox model including estrogen-receptor status (either positive or negative, We found that switching patients to adjuvant treat- unknown or missing), nodal status (negative, 1 to 3 positive nodes, 4 or more positive nodes, or unknown or missing), chemotherapy (yes or no), and use of ment with exemestane after two to three years of ta- hormone-replacement therapy (yes, no, or unknown or missing) was used to moxifen therapy was associated with a statistically estimate the adjusted hazard ratios. Forty patients with unknown chemother- and clinically significant improvement in disease- apy status were excluded from the analysis. CI denotes confidence interval. P values were determined by the log-rank test.
free survival, which included a reduction in the in-cidence of metastatic disease. This strategy alsoreduced the risks of contralateral breast cancer, en- cramps were more common with tamoxifen (Table dometrial cancer, and intriguingly, other primary4). Thromboembolic events were recorded more cancers. At the time of this report, the observedfrequently in the tamoxifen group than in the exe- number of deaths over the relatively short follow-upmestane group (55 patients [2.4 percent] vs. 30 pa- period precludes the detection of a statistically sig-tients [1.3 percent], P=0.007). There was also a sug- nificant difference in overall survival.
gestion of an increased incidence of osteoporosis The data and safety monitoring committee rec- and visual disturbances associated with exemestane. ommended the early release of results on the basisFractures were reported more frequently in the ex- of a planned interim analysis. More than 90 per-emestane group than in the tamoxifen group, al- cent of the patients will have completed their ran-though the difference was not statistically signifi- domly assigned treatment by the time this report iscant (72 patients [3.1 percent] vs. 53 patients [2.3 published; thus, the trial should still be able topercent], P=0.08). More patients in the tamoxifen achieve its long-term assessment of survival bene-group than in the exemestane group had a second fit. There are several theoretical reasons to suggestprimary non-breast cancer that occurred before a a benefit of sequential endocrine therapy involvingdistant relapse (53 patients [2.2 percent] vs. 27 pa- switching from tamoxifen to an aromatase inhibi-tients [1.1 percent]; hazard ratio, 0.51; 95 percent tor after two to three years. First, many patients withconfidence interval, 0.32 to 0.80; P=0.003) (Table breast cancer have a relapse and die of metastatic2). Specifically, cancer of the endometrium, lung disease within five years after the initial diagnosis.
cancer, and melanoma developed in fewer patients Second, in both patients with primary cancer andin the exemestane group than in the tamoxifen those with metastatic disease, resistance occurs asgroup, although these individual differences were early as 12 to 18 months after the initiation of ta-not statistically significant.
moxifen therapy. In some patients with resistantdisease, tamoxifen may act as an agonist, potential- treatment compliance
ly stimulating the division of breast-cancer cells.
Randomly assigned treatment was stopped early in Third, serious side effects of tamoxifen, including667 patients (365 in the exemestane group and 302 thromboembolism and uterine carcinoma, can oc-in the tamoxifen group; 14.1 percent of the total cur after prolonged use. Fourth, since tamoxifen canstudy population) for reasons other than relapse or decrease bone resorption,21 we reasoned that pre-death, after a median total duration of treatment of treatment with tamoxifen might lessen the effect of36.1 months (from the initiation of tamoxifen ther- any osteopenia caused by exemestane.
apy). A total of 138 patients in the exemestane group When we designed this study, there was consid- and 121 in the tamoxifen group discontinued ther- erable uncertainty regarding the optimal duration Downloaded from www.nejm.org at CILEA BIBLIOSAN on December 11, 2007 . Copyright 2004 Massachusetts Medical Society. All rights reserved. e x e m e s t a n e v e r s u s t a m o x i f e n a f t e r i n i t i a l t a m o x i f e n t h e r a p y f o r b r e a s t c a n c e r Subgroup (no.)
Exemestane
Tamoxifen
Hazard Ratio
Hazard Ratio (log scale)
Figure 3. Subgroup Analysis of Disease-free Survival.
The hazard ratio given for all patients was adjusted for estrogen-receptor status, nodal status, receipt or nonreceipt of chemotherapy, and use
or nonuse of hormone-replacement therapy (P=0.00004). The size of the rectangles is proportional to the size of the subgroups.
of adjuvant tamoxifen therapy in patients with pri- al.19 found that after five years of tamoxifen thera-mary breast cancer. The 1990 overview by the Early py, patients who received letrozole had a higher rateBreast Cancer Trialists’ Collaborative Group had of disease-free survival than those who received pla-suggested that there was a likely benefit of continu- cebo. Our large, multicenter study challenges theing tamoxifen therapy for five years.22 Randomized concept of five years of monotherapy with endocrinetrials directly comparing two years of tamoxifen agents after the surgical treatment of primary breasttherapy with five years of tamoxifen therapy23,24 cancer. Two smaller studies conducted by Italian re-confirmed that there was a relative risk reduction of searchers have used sequential aminoglutethimide18 to 19 percent with the longer-term therapy. Thus, after tamoxifen therapy in 308 patients26 and anas-although five years of tamoxifen treatment was the trozole after tamoxifen therapy in 426 patients.27identified standard, switching treatment after only Although they were underpowered, both trials sug-two to three years was postulated to offer patients gested that the sequence may be better than tamox-the bulk of the benefit of tamoxifen while minimiz- ifen alone, supporting the results we present here.
ing the risk of long-term side effects.
Despite the promising results of the Anastrozole, achieved by switching from tamoxifen to exemes- Tamoxifen Alone or in Combination Trialists’ Group tane is consistent with the hypothesis that breast(ATAC) study, which showed that anastrozole was cancer frequently becomes resistant to tamoxifensuperior to tamoxifen,25 five years of tamoxifen within five years after treatment is initiated. The mo-therapy remains the widely recommended standard lecular mechanisms underlying such resistance arefor adjuvant treatment,8 although the Food and unclear. Laboratory studies indicate that a reductionDrug Administration recently approved anastrozole in the antagonist properties of tamoxifen caused bymonotherapy as an alternative. A study by Goss et the up-regulation of tyrosine kinase receptors (in Downloaded from www.nejm.org at CILEA BIBLIOSAN on December 11, 2007 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Table 4. Adverse Events.*
Type of Event
Exemestane Group
Tamoxifen Group
* Data are given for adverse events whose incidence in the two groups differed by 1 percent or more, for which the difference between groups was significant at the 1 percent level, or whose incidence was at least 10 percent in either group. Grades are according to Common Toxicity Cri-teria of the National Cancer Institute (version 1.0). Data on cardiovascular disease, gynecologic symptoms, osteoporosis, and arthralgia were available for 2309 patients in the exemestane group and 2332 patients in the tamoxifen group; data on the other adverse effects were available for 2305 and 2329 patients, respectively. Pain or aches, arthralgia, depression, diarrhea, and cramps were recorded in an “other” category; data are preliminary and may underestimate the true incidence. For graded adverse events, P values were determined by trend tests combin-ing grades 3 and 4.
particular, HER2 and epidermal growth-factor re- contrary to the report suggesting that patients withceptors), downstream protein kinases (such as mi- estrogen-receptor–positive and progesterone-recep-togen-activated protein kinase28 and protein kinase tor–negative carcinomas may preferentially benefitB, or Akt29), or both may result in a significant in- from anastrozole therapy.30crease in the agonist activity of tamoxifen, as well The reduction in the incidence of contralateral as increased sensitivity to estradiol. These effects breast cancer in the exemestane group as comparedcould explain the benefit that has been observed to with the tamoxifen group (hazard ratio, 0.44; 95result from lowering the estradiol level through the percent confidence interval, 0.20 to 0.98; P=0.04)sequential use of an aromatase inhibitor.9 suggests that preventive strategies involving the Results in the subgroup with estrogen-receptor– prolonged use of tamoxifen monotherapy31,32 may positive breast cancer were very similar to those not be optimal. The nonsignificant decrease in theamong all patients. According to an unplanned sub- rate of endometrial cancer is consistent with ex-group analysis, exemestane seemed to be equally ef- pectations, since tamoxifen therapy is a well-rec-fective in both progesterone-receptor–positive and ognized risk factor for endometrial cancer.33,34progesterone-receptor–negative subgroups, as well The decreased incidence of other second primaryas in node-positive and node-negative subgroups, (non-breast) cancers is more difficult to explain.
Downloaded from www.nejm.org at CILEA BIBLIOSAN on December 11, 2007 . Copyright 2004 Massachusetts Medical Society. All rights reserved. e x e m e s t a n e v e r s u s t a m o x i f e n a f t e r i n i t i a l t a m o x i f e n t h e r a p y f o r b r e a s t c a n c e r Reports of associations between tamoxifen therapy The answers to these questions will have to awaitand cancer at other sites have been inconclusive,34 the results of ongoing and new studies. Our resultsand such associations were not substantiated by the add to the evidence that the sequential use of aro-Early Breast Cancer Trialists’ Collaborative Group matase inactivators and tamoxifen provides addi-study.5 Thus, it is not clear whether the observed dif- tional options for improving adjuvant endocrineferences in the incidence of new primary cancers therapy for postmenopausal women with hormone-represent increases in risks due to tamoxifen treat- responsive primary breast cancer. Our results indi-ment, a previously unreported protective effect of an cate that five years of tamoxifen monotherapy afteraromatase inactivator, or chance findings.
surgery may be suboptimal for postmenopausal pa- The rate of discontinuation of treatment was tients with estrogen-receptor–positive breast cancer slightly higher in the exemestane group than in the and suggest that clinicians should consider switch-tamoxifen group, perhaps reflecting differences ing patients to exemestane between two and threein the side-effect profiles of the two treatments years after the start of tamoxifen therapy.
that may have been particularly evident to patients Supported by Pfizer. The coordinating units at Imperial College switching from one treatment to another. The analy- London and the Institute of Cancer Research also receive funding sis of adverse events indicated that there was a low- In addition to grant support to all authors from Pfizer, Prof.
er incidence of thromboembolic events among Coombes reports having received lecture fees from Pfizer, AstraZen-women who switched to exemestane. There was a eca, and Aventis; Prof. Paridaens consulting or lecture fees from Amgen, Pfizer, Lilly, and Novartis; Dr. Jassem lecture fees from No- slight but nonsignificant increase in the rate of os- vartis; Dr. Jones consulting or lecture fees from AstraZeneca andteoporosis and reported fractures in the exemes- Pfizer; Dr Alvarez lecture fees from Schering-Plough; Dr. Bertellitane group as compared with the tamoxifen group. lecture fees from Novartis and Pfizer; Dr. Ortmann consulting fees from Pharmacia and AstraZeneca and lecture fees from Pfizer and Recent studies have shown that all third-generation Organon; Dr. Bajetta lecture fees from Pfizer; Dr. Dodwell consult-aromatase inhibitors or inactivators increase bone ing fees from Pfizer; Prof. Coleman consulting or lecture fees fromresorption.35,36 The substudy of the IES on bone Pfizer, Novartis, and AstraZeneca and grant support from Astra- Zeneca; Prof. Fallowfield lecture fees from AstraZeneca, Johnson mineral density aims to determine the degree of and Johnson, and Roche; Dr. Andersen consulting fees from Pfizer;bone mineral loss in patients who have been treat- Prof. Lønning consulting and lecture fees from Pfizer; and Dr. Stew-ed with tamoxifen and then switched to exemestane. art consulting and lecture fees from AstraZeneca; Dr. Stewart also holds equity in AstraZeneca. Dr. Stuart reports having received con- The increase in the rate of arthralgia in the exemes- sulting fees from AstraZeneca. Drs. Carpentieri and Massimini aretane group is similar to that seen with other aroma- employees of Pfizer and hold equity in the company.
tase inhibitors,37 and diarrhea has been reported We are indebted to the women who participated in the study; to the Breast International Group for their support; to the study steer- previously in patients receiving exemestane.16 Cho- ing committee; to the independent data monitoring committee; andlesterol levels, which were reduced by tamoxifen to the doctors, nurses, monitors, and data managers from the Ar-treatment,38 were found to be unaltered in another gentine Breast Cancer Group, the Australian–New Zealand Breast Cancer Trials Group, the Central and Eastern European Oncology study of exemestane39 but were not systematically Group, the Danish Breast Cancer Group, the European Organiza-measured in the present study; we have not observed tion for Research and Treatment of Cancer, the Grupo Español dea significantly increased incidence of myocardial Investigacíon del Cancer de Mama, the Gruppo Oncologico Nord Ovest, the Gruppo Oncologico Italiano di Ricerca Clinica, the Inter- infarction (1.0 percent in the exemestane group vs. national Breast Cancer Study Group, the International Collaborative0.4 percent in the tamoxifen group). Cancer Group, the Israeli Clinical Oncology Group, the Italian Trials Several issues still need to be clarified, including in Medical Oncology, the North West England Group, the Norwe- gian Breast Cancer Group, the Yorkshire Breast Group, the Federa- the correct sequence of therapy, which we believe to tion Nationale des Centres de Lutte contre le Cancer, the Germanbe an important factor in the success of this study Exemestane Adjuvant Group, the Wales Cancer Trials Network, U.S.
and that reported by Goss et al.,19 as well as the ef- Oncology, and the Swedish Breast Cancer Group. Additional ac- knowledgments can be found in Supplementary Appendix 1 (avail- fect of aromatase inhibition on bone metabolism. able with the full text of this article at www.nejm.org).
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Downloaded from www.nejm.org at CILEA BIBLIOSAN on December 11, 2007 . Copyright 2004 Massachusetts Medical Society. All rights reserved. CORRECTION
A Randomized Trial of Exemestane after Two to Three
Years of Tamoxifen Therapy in Postmenopausal
Women with Primary Breast Cancer
A Randomized Trial of Exemestane after Two to Three Years of Ta- moxifen Therapy in Postmenopausal Women with Primary Breast Cancer . On page 1083, in Figure 1, the number of patients who were assigned to receive two to three years of tamoxifen therapy should have read 2380, rather than 2362, as printed, and the number of patients assigned to receive exemestane therapy should have read Downloaded from www.nejm.org at CILEA BIBLIOSAN on December 11, 2007 . Copyright 2004 Massachusetts Medical Society. All rights reserved. CORRECTION
A Randomized Trial of Exemestane after Two to Three
Years of Tamoxifen Therapy in Postmenopausal
Women with Primary Breast Cancer
A Randomized Trial of Exemestane after Two to Three Years of Ta- moxifen Therapy in Postmenopausal Women with Primary Breast Cancer . On page 1081, the list of authors should have included ``Cornelius van de Velde, M.D., Department of Surgery, Leiden Uni- versity Medical Center, Leiden, the Netherlands.´´ On page 1083, the legend for Figure 1 should have read ``The percentage of patients who continue to receive treatment represents the percentage who are not known to have discontinued their randomized treatment and who began initial tamoxifen therapy less than five years before March 31, 2004,´´ not ``December 31, 2004,´´ as printed. On page 1089, in Fig- ure 3, the upper limit of the 95 percent confidence interval for the previous-chemotherapy subgroup should have been 0.92 and should not have crossed 1.0, as printed. On page 1090, the P values listed The table has been corrected on the Journal’s Web site at Downloaded from www.nejm.org at CILEA BIBLIOSAN on December 11, 2007 . Copyright 2004 Massachusetts Medical Society. All rights reserved.

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