This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mouridsen, H. Articles by Bhatnagar, A. Search for Related Content PubMed PubMed Citation Articles by Mouridsen, H. Articles by Bhatnagar, A. Related Articles Related Correspondence Social Bookmarking                            What's this?

Phase III Study of Letrozole Versus Tamoxifen as First-Line Therapy of Advanced Breast Cancer in Postmenopausal Women: Analysis of Survival and Update of Efficacy From the International Letrozole Breast Cancer Group

Henning Mouridsen, Mikhail Gershanovich, Yan Sun, Ramón Pérez-Carrión, Corrado Boni, Alain Monnier, Justus Apffelstaedt, Robert Smith, Harm P. Sleeboom, Fritz Jaenicke, Anna Pluzanska, Magdolna Dank, Dominique Becquart, Poonamalle P. Bapsy, Eeva Salminen, Ray Snyder, Hilary Chaudri-Ross, Raquel Lang, Peter Wyld, Ajay Bhatnagar

From the Rigshospitalet, Copenhagen, Denmark; Petrov Research Institute of Oncology, St Petersburg, Russia; Chinese Academy of Medical Sciences, Beijing, China; Hospital Universitario de la Princesa, Madrid, Spain; Arcipedale Santa Maria Nuova, Reggio Emilia, Italy; Centre Hospitalier General Andre-Boulloche, Montbeliard, France; University of Stellenbosch, Cape Town, South Africa; South Carolina Oncology Associates, Columbia, SC; Ziekenhuis Leyenburg, Den Haag, the Netherlands; University of Hamburg, Hamburg, Germany; Regional Center of Oncology, Lodz, Poland; Semmelweis University, Budapest, Hungary; Z.A. Middelheim, Antwerpen, Belgium; Kidwai Memorial Institute of Oncology, Bangalore, India; Turku University Central Hospital, Turku, Finland; St. Vincent’s Hospital, Fitzroy, Victoria, Australia; Novartis Pharma AG, Basel, Switzerland.

Address reprint requests to Hilary A. Chaudri-Ross, Novartis Pharma AG, WSJ-27.2.023, CH-4002 Basel, Switzerland; email: hilary_anne.chaudri{at}pharma.novartis.com.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Purpose: To analyze overall survival (OS) and update efficacy data for letrozole versus tamoxifen as first-line therapy in postmenopausal women with locally advanced or metastatic breast cancer.

Patients and Methods: This multicenter phase III trial randomly assigned 916 patients with hormone receptor–positive or unknown tumors letrozole 2.5 mg (n = 458) or tamoxifen 20 mg (n = 458) daily until disease progression. Optional cross-over was permitted at the treating physician’s discretion. This report updates efficacy at a median follow-up of 32 months.

Results: The superiority of letrozole to tamoxifen was confirmed for time to progression (median, 9.4 v 6.0 months, respectively; P < .0001), time to treatment failure (median, 9 v 5.7 months, respectively; P < .0001), overall objective response rate (32% v 21%, respectively; P = .0002), and overall clinical benefit. Median OS was slightly prolonged for the randomized letrozole arm (34 v 30 months, respectively). Although this difference in OS is not significant, survival was improved in the randomized letrozole arm over the first 2 years of the study. Approximately one half of the patients in each arm crossed over. Total duration of endocrine therapy ("time to chemotherapy") was significantly longer (P = .005) for patients initially on letrozole (median, 16 months) than for patients initially on tamoxifen (median, 9 months). Time to worsening of Karnofsky performance score was significantly delayed with letrozole compared with tamoxifen (P = .001).

Conclusion: This study documents the superiority of letrozole over tamoxifen in first-line endocrine therapy in postmenopausal women with advanced breast cancer.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
FOR MORE than 20 years, tamoxifen has been the established standard of care for first-line therapy in postmenopausal women with advanced breast cancer considered eligible for endocrine therapy.¹ In the search for therapeutic alternatives for women who are refractory or for whom tamoxifen has failed, aromatase inhibitors were developed as agents that prevent estrogen biosynthesis rather than blocking estrogen binding to its receptor (ER).² Earlier aromatase inhibitors such as aminoglutethimide and fadrozole were effective as second-line therapy after disease progression or relapse after tamoxifen.^3,4 More recently, the newer third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, have been shown to be more potent and highly selective, and in the second-line setting, these drugs have demonstrated a superior therapeutic index compared with the recent standard second-line therapies, aminoglutethimide and progestins.^5–8 As a result, third-generation aromatase inhibitors have become the gold standard in second-line therapy and are being considered as an alternative to tamoxifen for first-line endocrine therapy based on results from randomized trials in postmenopausal patients with metastatic, receptor-positive, or receptor-unknown breast cancer.

Two trials comparing anastrozole with tamoxifen have been reported.^9,10 The North American study, conducted in United States and Canada, demonstrated superior time to progression (TTP) for anastrozole over tamoxifen, but no benefit in the other primary end point, objective response rate (ORR).⁹ However, the larger TARGET (Tamoxifen or Anastrozole Randomized Group Efficacy and Tolerability) trial, conducted in Europe, Australia, New Zealand, South America, and South Africa, failed to show any improvement in TTP with anastrozole compared with tamoxifen (median 8.2 v 8.3 months).¹⁰ The two trials were designed to enable a combined analysis, which was published recently.¹¹ No significant differences were observed between the tamoxifen and anastrozole groups for any of the major end points: TTP, response rate, clinical benefit rate, or time to treatment failure (TTF). These retrospective analyses demonstrated anastrozole to be superior to tamoxifen only in the subgroup of patients with receptor-positive tumors.

Preliminary data from a randomized phase II trial with exemestane¹² indicate that this drug is active as a first-line agent, but results from the ongoing phase III trial versus tamoxifen are not yet available.

Recently, we reported results of a randomized phase III trial of letrozole versus tamoxifen in postmenopausal women with advanced breast cancer. The median follow-up was 18 months. This trial, the largest single study of its kind conducted to date, showed that letrozole was significantly superior to tamoxifen in TTP, response rate, rate of clinical benefit, and TTF.¹³ Prospectively planned analyses of subgroups for TTP and response rate showed consistent superiority over tamoxifen across all major subgroups of patients.

In this article, we update TTP, TTF, and rates of objective response and clinical benefit, report on overall survival (OS) at a median follow-up of 32 months, and discuss some of the effects of the optional cross-over on OS.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Study Design
The design and ethical principles of this study were described previously.¹³ In summary, this double-blind, double-dummy, parallel-group, phase III trial of first-line endocrine therapy for patients with advanced breast cancer recruited patients from 201 centers in 29 countries. Patients were randomly assigned letrozole 2.5 mg (n = 458) or tamoxifen 20 mg (n = 458), with matching placebo tablets, taken orally once daily. For efficacy, four patients from a Good Clinical Practice (GCP) noncompliant site and five patients who did not have actively progressive breast cancer at enrollment were excluded, such that 453 patients were randomly assigned letrozole and 454 tamoxifen as previously described. This defined the intent-to-treat (ITT) population for efficacy. For assessment of safety, all patients who received monotherapy were included, except those from the GCP noncompliant site (n = 455 for each treatment arm). For OS, all patients enrolled on monotherapy were included (n = 458 for each treatment arm).

Patients continued treatment until progression of disease (PD) or until other reasons necessitated discontinuation. If, after PD or discontinuation of treatment due to an adverse event (AE), the patient remained suitable for further endocrine therapy, at the discretion of the investigator, she could be switched to the alternative treatment in a double-blind fashion (optional cross-over). Treatment after first progression in patients who did not cross over, and after second progression in patients who earlier did cross over, was also at the discretion of the individual investigators. All patients were followed for OS.

Eligibility Criteria
Requirements for patient inclusion or exclusion were detailed previously.¹³ Key inclusion criteria were postmenopausal status with stage IIIB locally advanced breast cancer or locoregionally recurrent or metastatic measurable or assessable disease considered suitable for endocrine therapy. Patients were required to have tumors with ER-positive or progesterone receptor (PgR)–positive status or with both receptors unknown. One prior chemotherapy regimen for advanced disease was permitted provided progressive disease was documented. Patients were excluded for prior endocrine therapy for advanced disease, or for disease recurrence either during adjuvant antiestrogen therapy or within 12 months of completing such therapy.

Assessment of Efficacy and Safety
Assessment of efficacy according to International Union Against Cancer (IUCC) criteria at baseline and during treatment has been detailed previously.¹³ All patients were monitored for survival at least every 6 months after termination of study treatment(s).

The prospectively defined primary efficacy end point was TTP, defined as the interval between date of randomization and the earliest date of PD.¹³ An increase of 25% in measurable lesions, an estimated increase of the same magnitude in nonmeasurable disease, or the appearance of new lesions constituted evidence of progression. Additional criteria for progression were discontinuation of treatment with documentation of clinical deterioration due to breast cancer or death from breast cancer while on study treatment or within 6 weeks of treatment discontinuation. Progression was determined by computer algorithm based on objective criteria and required complete tumor assessments, with the date of progression backdated to an earlier complete assessment, if necessary. For example, the date of progression noted at a site that had not been fully assessed at the previous visit (in most cases, incomplete x-ray evaluation of skeletal sites) would be backdated to the previous complete tumor assessment plus 1 day. Response was also calculated by computer algorithm. Complete response (CR) was downgraded to partial response (PR) in the continued presence of nonmeasurable, nonassessable lesions (eg, pulmonary effusion or ascites).

Secondary end points included overall tumor ORR, rate of clinical benefit, TTF, time to response, OS, and safety. ORR was defined as the proportion of patients who achieved CR or PR confirmed by a second evaluation 3 months later. Response in patients with bone lesions only and 50% blastic component was categorized as not assessable unless there was PD, in which case response was considered as PD.¹³

Time to response (in patients with confirmed CR or PR) was the interval between randomization and the earliest documentation of response. The rate of clinical benefit was defined as the proportion of patients who achieved a confirmed CR or PR or who had stabilization of disease or no change (SD) lasting for 24 weeks or longer. TTF was defined as the interval between date of randomization and the earliest date of PD, withdrawal of study treatment for any reason, withdrawal of consent, loss to follow-up, or death from any cause. Duration of OS was defined as the interval between randomization and death for any reason.

Time to chemotherapy or total duration of endocrine therapy was calculated as follows: for patients who switched treatments, as the sum of the duration of first-line therapy and the duration of the cross-over therapy (censored at the last date available if the patient remained on the cross-over treatment at the cutoff date for analysis); and for patients who did not switch treatments, as the duration of first-line therapy (censored if the patient remained on first-line treatment at the cutoff date for analysis).

Assessment of safety was performed according to the National Cancer Institute’s common toxicity criteria (version 1.3). In addition, investigators rated AEs on their suspected relationship to study treatment (none or unlikely classified as "not suspected"; possible, probable, highly probable, or a missing relationship classified as "suspected to be related"). We report here all AEs irrespective of relationship, reported by 10% of patients in either treatment arm, as well as AEs suspected of being related to study treatment reported by 5% in either treatment arm. AEs are summarized using Medical Dictionary for Regulatory Activities (MedDRA) preferred terms. As fractures were reported under several preferred terms, we grouped all reported fractures, regardless of etiology (traumatic, osteoporotic, pathologic, or not stated), and report the total occurrence during the period of first-line randomized therapy, as well as the fracture rate per patient-year of treatment.

Changes in Karnofsky performance score (KPS) during first-line treatment were also evaluated as an additional indicator of overall benefit, based on the patient’s ability to care for herself. A deterioration of 20 points in KPS was considered clinically relevant, as was an improvement of 20 points sustained over at least 6 months.

Statistical Analysis
Analyses of time-to-event data and of categorical data have previously been described.¹³ Cox proportional hazards regression models were applied to time-to-event data (except for time to death and time to chemotherapy) and logistic regression models to categorical data. Estimates of the survivor function were made by the Kaplan-Meier product-limit method for all time-to-event data (including time to chemotherapy). Time to response was estimated only in the subset of patients with a subsequently confirmed CR or PR. Tamoxifen was the reference treatment for comparison of letrozole.

In this article we report OS. Two interim analyses of OS based on calendar time were prospectively planned (protocol amendment) before the final analysis, which was also based on calendar time (18 months after the primary analysis of TTP), following O’Brien-Fleming boundaries and a Lan-DeMets alpha spending function. The first interim analysis was conducted at the time of the primary analysis of TTP (median follow-up of around 18 months) whereas the second was conducted about 8 months later. The independent external Data Monitoring Committee (chaired by Thomas Fleming, University of Washington, Seattle) recommended that the results of both interim analyses not be divulged. The protocol-specified method of analysis was an overall log-rank test. It was expected that the (optional) cross-over design could entail nonproportional hazards. Therefore, as the log-rank test assumes an underlying proportional hazards distribution (although it is robust to minor departures from this assumption), additional supportive methods were planned before database lock: a nonparametric Kolmogorov-Smirnov-type test,¹⁴ to compare the two survival distributions; and repeated truncated log-rank tests at 6-month intervals throughout the observation time. The former method, which maintains the overall type I error (significance level) for making treatment comparisons at all possible time points, was based on the logarithmic Nelson-Aalen estimators (rather than Kaplan-Meier estimators) and is a conservative test. The latter method (repeated log-rank tests) requires adjustment of the type I error for treatment comparisons at multiple time points. The 6-month intervals were prospectively selected as they were compatible with the once every 3 months tumor assessments and once every 6 months collection of survival data after progression on study treatment(s).

The same subgroup analyses as prospectively defined for the primary analysis of TTP (and ORR) were defined for the analysis of OS, although the method of analysis differed; for OS, the stratified log-rank test was applied. In addition, a descriptive analysis of survival in the first-line setting was prospectively defined (time to death censored at the date of cross-over if the patient switched treatments) as well as a descriptive analysis of survival in the subset of patients who switched treatments (second-line survival).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
A total of 939 patients were enrolled onto the study between November 1996 and early January 1999. As described previously, 32 patients were excluded from the efficacy analyses (23 patients treated with the combination of letrozole and tamoxifen, four patients in a site suspected of GCP noncompliance, and five patients who did not have actively progressing breast cancer at enrollment).¹³ Of the 907 patients included in the efficacy (tumor assessment) population, 453 were allocated letrozole therapy and 454 were allocated tamoxifen. Patient demographics and baseline characteristics were well balanced between the two groups. For the analysis of OS, all patients randomly allocated monotherapy were included (ie, the enrolled 939 patients minus the 23 patients allocated to the combination of tamoxifen and letrozole). In total, 458 patients in each arm were followed for OS.

The data cutoff for the present analysis was September 2001, when median follow-up was 32 months, with a maximum observation period of 57 months. The timing of the update analysis was specified in the protocol: 18 months after the primary analysis (which was event-driven).

Patient Disposition and Response to Therapy
The numbers and proportions of patients who, at the cutoff date, were still on the allocated first-line therapy, who crossed over to second-line endocrine therapy, and who did not cross over are listed in Table 1. The updated analysis confirmed the superiority of first-line letrozole over first-line tamoxifen in the primary end point, TTP (Table 2). Median TTP remained unchanged from the primary analysis,¹³ and, as before, median TTP was prolonged by 57%, from 6.0 months for tamoxifen to 9.4 months for letrozole (Table 2). TTP remained longer for letrozole than for tamoxifen throughout the observation period for the study as a whole (Fig 1) and in various prospectively defined subgroups (Fig 2). TTF was similar to TTP (Table 2), indicating that both treatments were generally well tolerated, with median TTF remaining the same as previously reported (9.0 months for letrozole, 5.7 months for tamoxifen).

View larger version (14K): [in this window] [in a new window]   Fig 1. Time to progression (TTP) at median follow-up of 32 months for patients on first-line letrozole versus tamoxifen. Of patients in the letrozole arm, 359 (79%) progressed, compared with 387 (85%) in the tamoxifen arm.

View larger version (8K): [in this window] [in a new window]   Fig 2. Forest plot of treatment comparisons for time to progression (TTP) by key baseline covariates. Squares denote hazards ratios, drawn proportional to the number of events, and lines represent 95% confidence intervals. Hazards ratios < 1 favor letrozole.

View larger version (9K): [in this window] [in a new window]   Fig 3. Forest plot of treatment comparisons for objective response rate by key baseline covariates. Squares denote odds ratios, drawn proportional to the number of events, and lines represent 95% confidence intervals. Odds ratios > 1 favor letrozole.

View larger version (9K): [in this window] [in a new window]   Fig 4. Overall survival (OS) at median follow-up of 32 months, by randomized treatment arm. Median OS was not significantly different (overall log-rank, P = .53). There was a significant difference in favor of the randomized letrozole arm between 6 and 20 months (Kolmogorov-Smirnov-type test, P = .003).

Time to Chemotherapy
Time to chemotherapy (defined as the total duration of endocrine therapy) was significantly longer for patients whose initial treatment was letrozole (median, 16.3 months; 95% CI, 14.8 to 18.3 months; failure of endocrine treatment in 401 patients, 89%) than for patients whose initial treatment was tamoxifen (median, 9.3 months; 95% CI, 8.4 to 11.9 months; failure of endocrine treatment in 426 patients, 94%) (Fig 5; log-rank P = .005). A longer chemotherapy-free interval is important for patient quality of life and provides additional evidence of benefit with letrozole in this trial.

View larger version (15K): [in this window] [in a new window]   Fig 5. Time to chemotherapy, after failure of endocrine treatment. A number of patients in each randomized treatment arm remained with no evidence of progression: letrozole arm, 11%; tamoxifen arm, 6%. Median time to chemotherapy was significantly longer with initial letrozole treatment.

View this table: [in this window] [in a new window]   Table 6. Deterioration of KPS* by 20 Points and Improvement of 20 Points Sustained Over 6 Months

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

Updated analysis confirms all previously reported results: significantly longer TTP and TTF, and significantly higher rates of objective response and clinical benefit for the letrozole arm in comparison with tamoxifen. The data also showed a strong trend in improvement of KPS for letrozole and, in addition, a significant delay in time to worsening of KPS.

Although there was no significant difference between treatment arms in OS, we report the significant survival advantage in the randomized letrozole arm over the randomized tamoxifen arm in the first 2 years of the study. The conservative Kolmogorov-Smirnov-type test showed that the maximum differential survival effect occurred at around 14 months, with 85 deaths (19%) in the randomized letrozole arm compared with 132 deaths (29%) in the randomized tamoxifen arm. Dissipation of the early survival advantage for letrozole beyond 2 years may reflect the progressive effect of cross-over to the other treatment agent. This early survival superiority achieved in the randomized letrozole arm during the first 2 years of the study is consistent with the significantly greater efficacy of letrozole over tamoxifen in the major end point, TTP. At final data cutoff, nearly twice as many patients remained progression-free on letrozole first-line as on tamoxifen first-line (11% v 6%).

It is well established that, in general, second-line treatment is less effective than first-line treatment in patients who originally responded to first-line therapy. If the second-line treatment is significantly better than the original first-line treatment, cross-over may impair the evaluation of OS attributable to the first-line agent. Indeed, duration of survival with second-line letrozole was substantially longer than with second-line tamoxifen, and the descriptive analysis of OS in patients whose time to death was censored at cross-over suggested that first-line letrozole may have a survival advantage over tamoxifen well beyond 2 years. Caution in overinterpreting the exploratory analysis censoring time to death at cross-over is necessary, as the prerequisite assumption that censoring be noninformative is violated. Cross-over occurred at the time of first progression. As letrozole was significantly more effective than tamoxifen in delaying time to first progression, so first-line survival was prolonged (with fewer deaths on first-line letrozole than on first-line tamoxifen), even if time to progression is an imperfect surrogate marker of survival. The effects on duration of survival in the nonrandom subset of patients who switched treatments on progression are thoroughly confounded with letrozole’s second-line effectiveness after tamoxifen failure.⁶ However, as cross-over was not randomized (and could not be so on ethical grounds, or while still maintaining the double-blind nature of the study) and was not independent of treatment, and as patients who crossed over could not be prospectively identified (at baseline), the interpretation of a long-term survival advantage of letrozole over tamoxifen must be considered speculative,¹⁵ but warranting further exploration.

Modeling of survival curves following an exponential distribution, with median survival 4 years in one arm and 2.5 years in the other, was undertaken (data not shown). When cross-over to the alternate treatment was introduced for half of the patients in each arm, with cross-overs being complete by around 3 years, the simulated curves seemed similar to the survival curves actually observed in this study (Fig 4).

Early-generation aromatase inhibitors have previously failed to show any survival improvement over tamoxifen in the advanced breast cancer setting. A phase III trial of first-generation aminoglutethimide versus tamoxifen also included a cross-over extension phase at PD, but survival rates were identical for the two agents,³ and second-generation fadrozole was inferior to tamoxifen in OS.⁴

Survival data for the other available third-generation aromatase inhibitors have not been published to date. Data for anastrozole have been posted on the Food and Drug Administration Web site¹⁶ and indicate that there is no survival advantage for anastrozole over tamoxifen in either of the two trials.

Second-line chemotherapy is typically recommended for patients with disease that is refractory to endocrine therapy or has developed resistance. The significantly longer "time to chemotherapy" is additional evidence of benefit with letrozole in this trial. The longer chemotherapy-free interval resulting from letrozole treatment represents an important consideration in patients’ quality of life.

The earlier report on this trial comparing letrozole with tamoxifen indicated that the safety and tolerability of the two agents were similar. Despite its greater activity, letrozole treatment was not associated with any increase in the number or severity of AEs compared with tamoxifen.¹³ In particular, at 32-months’ median follow-up, there was no statistically significant difference between the letrozole and tamoxifen arms in incidence of bone fracture from all causes. The safety and efficacy results are consistent with the significant delay in worsening of KPS, the significantly fewer patients with a clinically relevant deterioration in KPS, and the suggestion even of a clinically relevant improvement in KPS, associated with the randomized letrozole arm compared with the randomized tamoxifen arm. KPS, however, is relatively insensitive to change. A change of 20 points is equivalent to a change of one class in Eastern Cooperative Oncology Group or World Health Organization performance status and reflects the patient’s ability for self-care rather than her tumor status. Although the majority of patients in each randomized treatment arm progressed (79% for letrozole, 85% for tamoxifen), 19% of patients in the letrozole arm and 25% in the tamoxifen arm showed a clinically relevant worsening of KPS.

This study provides evidence of the superiority of letrozole over tamoxifen in the first-line setting: a reduction in risk of progression of approximately 30%, significantly prolonged TTP, significantly greater odds of a response, and of clinical benefit (all of these irrespective of prior adjuvant antiestrogen therapy, receptor status, or dominant site of disease). Overall survival was similar in both randomized treatment arms; however, the risk of death during the first 2 years was significantly reduced in the randomized letrozole arm compared with the risk in the randomized tamoxifen arm. It is important to remember that, for all investigators, patients, and monitors, the study remained blinded until after formal study closure; the more subjective end points of KPS and "time to chemotherapy" were not influenced by awareness of treatment. The consistency of the results in this trial supports the use of letrozole as superior first-line endocrine therapy compared with tamoxifen in postmenopausal women with hormone-sensitive advanced breast cancer.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The appendix of participating investigators is available online at www.jco.org.

Principal investigators for the Letrozole International Letrozole Breast Cancer Group (in addition to listed authors) were as follows: Argentina: L. Balbiani, C. Castillo, F. Coppola, R. De Angelis, L. Fein, L. Freue, C. Lopez, J. Martinez, E. Mickiewicz, E. Palazzo, H. Requejo, L. Silberman, M. Torello, R. Viroglio, and R. Wainstein; Australia: E. Abdi, R. Bell, P. Craft, D. Dalley, M. Green, D. Grimes, P. Harnett, R. Kimber, J. McKendrick, J. Stewart, and J. Trotter; Austria: M. Stierer and V. Wette; Belgium: F. Bastin, L. Dirix, L. Marcelis, and D. Vanstraelen; Canada: M. Blackstein, F. Couture, C. Germond, and S. Legault-Poisson; Chile: L. Prieto and L. Soto Diaz; Denmark: E. Andersen, J. Andersen, S. Cold, C. Gadeberg, P. Grundtvig, C. Kamby, N. Keldsen, M. Kjaer, E. Madsen, K. Møller, P. Philip, and E. Sandberg; Egypt: M. Hamza and O. Zaki; Finland: G. Blanco and V. Kataja; France: B. Audhuy, A. Daban, T. Delozier, P. Fargeot, O. LeFloch, A. Lortholary, E. Malaurie, M. Marty, L. Mauriac, L. Mignot, F. Morvan, M. Namer, G. Netter-Pinon, P. Quetin, G. Romieu, M. Spielmann, N. Tubiana-Mathieu, and B. Weber; Germany: W. Abenhardt, M. Brandtner, R. Dengler, G. von Minckwitz, P. Reichardt, F. Opri, K. Possinger, and S. Völkl; Great Britain: S. Chan, N. Davidson, TRJ Evans, T. Iveson, R. Leonard, R. Mansel, C. Price, and J. Robertson; Greece: G. Arvantinos, V-A Georgoulias, and N. Pavlidis; Hungary: Z. Faluhelyi, M. Kispál, T. Nagykálnai, and J. Szántó; Iceland: H. Sigurdsson; India: I. Mittra and V. Raina; Israel: B. Kaufman, T. Tichler, and N. Wigler; Italy: P. Carlini, M. Cremonesi, M. D’Aprile, F. Di Costanzo, M. Fornasiero G. Francini, M. Indelli, A. Molino, G. Monti, A. Pacagnella, R. Silva, and E. Villa; Netherlands: E. Balk, J. Coenen, E. Maartense, J. Nortier, D. Richel, W. van Deijk, S. van der Vegt, F. van Nierop, and H. van Veelen; New Zealand: S. Costello; Poland: P. Koralewski; Portugal: M. Pinto; Russia: A. Garin, V. Gorbunova, and M. Litchinitser; South Africa: N. Cronje, C. Falkson, L. Goedhals, C. Jacobs, J. Jordaan, J. Raats, I. Werner, and A. Zietsman; Spain: A. Balil, R. Bastús, J. Illarramendi, and A. Llombart-Cussac; Sweden: M. Albertsson and A. Malmstrøm; United States: M. Alden, R. Asbury, C. Badolato, E. Balcueva, J. Bitran, R. Blachly, D. Blayney, T. Brotherton, R. Brown, L. Campos, R. Chapman, F. Cummings, M. Ellis, R. Fredric, J. Hainsworth, G. Harrer, S. Jubelirer, L. Kalman, J. Kroener, M. Levin, M. Lewis, J. Liebmann, R. Marsh, J. McCann, S. McCachren, J. McCracken, B. O’Connor, R. Odders, D. Osborn, K. Pendergrass, B. Pruitt, R. Rodriguez, M. Rubin, T. Shiftan, P. Silverman, S. Tchekmedyian, W. Waterfield, K. Weichert, R. Yanagihara, B. Yanes, F. Yunus, and M. Zimmer; Uruguay: C. Garbino and G. Sabini.

Members of the Data Monitoring Committee, who reviewed all survival analyses, were Dr Thomas Fleming (Chair), University of Washington, Seattle, WA; Dr Klaus Hoeffken, University of Jena, Jena, Germany; Dr Per Lønning, University of Bergen, Bergen, Norway; Dr Kathleen Pritchard, Toronto-Sunnybrook Regional Cancer Centre, Toronto, Canada; Dr Beat Thuerlimann, International Breast Cancer Study Group, St Gall, Switzerland; and Dr Lawrence Wickerham, National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA.

	ACKNOWLEDGMENTS

 
We thank Drs Christian Reboulleau and Christopher Stackpole for editorial support, and Hollister Robinson for coordinating efforts, in the preparation of this manuscript. We would also like to acknowledge Danyu Lin, University of North Carolina (external independent statistical consultant), for performing the Kolmogorov-Smirnov-type test, and Dr Michael Branson, Novartis Pharma AG, Basel (Novartis independent statistical consultant), Switzerland, for his support and liaison with Professor Lin. Interim analyses of overall survival were conducted by Dr Paul Gallo, Novartis Pharmaceuticals, East Hanover, NJ (Novartis independent statistician), who also liaised with the external Data Monitoring Committee. Dr Jean Gloor, Novartis Pharma Switzerland, is acknowledged for his work on modeling theoretical survival curves with an integral cross-over. The Data Management team, headed by Elizabeth Baguley, Novartis Pharmaceuticals, Horsham, UK, and the programming team headed by Wolfgang Schaffranek, Novartis Pharma AG, Basel, are gratefully acknowledged. Above all, we thank the patients who participated in this study, and their medical support teams, who made this publication possible.

	NOTES

 
Supported by Novartis Pharma AG, Basel, Switzerland.

Peter Wyld is currently at British Biotech PLC, Oxford, UK.

The following authors own stock (not including shared held through a public mutual fund): Ajay Bhatnagar (Novartis-Pharma), Peter Wyld, Raquel Lang, Hilary Chaudri-Ross. The following authors acted as consultants within the past two years: Henning Mouridsen (Novartis, Pharmacia, Glaxo-Smith Kline), Robert Smith, Harm P. Sleeboom, Ajay Bhatnagar, (Novartis-Pharma), Alain Monnier (Pharmacia-Novartis), Hilary Chaudri-Ross. The following authors performed contract work within the past 2 years: Justin Appfelstaedt. The following authors served as an officer or member of the Board of a company: Fritz Jaenicke (Advisory Board: Novartis [European]). The following authors received more than $2,000 a year from a company for either of the past 2 years: Fritz Jaenicke (Novartis [European]), Henning Mouridsen (Novartis), Robert Smith, Harm P. Sleeboom, Peter Wyld, Alain Monnier (Pharmacia). The following authors are employees of Novartis: Hilary Chaudri-Ross, Raquel Lang, Ajay Bhatnagar (until June 30, 2001).

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
1. Rose C, Mouridsen HT: Endocrine therapy of advanced breast cancer. Acta Oncol 27:721–728, 1988[Medline]

2. Santen RJ, Harvey HA: Use of aromatase inhibitors in breast carcinoma. Endocr Relat Cancer 6:75–92, 1999[Abstract]

3. Gale KE, Andersen JW, Tormey DC, et al: Hormonal treatment for metastatic breast cancer: An Eastern Cooperative Oncology Group phase III trial comparing aminoglutethimide to tamoxifen. Cancer 73:354–361, 1994[CrossRef][Medline]

4. Thuerlimann B, Beretta K, Bacchi M, et al: First line fadrozole HCl (CGS 16949A) versus tamoxifen in postmenopausal patients with advanced breast cancer. Ann Oncol 7:471–479, 1996[Abstract/Free Full Text]

5. Buzdar A, Jonat W, Howell A, et al: Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: Results of overview analysis of two phase III trials. J Clin Oncol 14:2000–2011, 1996[Abstract/Free Full Text]

6. Dombernowsky P, Smith I, Falkson G, et al: Letrozole, a new oral aromatase inhibitor for advanced breast cancer: Double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 16:453–461, 1998[Abstract]

7. Gershanovich M, Chaudri HA, Campos D, et al: Letrozole, a new aromatase inhibitor: Randomized trial comparing 0.5 mg and 2.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Ann Oncol 9:639–645, 1998[Abstract/Free Full Text]

8. Kaufmann M, Bajetta E, Dirix LY, et al: Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: Results of a phase III randomized double-blind trial. J Clin Oncol 18:1399–1411, 2000[Abstract/Free Full Text]

9. Nabholtz A, Buzdar A, Pollak M, et al: Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: Results of a North American multicenter randomized trial. J Clin Oncol 18:3758–3767, 2000[Abstract/Free Full Text]

10. Bonneterre J, Thuerlimann B, Robertson J, et al: Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: Results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability Study. J Clin Oncol 18:3748–3757, 2000[Abstract/Free Full Text]

11. Bonneterre J, Buzdar A, Nabholtz JM, et al: Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. Cancer 92:2247–2258, 2001[CrossRef][Medline]

12. Dirix J, Piccart MJ, Lohrisch C, et al: Efficacy of and tolerance to exemestane versus tamoxifen in first-line hormonal therapy of postmenopausal metastatic breast cancer patients: A European Organization for the Research and Treatment of Cancer Phase II Trial with Pharmacia and Upjohn. Proc Am Soc Clin Oncol 20:29a, 2001 (abstr 114)

13. Mouridsen H, Gershanovich M, Sun Y, et al: Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: Results of a phase III study of the International Letrozole Cancer Group. J Clin Oncol 19:2596–2606, 2001[Abstract/Free Full Text]

14. Schumacher M: Two-sample tests of Cramer-von Mises and Kolmogorov-Smirnov-type for randomly censored data. Int Stat Rev 52:261–281, 1984

15. Geisler J, Haynes B, Anker G, et al: Influence of letrozole (Femara) and anastrozole (Arimidex) on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a random, cross-over design study. J Clin Oncol 20:751–757, 2002[Abstract/Free Full Text]

16. Center for Drug Evaluation and Research: Food and Drug Administration application. http://www.fda.gov/cder/foi/nda/2000/20-541S006_Arimidex.htm

Submitted April 30, 2002; accepted March 12, 2003.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Correspondence

• Phase III Study of Letrozole Versus Tamoxifen As First-Line Therapy of Advanced Breast Cancer in Postmenopausal Women: Analysis of Survival and Update of Efficacy From the International Letrozole Breast Cancer Group
  Aman U. Buzdar
  JCO 2004 22: 3199-3200 [Full Text]

This article has been cited by other articles:

				E. D. Saad, A. Katz, P. M. Hoff, and M. Buyse Progression-free survival as surrogate and as true end point: insights from the breast and colorectal cancer literature Ann. Onc., November 9, 2009; (2009) mdp523v1. [Abstract] [Full Text] [PDF]

				E. Rossi, A. Morabito, F. Di Rella, G. Esposito, A. Gravina, V. Labonia, G. Landi, F. Nuzzo, C. Pacilio, E. De Maio, et al. Endocrine Effects of Adjuvant Letrozole Compared With Tamoxifen in Hormone-Responsive Postmenopausal Patients With Early Breast Cancer: The HOBOE Trial J. Clin. Oncol., July 1, 2009; 27(19): 3192 - 3197. [Abstract] [Full Text] [PDF]

				A. Giobbie-Hurder, K. N Price, and R. D Gelber Design, conduct, and analyses of Breast International Group (BIG) 1-98: A randomized, double-blind, phase-III study comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive, early breast cancer Clinical Trials, June 1, 2009; 6(3): 272 - 287. [Abstract] [PDF]

				K. Azuma, T. Urano, K. Horie-Inoue, S.-i. Hayashi, R. Sakai, Y. Ouchi, and S. Inoue Association of Estrogen Receptor {alpha} and Histone Deacetylase 6 Causes Rapid Deacetylation of Tubulin in Breast Cancer Cells Cancer Res., April 1, 2009; 69(7): 2935 - 2940. [Abstract] [Full Text] [PDF]

				E. D. Saad and A. Katz Progression-free survival and time to progression as primary end points in advanced breast cancer: often used, sometimes loosely defined Ann. Onc., March 1, 2009; 20(3): 460 - 464. [Abstract] [Full Text] [PDF]

				R. J. Paridaens, L. Y. Dirix, L. V. Beex, M. Nooij, D. A. Cameron, T. Cufer, M. J. Piccart, J. Bogaerts, and P. Therasse Phase III Study Comparing Exemestane With Tamoxifen As First-Line Hormonal Treatment of Metastatic Breast Cancer in Postmenopausal Women: The European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group J. Clin. Oncol., October 20, 2008; 26(30): 4883 - 4890. [Abstract] [Full Text] [PDF]

				Q. S.C. Chu, M. E. Cianfrocca, L. J. Goldstein, M. Gale, N. Murray, J. Loftiss, N. Arya, K. M. Koch, L. Pandite, R. A. Fleming, et al. A Phase I and Pharmacokinetic Study of Lapatinib in Combination with Letrozole in Patients with Advanced Cancer Clin. Cancer Res., July 15, 2008; 14(14): 4484 - 4490. [Abstract] [Full Text] [PDF]

				P. E. Goss, J. N. Ingle, J. L. Pater, S. Martino, N. J. Robert, H. B. Muss, M. J. Piccart, M. Castiglione, L. E. Shepherd, K. I. Pritchard, et al. Late Extended Adjuvant Treatment With Letrozole Improves Outcome in Women With Early-Stage Breast Cancer Who Complete 5 Years of Tamoxifen J. Clin. Oncol., April 20, 2008; 26(12): 1948 - 1955. [Abstract] [Full Text] [PDF]

				D. Crivellari, Z. Sun, A. S. Coates, K. N. Price, B. Thurlimann, H. Mouridsen, L. Mauriac, J. F. Forbes, R. J. Paridaens, M. Castiglione-Gertsch, et al. Letrozole Compared With Tamoxifen for Elderly Patients With Endocrine-Responsive Early Breast Cancer: The BIG 1-98 Trial J. Clin. Oncol., April 20, 2008; 26(12): 1972 - 1979. [Abstract] [Full Text] [PDF]

				S. Chia, W. Gradishar, L. Mauriac, J. Bines, F. Amant, M. Federico, L. Fein, G. Romieu, A. Buzdar, J. F.R. Robertson, et al. Double-Blind, Randomized Placebo Controlled Trial of Fulvestrant Compared With Exemestane After Prior Nonsteroidal Aromatase Inhibitor Therapy in Postmenopausal Women With Hormone Receptor-Positive, Advanced Breast Cancer: Results From EFECT J. Clin. Oncol., April 1, 2008; 26(10): 1664 - 1670. [Abstract] [Full Text] [PDF]

				M. Trinkaus, S. Chin, W. Wolfman, C. Simmons, and M. Clemons Should Urogenital Atrophy in Breast Cancer Survivors Be Treated with Topical Estrogens? Oncologist, March 1, 2008; 13(3): 222 - 231. [Abstract] [Full Text] [PDF]

				R. E. Greene and V. Tsang Hormonal Therapy for the Treatment of Postmenopausal Breast Cancer Patients Journal of Pharmacy Practice, February 1, 2008; 21(1): 36 - 45. [Abstract] [PDF]

				R. Colomer, M. Monzo, I. Tusquets, J. Rifa, J. M. Baena, A. Barnadas, L. Calvo, F. Carabantes, C. Crespo, M. Munoz, et al. A Single-Nucleotide Polymorphism in the Aromatase Gene Is Associated with the Efficacy of the Aromatase Inhibitor Letrozole in Advanced Breast Carcinoma Clin. Cancer Res., February 1, 2008; 14(3): 811 - 816. [Abstract] [Full Text] [PDF]

				M. Crump, S. Gluck, D. Tu, D. Stewart, M. Levine, P. Kirkbride, J. Dancey, S. O'Reilly, T. Shore, S. Couban, et al. Randomized Trial of High-Dose Chemotherapy With Autologous Peripheral-Blood Stem-Cell Support Compared With Standard-Dose Chemotherapy in Women With Metastatic Breast Cancer: NCIC MA.16 J. Clin. Oncol., January 1, 2008; 26(1): 37 - 43. [Abstract] [Full Text] [PDF]

				H. S. Rugo The breast cancer continuum in hormone-receptor positive breast cancer in postmenopausal women: evolving management options focusing on aromatase inhibitors Ann. Onc., January 1, 2008; 19(1): 16 - 27. [Abstract] [Full Text] [PDF]

				P. Goss, I. N. Bondarenko, G. N. Manikhas, K. B. Pendergrass, W. H. Miller Jr, P. Langecker, and D. Blanchett Phase III, Double-Blind, Controlled Trial of Atamestane Plus Toremifene Compared With Letrozole in Postmenopausal Women With Advanced Receptor-Positive Breast Cancer J. Clin. Oncol., November 1, 2007; 25(31): 4961 - 4966. [Abstract] [Full Text] [PDF]

				S Dawood and M Cristofanilli Endocrine resistance in breast cancer: what really matters? Ann. Onc., August 1, 2007; 18(8): 1289 - 1291. [Full Text] [PDF]

				P. E. Goss, J. N. Ingle, S. Martino, N. J. Robert, H. B. Muss, M. J. Piccart, M. Castiglione, D. Tu, L. E. Shepherd, K. I. Pritchard, et al. Efficacy of Letrozole Extended Adjuvant Therapy According to Estrogen Receptor and Progesterone Receptor Status of the Primary Tumor: National Cancer Institute of Canada Clinical Trials Group MA.17 J. Clin. Oncol., May 20, 2007; 25(15): 2006 - 2011. [Abstract] [Full Text] [PDF]

				D. Crivellari, M. Aapro, R. Leonard, G. von Minckwitz, E. Brain, A. Goldhirsch, A. Veronesi, and H. Muss Breast Cancer in the Elderly J. Clin. Oncol., May 10, 2007; 25(14): 1882 - 1890. [Abstract] [Full Text] [PDF]

				G. Sabnis, O. Goloubeva, D. Jelovac, A. Schayowitz, and A. Brodie Inhibition of the Phosphatidylinositol 3-Kinase/Akt Pathway Improves Response of Long-term Estrogen-Deprived Breast Cancer Xenografts to Antiestrogens Clin. Cancer Res., May 1, 2007; 13(9): 2751 - 2757. [Abstract] [Full Text] [PDF]

				M. Colozza, E. de Azambuja, N. Personeni, F. Lebrun, M. J. Piccart, and F. Cardoso Achievements in Systemic Therapies in the Pregenomic Era in Metastatic Breast Cancer Oncologist, March 1, 2007; 12(3): 253 - 270. [Abstract] [Full Text] [PDF]

				S Beslija, J Bonneterre, H Burstein, V Cocquyt, M Gnant, P Goodwin, V Heinemann, J Jassem, W. Kostler, M Krainer, et al. Second consensus on medical treatment of metastatic breast cancer Ann. Onc., February 1, 2007; 18(2): 215 - 225. [Abstract] [Full Text] [PDF]

				A. J. Chien and P. E. Goss Aromatase Inhibitors and Bone Health in Women With Breast Cancer J. Clin. Oncol., November 20, 2006; 24(33): 5305 - 5312. [Full Text] [PDF]

				K. Oktay, A. Hourvitz, G. Sahin, O. Oktem, B. Safro, A. Cil, and H. Bang Letrozole Reduces Estrogen and Gonadotropin Exposure in Women with Breast Cancer Undergoing Ovarian Stimulation before Chemotherapy J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 3885 - 3890. [Abstract] [Full Text] [PDF]

				A. Howell Pure oestrogen antagonists for the treatment of advanced breast cancer. Endocr. Relat. Cancer, September 1, 2006; 13(3): 689 - 706. [Abstract] [Full Text] [PDF]

				A. U Buzdar and J. F. Robertson Fulvestrant: Pharmacologic Profile Versus Existing Endocrine Agents for the Treatment of Breast Cancer Ann. Pharmacother., September 1, 2006; 40(9): 1572 - 1582. [Abstract] [Full Text] [PDF]

				F Labrie Future perspectives of selective estrogen receptor modulators used alone and in combination with DHEA. Endocr. Relat. Cancer, June 1, 2006; 13(2): 335 - 355. [Abstract] [Full Text] [PDF]

				K. Altundag and N. K. Ibrahim Aromatase inhibitors in breast cancer: an overview. Oncologist, June 1, 2006; 11(6): 553 - 562. [Abstract] [Full Text] [PDF]

				M. Sonmezer and K. Oktay Fertility preservation in young women undergoing breast cancer therapy. Oncologist, May 1, 2006; 11(5): 422 - 434. [Abstract] [Full Text] [PDF]

				S. E. Come A 62-Year-Old Woman With a New Diagnosis of Breast Cancer JAMA, March 22, 2006; 295(12): 1434 - 1442. [Full Text] [PDF]

				I. Vergote and P. Abram Fulvestrant, a new treatment option for advanced breast cancer: tolerability versus existing agents Ann. Onc., February 1, 2006; 17(2): 200 - 204. [Abstract] [Full Text] [PDF]

				The Breast International Group (BIG) 1-98 Collabor A Comparison of Letrozole and Tamoxifen in Postmenopausal Women with Early Breast Cancer N. Engl. J. Med., December 29, 2005; 353(26): 2747 - 2757. [Abstract] [Full Text] [PDF]

				N. Normanno, M. Di Maio, E. De Maio, A. De Luca, A. de Matteis, A. Giordano, F. Perrone, and on behalf of the NCI-Naples Breast Cancer Group Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer Endocr. Relat. Cancer, December 1, 2005; 12(4): 721 - 747. [Abstract] [Full Text] [PDF]

				F Labrie, V Luu-The, A Belanger, S-X Lin, J Simard, G Pelletier, and C Labrie Is dehydroepiandrosterone a hormone? J. Endocrinol., November 1, 2005; 187(2): 169 - 196. [Abstract] [Full Text] [PDF]

				G A Clines and T A Guise Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone Endocr. Relat. Cancer, September 1, 2005; 12(3): 549 - 583. [Abstract] [Full Text] [PDF]

				W. Irish, B. Sherrill, B. Cole, C. Gard, G. A. Glendenning, and H. Mouridsen Quality-adjusted survival in a crossover trial of letrozole versus tamoxifen in postmenopausal women with advanced breast cancer Ann. Onc., September 1, 2005; 16(9): 1458 - 1462. [Abstract] [Full Text] [PDF]

				P. E. Lonning, J. Geisler, L. E. Krag, B. Erikstein, Y. Bremnes, A. I. Hagen, E. Schlichting, E. A. Lien, E. S. Ofjord, J. Paolini, et al. Effects of Exemestane Administered for 2 Years Versus Placebo on Bone Mineral Density, Bone Biomarkers, and Plasma Lipids in Patients With Surgically Resected Early Breast Cancer J. Clin. Oncol., August 1, 2005; 23(22): 5126 - 5137. [Abstract] [Full Text] [PDF]

				A. Boulay, J. Rudloff, J. Ye, S. Zumstein-Mecker, T. O'Reilly, D. B. Evans, S. Chen, and H. A. Lane Dual Inhibition of mTOR and Estrogen Receptor Signaling In vitro Induces Cell Death in Models of Breast Cancer Clin. Cancer Res., July 15, 2005; 11(14): 5319 - 5328. [Abstract] [Full Text] [PDF]

				K. Oktay, E. Buyuk, N. Libertella, M. Akar, and Z. Rosenwaks Fertility Preservation in Breast Cancer Patients: A Prospective Controlled Comparison of Ovarian Stimulation With Tamoxifen and Letrozole for Embryo Cryopreservation J. Clin. Oncol., July 1, 2005; 23(19): 4347 - 4353. [Abstract] [Full Text] [PDF]

				A. Howell and A. M Wardley Overview of the impact of conventional systemic therapies on breast cancer Endocr. Relat. Cancer, July 1, 2005; 12(Supplement_1): S9 - S16. [Abstract] [Full Text] [PDF]

				D. Jelovac, G. Sabnis, B. J. Long, L. Macedo, O. G. Goloubeva, and A. M.H. Brodie Activation of Mitogen-Activated Protein Kinase in Xenografts and Cells during Prolonged Treatment with Aromatase Inhibitor Letrozole Cancer Res., June 15, 2005; 65(12): 5380 - 5389. [Abstract] [Full Text] [PDF]

				D. Jelovac, L. Macedo, O. G. Goloubeva, V. Handratta, and A. M.H. Brodie Additive Antitumor Effect of Aromatase Inhibitor Letrozole and Antiestrogen Fulvestrant in a Postmenopausal Breast Cancer Model Cancer Res., June 15, 2005; 65(12): 5439 - 5444. [Abstract] [Full Text] [PDF]

				R. Kudachadkar and R. M. O'Regan Aromatase Inhibitors as Adjuvant Therapy for Postmenopausal Patients With Early Stage Breast Cancer CA Cancer J Clin, May 1, 2005; 55(3): 145 - 163. [Abstract] [Full Text] [PDF]

				M. Cristofanilli, D. F. Hayes, G. T. Budd, M. J. Ellis, A. Stopeck, J. M. Reuben, G. V. Doyle, J. Matera, W. J. Allard, M. C. Miller, et al. Circulating Tumor Cells: A Novel Prognostic Factor for Newly Diagnosed Metastatic Breast Cancer J. Clin. Oncol., March 1, 2005; 23(7): 1420 - 1430. [Abstract] [Full Text] [PDF]

				P. E. Lonning Exemestane for Breast Cancer Prevention: A Feasible Strategy? Clin. Cancer Res., January 15, 2005; 11(2): 918s - 924s. [Abstract] [Full Text] [PDF]

				Y. Yamamoto, J. Shibata, K. Yonekura, K. Sato, A. Hashimoto, Y. Aoyagi, K. Wierzba, S. Yano, T. Asao, A. U. Buzdar, et al. TAS-108, a Novel Oral Steroidal Antiestrogenic Agent, Is a Pure Antagonist on Estrogen Receptor {alpha} and a Partial Agonist on Estrogen Receptor {beta} with Low Uterotrophic Effect Clin. Cancer Res., January 1, 2005; 11(1): 315 - 322. [Abstract] [Full Text] [PDF]

				D. Jelovac, L. Macedo, V. Handratta, B. J. Long, O. G. Goloubeva, J. N. Ingle, and A. M. H. Brodie Effects of Exemestane and Tamoxifen in a Postmenopausal Breast Cancer Model Clin. Cancer Res., November 1, 2004; 10(21): 7375 - 7381. [Abstract] [Full Text] [PDF]

				C. Bernard-Marty, F. Cardoso, and M. J. Piccart Facts and Controversies in Systemic Treatment of Metastatic Breast Cancer Oncologist, November 1, 2004; 9(6): 617 - 632. [Abstract] [Full Text] [PDF]

				H. Mouridsen, Y. Sun, M. Gershanovich, R. Perez-Carrion, D. Becquart, H.A. Chaudri-Ross, and R. Lang Superiority of Letrozole to Tamoxifen in the First-Line Treatment of Advanced Breast Cancer: Evidence from Metastatic Subgroups and a Test of Functional Ability Oncologist, September 1, 2004; 9(5): 489 - 496. [Abstract] [Full Text] [PDF]

				H. Mouridsen and H.A. Chaudri-Ross Efficacy of First-Line Letrozole Versus Tamoxifen as a Function of Age in Postmenopausal Women with Advanced Breast Cancer Oncologist, September 1, 2004; 9(5): 497 - 506. [Abstract] [Full Text] [PDF]

				L. J. Blakely, A. Buzdar, H.-Y. Chang, D. Frye, R. Theriault, V. Valero, E. Rivera, D. Booser, J. Kuritani, and M. Tsuda A Phase I and Pharmacokinetic Study of TAS-108 in Postmenopausal Female Patients with Locally Advanced, Locally Recurrent Inoperable, or Progressive Metastatic Breast Cancer Clin. Cancer Res., August 15, 2004; 10(16): 5425 - 5431. [Abstract] [Full Text] [PDF]

				A. U. Buzdar Phase III Study of Letrozole Versus Tamoxifen As First-Line Therapy of Advanced Breast Cancer in Postmenopausal Women: Analysis of Survival and Update of Efficacy From the International Letrozole Breast Cancer Group J. Clin. Oncol., August 1, 2004; 22(15): 3199 - 3200. [Full Text] [PDF]

				H. Mouridsen and H. A. Chaudri-Ross In Reply: J. Clin. Oncol., August 1, 2004; 22(15): 3200 - 3201. [Full Text] [PDF]

				V. T. Gaddy, J. T. Barrett, J. N. Delk, A. M. Kallab, A. G. Porter, and P. V. Schoenlein Mifepristone Induces Growth Arrest, Caspase Activation, and Apoptosis of Estrogen Receptor-Expressing, Antiestrogen-Resistant Breast Cancer Cells Clin. Cancer Res., August 1, 2004; 10(15): 5215 - 5225. [Abstract] [Full Text] [PDF]

				M. Sonmezer and K. Oktay Fertility preservation in female patients Hum. Reprod. Update, May 1, 2004; 10(3): 251 - 266. [Abstract] [Full Text] [PDF]

				A. Howell, J. F.R. Robertson, P. Abram, M. R. Lichinitser, R. Elledge, E. Bajetta, T. Watanabe, C. Morris, A. Webster, I. Dimery, et al. Comparison of Fulvestrant Versus Tamoxifen for the Treatment of Advanced Breast Cancer in Postmenopausal Women Previously Untreated With Endocrine Therapy: A Multinational, Double-Blind, Randomized Trial J. Clin. Oncol., May 1, 2004; 22(9): 1605 - 1613. [Abstract] [Full Text] [PDF]

				E. R. Kisanga, J. Gjerde, A. Guerrieri-Gonzaga, F. Pigatto, A. Pesci-Feltri, C. Robertson, D. Serrano, G. Pelosi, A. Decensi, and E. A. Lien Tamoxifen and Metabolite Concentrations in Serum and Breast Cancer Tissue during Three Dose Regimens in a Randomized Preoperative Trial Clin. Cancer Res., April 1, 2004; 10(7): 2336 - 2343. [Abstract] [Full Text] [PDF]

				B. J. Long, D. Jelovac, V. Handratta, A. Thiantanawat, N. MacPherson, J. Ragaz, O. G. Goloubeva, and A. M. Brodie Therapeutic Strategies Using the Aromatase Inhibitor Letrozole and Tamoxifen in a Breast Cancer Model J Natl Cancer Inst, March 17, 2004; 96(6): 456 - 465. [Abstract] [Full Text] [PDF]

				J. Karnon, S. R. D. Johnston, T. Jones, and A. Glendenning A trial-based cost-effectiveness analysis of letrozole followed by tamoxifen versus tamoxifen followed by letrozole for postmenopausal advanced breast cancer Ann. Onc., November 1, 2003; 14(11): 1629 - 1633. [Abstract] [Full Text] [PDF]

				Should aromatase inhibitors replace tamoxifen? DTB, August 1, 2003; 41(8): 57 - 59. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mouridsen, H. Articles by Bhatnagar, A. Search for Related Content PubMed PubMed Citation Articles by Mouridsen, H. Articles by Bhatnagar, A. Related Articles Related Correspondence Social Bookmarking                            What's this?