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The Oncologist, Vol. 9, No. 5, 497-506, September 2004; doi:10.1634/theoncologist.9-5-497
© 2004 AlphaMed Press

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Efficacy of First-Line Letrozole Versus Tamoxifen as a Function of Age in Postmenopausal Women with Advanced Breast Cancer

H. Mouridsena, H.A. Chaudri-Rossb

a Rigshospitalet, Copenhagen, Denmark; b Novartis Pharma AG, Basel, Switzerland

Correspondence: Hilary A. Chaudri-Ross, M.A., DEP, Novartis Pharma AG, WKL-490.1.04, CH-4057 Basel, Switzerland. Telephone: 41-61-696-1758; Fax: 41-61-696-1820; e-mail: hilary_anne.chaudri{at}pharma.novartis.com


   LEARNING OBJECTIVES
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 Learning Objectives
Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
After completing this course, the reader will be able to:

  1. Identify those patients in both age groups who responded most favorably to first-line therapy with letrozole.
  2. Describe the advantages of first-line treatment with letrozole in older patients with advanced breast cancer.
  3. Discuss the role of first-line therapy with letrozole in the management of advanced breast cancer.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
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 Learning Objectives
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Purpose. To compare the efficacy, in regard to time to progression (TTP) and objective response rate (ORR), of letrozole (Femara®; Novartis Pharma AG; Basel Switzerland), an oral aromatase inhibitor, with that of tamoxifen (Tamofen®; Leiras OY; Turku, Finland) as first-line therapy in younger (<70 years) and older (≥70 years) postmenopausal women with advanced breast cancer.

Materials and Methods. Nine hundred seven patients with advanced breast cancer were randomly assigned to receive 2.5 mg letrozole (n = 453) or 20 mg tamoxifen (n = 454) once daily in a double-blind, multicenter, international trial. Among the prospectively planned analyses were analyses of TTP and ORR by age (<70 and ≥70 years). The results of these prospectively planned analyses are reported here.

Results. Letrozole was as effective in older postmenopausal women (≥70 years of age) as it was in younger postmenopausal women (<70 years of age). The overall ORR in the older subgroup was significantly higher in patients treated with letrozole (38%) than in patients treated with tamoxifen (18%). In the younger subgroup of postmenopausal patients, the ORRs were not significantly different (letrozole, 26%; tamoxifen, 22%). TTP was significantly longer for letrozole than for tamoxifen in both age groups (younger: letrozole median TTP, 8.8 months; tamoxifen, 6.0 months; older: letrozole median TTP, 12.2 months; tamoxifen, 5.8 months). Although age was independently prognostic of TTP, there was no significant effect of age on ORR in the presence of other factors.

Conclusion. The data show that letrozole, 2.5 mg once daily, is as effective in older, postmenopausal women as it is in younger postmenopausal women with advanced breast cancer. In addition, letrozole was more effective than tamoxifen in both younger and older patients.

Key Words. Letrozole • Tamoxifen • Advanced breast cancer • Elderly • Aromatase inhibitors


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Breast cancer is a common problem in older women. Presently, 48% of breast cancer cases occur in elderly women (aged 65 years and older) [1], and it is the most common cause of cancer death in women of that age group [2]. Demographic changes in the growing age segment of our population are dramatic: with the aging of the general population, the association between cancer and aging has become more evident and paramount as a pandemic public health concern. As such, formidable increases in the incidence and prevalence of breast cancer can be expected in the coming decades if the older population continues to expand at the present rate [1].

Eighty percent of breast tumors occurring in women aged 70 and older are rich in hormone receptors, while the remaining 20% of women have aggressive tumors that have few hormone receptors [3, 4]. Knowledge of the steroid receptor content of human breast cancer is important for deciding the proper treatment for advanced breast cancer.

Endocrine therapy is the established treatment in women with hormone-sensitive tumors, as manifested by positive receptor status, a long disease-free interval, and primarily soft tissue disease. Tamoxifen (Nolvadex®; AstraZeneca Pharmaceuticals; Wilmington, DE), a synthetic antiestrogen with agonistic and antagonistic properties, has been firmly established as first-line endocrine treatment in postmenopausal women for over 20 years [2]. However, recent studies have found third-generation aromatase inhibitors to be more effective than [5], or at least as effective as, tamoxifen [6, 7] in the first-line treatment of advanced breast cancer. These drugs are very selective and potent in the suppression of aromatase activity [8].

There is a paucity of data from clinical trials in elderly women. This paper reports on a subgroup analysis by age (<70 years or ≥70 years) of postmenopausal women with advanced breast cancer who received either first-line letrozole (Femara®; Novartis Pharmaceuticals Corporation; East Hanover, NJ) at a dose of 2.5 mg once daily or tamoxifen (20 mg once daily) in a previously reported phase III study [5].


   MATERIALS AND METHODS
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 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Patients
Postmenopausal women with histologically or cytologically confirmed metastatic breast cancer, locally advanced disease (stage IIIB by the American Joint Committee on Cancer criteria, 1992), or locoregionally recurrent disease not amenable to surgery were eligible for the study.

Patients were required to have tumors with estrogen receptor (ER)- and/or progesterone receptor (PgR)-positive status, or with the status of both receptors unknown. Patients were regarded as ER or PgR positive if any assay of primary or secondary tumor tissue was positive. Patients were regarded as receptor unknown, if no assays were known to be positive or negative.

Patients who had received one regimen of chemotherapy for advanced disease were eligible. Prior adjuvant endocrine therapy was allowed provided it was discontinued at least 12 months prior to entry in the study. Patients also had to have a Karnofsky Performance Status (KPS) score of at least 50 (World Health Organization grade 0–2).

Important exclusion criteria included: rapidly progressing disease (such as that with central nervous system involvement), diffuse lymphangitis carcinomatosa of the lung, hepatic metastases that involved more than one-third of the liver, inflammatory breast cancer, concurrent or previous malignant diseases (other than contralateral breast cancer, in situ carcinoma of the cervix treated by cone biopsy, or adequately treated squamous or basal cell skin carcinoma), uncontrolled diabetes mellitus, or cardiac disease.

Adjuvant endocrine therapy other than antiestrogens, previous systemic endocrine therapy for advanced disease, topical investigational drugs within the past 7 days, and systemic investigational therapy within the past 30 days, were not allowed. Prolonged systemic corticosteroid treatment and concomitant anticancer treatment, except for radiotherapy or surgery to areas other than the sole site of disease, were also not permitted during the trial.

Bisphosphonate treatment for the prevention of bone metastases and chronic concomitant bisphosphonate therapy for hypercalcemia were not permitted. Bisphosphonate therapy started at the time of randomization or before, or at the start of crossover therapy, was allowed for treatment of bone metastases.

All patients gave written informed consent to take part in the study, which was approved by the appropriate local ethics board. The study was conducted according to the requirements of Good Clinical Practice, and the ethical principles originated in the Declaration of Helsinki.

Study Design
This randomized, double-blind, parallel group study was conducted in 201 centers in 29 countries. Once-daily letrozole (2.5 mg) and tamoxifen (20 mg) were randomly assigned according to a predetermined randomization list. Treatments were randomized using permuted blocks of a fixed size such that both treatments were assigned equally often within each block. The double-dummy technique was used to maintain blindness (placebo tablets matching tamoxifen dispensed with letrozole and placebo tablets matching letrozole dispensed with tamoxifen). Treatment codes could be unblinded in an emergency only for individual patients. Patients were seen for physical examinations and tumor evaluations before the start of trial treatment and every 3 months during the trial. Superficial or palpable lesions were measured, and performance status scores and adverse events were recorded at each visit. Bone scans and, if positive, skeletal surveys, liver ultrasonograms, or computerized tomography scans were performed at baseline and repeated at each visit for involved sites.

The primary efficacy end point was time to progression (TTP), defined as the interval between the date of randomization and the earliest date of documented disease progression. A secondary end point was objective response rate (ORR). Tumor assessments were conducted at 3-month intervals. On progression, patients could be switched to the opposite treatment at the investigator’s discretion if they remained suitable for further endocrine therapy.

Statistical Methodology
TTP was estimated by the Kaplan-Meier product-limit method. Within each age group (<70 or ≥70 years), treatments were compared by a Cox proportional hazards model for TTP and a logistic regression model for ORR. Age-adjusted treatment comparisons were performed to obtain estimates of overall treatment effects (Cox model for TTP, Cochrane-Mantel-Haenszel test for ORR). Multivariate analyses of TTP and ORR were conducted to estimate the effects of other baseline covariates of interest (receptor status, adjuvant antiestrogen therapy, liver metastasis, bone metastasis, chemotherapy for advanced disease, KPS score, disease-free interval (DFI), number of metastatic lesions, number of anatomic sites involved, and geographic region)—Cox model for TTP and logistic model for ORR, with all covariates fitted at the same time.

In a subset of patients with baseline serum marker measurements, multivariate analyses were conducted by applying the same methodology on a restricted set of baseline covariates (human epidermal growth factor receptor [HER]-2 status, treatment, and age).


   RESULTS
Top
 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Patients
The demographic characteristics within each age group between the two treatment arms were well balanced. The median age for patients younger than 70 years was 60 years for patients on letrozole and 59 years for those on tamoxifen; the median age for patients 70 years old and older was 75 years for both treatment groups (Table 1Go). Also, between the age groups, the general demographic balance was fairly good, with exceptions in regard to history of chemotherapy and the presence of metastatic disease: fewer elderly patients received chemotherapy for both adjuvant and advanced disease, and there was a greater tendency for elderly patients to present with stage IV disease (Table 1Go).


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  		Table 1. Demographic and patient characteristics
 
The body mass index ([BMI], expressed as kg/m2) range among the four subsets of patients was within 1 kg/m2 (Table 1Go). BMI values were missing for a total of 29 patients (15 who were younger than 70 and 14 who were 70 or older) because of a missing height and/or weight. A BMI of 30 kg/m2 or above is conventionally considered obese. There was no significant difference at baseline in the distributions of BMI between the two age groups (Table 2Go).


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  		Table 2. Baseline distribution of BMI
 
In total, 548 patients had baseline measurements of serum markers (HER-2, carcinoembryonic antigen [CEA], and the breast cancer-associated antigen CA15-3). Additional analyses were performed in this population, stratifying by age (<70 years or ≥70 years), treatment, and HER-2 expression (normal versus elevated, with 15 ng/ml as the cut off). In patients aged less than 70 years, the difference between treatment arms in the distribution of HER-2 elevation was of borderline significance, favoring tamoxifen (more HER-2– tumors). The situation was reversed in patients aged 70 years and older, favoring letrozole (Table 3Go).


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  		Table 3. Distribution of HER-2+ tumors by age and treatment
 
Similar proportions of the two patient groups (62% of letrozole patients, 61% of tamoxifen patients) had baseline determinations of serum HER-2 (Table 3Go). Fewer elderly patients on letrozole (20%) had HER-2+ tumors than elderly patients taking tamoxifen (32%). Women less than 70 years of age taking tamoxifen were less likely (26%) to have HER-2+ tumors than their counterparts assigned letrozole (37%).

In the subset of patients with baseline serum marker measurements, there was no significant difference between treatment arms or between HER-2 status in prior adjuvant antiestrogen treatment, soft tissue only disease, or liver metastases. In patients ≥70 years of age, there was no significant difference in receptor status. There was a significant difference in receptor status in patients younger than 70 years with more HER-2+ tumors in the tamoxifen arm (favorable receptor status) (Table 4Go).


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  		Table 4. Disease characteristics
 
Time to Progression
In both age groups, TTP was significantly longer in patients who had been treated with letrozole than in those treated with tamoxifen. In patients younger than 70, the median TTP in patients treated with letrozole was 8.8 months, compared with a median of 6.0 months in those treated with tamoxifen, with a corresponding lower risk for progression (hazard ratio, 0.81; 95% confidence interval [CI] = 0.67–0.97; p = 0.0233) (Table 5Go, Fig. 1AGo). In patients aged 70 or older, the median TTP was 12.2 months in patients who received letrozole and 5.8 months in the tamoxifen-treated patients, also with a correspondingly lower risk for progression (hazard ratio, 0.54; 95% CI = 0.41–0.72; p = 0.0001) (Table 5Go, Fig. 1BGo). Although age had a significant effect on TTP, the treatment comparison barely changed in the age-adjusted analysis (hazard ratio, 0.73; 95% CI = 0.63–0.84; p < 0.0001).


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  		Table 5. Analysis of TTP and ORR by age
 


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  		Figure 1. A) Patients >70 years at enrollment. Letrozole: 242 (80%) of 301 patients progressed. Median TTP 8.8 months (95% CI 6.2–9.5 months). Tamoxifen: 274 (88%) of 311 patients progressed. Median TTP 6.0 months (95% CI 5.7–6.8 months). Hazard ratio letrozole to placebo: 0.79; 95% CI 0.66–0.94; p = 0.007. B) Patients ≥70 years at enrollment. Letrozole: 117 (77%) of 152 patients progressed. Median TTP 12.1 months (95% CI 10.4–15.4 months). Tamoxifen: 113 (79%) of 143 patients progressed. Median TTP 5.8 months (95% CI 3.3–8.5 months). Hazard ratio: 0.61; 95% CI 0.47–0.79; p = 0.002.

 
In the subset of patients with baseline serum marker measurements, age had no significant influence on TTP after consideration of treatment and HER-2 expression level. Both the latter factors independently significantly affected TTP—patients treated with letrozole had a lower risk for progression than those treated with tamoxifen, and patients with elevated HER-2 levels had a greater risk for progression than those with normal HER-2 levels (Table 6Go, Fig. 2Go).


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  		Table 6. Time to progression and HER-2 status
 


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  		Figure 2. A) Patients >70 years at enrollment, serum HER-2–. Letrozole: 87 (76%) of 114 patients progressed. Median TTP 9.7 months (95% CI 7.8–14.4 months). Tamoxifen: 131 (87%) of 150 patients progressed. Median TTP 9.0 months (95% CI 6.2–10.7 months). B) Patients <70 years at enrollment, serum HER-2+. Letrozole: 56 (90%) of 62 patients progressed. Median TTP 6.0 months (95% CI 3.7–7.4 months). Tamoxifen: 50 (96%) of 52 patients progressed. Median TTP 3.2 months (95% CI 3.0–6.3 months). C) Patients ≥70 years at enrollment, serum HER-2–. Letrozole: 58 (73%) of 80 patients progressed. Median TTP 15.5 months (95% CI 11.7–21.5 months). Tamoxifen: 38 (76%) of 50 patients progressed. Median TTP 5.1 months (95% CI 3.1–9.2 months). D) Patients ≥70 years at enrollment, serum HER-2+. Letrozole: 15 (88%) of 17 patients progressed. Median TTP 8.9 months (95% CI 3.1–17.5 months). Tamoxifen: 20 (87%) of 23 patients progressed. Median TTP 3.3 months (95% CI 2.9–8.5 months).

 
Overall Objective Response Rate
The ORR (complete response [CR] + partial response [PR]) rate was more than twice as high in the elderly patients who received letrozole (38%) than in those who received tamoxifen (18%). This was statistically significant (odds ratio, 2.91; 95% CI = 1.69–5.01; p < 0.0001). In patients younger than 70, the difference in response between treatment groups was not statistically significant (letrozole, 26%; tamoxifen, 22%), although there was a trend in favor of letrozole (odds ratio, 1.30; 95% CI = 0.89–1.88; p = 0.1729) (Table 5Go). Overall, age had no significant influence on the odds of response, and the age-adjusted treatment comparison barely changed (odds ratio, 1.77; 95% CI = 1.31–2.39; p = 0.0002). The distribution of TTP by response and treatment according to age is presented in Figure 3Go.



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  		Figure 3. Distribution of TTP by treatment and response according to age. A) Patients <70 years at enrollment. Letrozole: CR+PR 84 (28%) of 301 patients progressed. Tamoxifen: CR+PR 68 (22%) of 311 patients progressed. B) Patients ≥70 years at enrollment. Letrozole: CR+PR 61 (40%) of 152 patients progressed. Tamoxifen: CR+PR 27 (19%) of 143 patients progressed.

 
Multivariate Analyses
In the subset of patients with baseline serum marker measurements, age had no significant influence on response rate. Patients who were treated with letrozole had a significantly greater odds of response than those treated with tamoxifen, while patients with elevated HER-2 levels had a significantly lower odds of response than those with normal HER-2 levels (Table 7Go).


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  		Table 7. Objective response rate (CR + PR) and HER-2 status
 
The influence of baseline covariates other than age was examined for both TTP and ORR. For both variables, significant covariates were: treatment assignment (longer TTP/lower risk for progression and higher ORR with letrozole); liver metastasis (shorter TTP/higher risk for progression and lower ORR in presence of liver involvement); adjuvant antiestrogen therapy (shorter TTP/higher risk for progression and lower ORR if given); and KPS score of 90–100 (longer TTP/lower risk for progression and higher ORR than if KPS score was ≤80). As previously shown [9], geographic region had no significant effect on either TTP or ORR. Other covariates appeared to affect TTP but not ORR (e.g., longer TTP when DFI ≥2 years, when a single anatomic site of disease was involved, or when there were up to four metastatic lesions) and vice versa (e.g., lower ORR in presence of bone metastasis or when chemotherapy for advanced disease had been given). In the multivariate analyses, age group significantly affected TTP but not ORR, confirming other analyses.

In patients younger than 70, half the patients in each treatment arm switched to the opposite treatment on progression. There was no significant difference between treatments in this group in overall survival, with median survival being very similar for both treatment arms (33 months for the randomized letrozole arm, 32 months for the randomized tamoxifen arm). In patients aged 70 years or older, however, significantly more (59%) patients were able to switch from letrozole to tamoxifen than from tamoxifen to letrozole (48%) on progression. The difference in overall survival time between treatments in this group was of borderline significance (median survival: 36 months for the randomized letrozole arm, 28 months for the randomized tamoxifen arm, p = 0.0487).


   DISCUSSION
Top
 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
In this analysis of the Mouridsen et al. [5] data comparing the efficacy of letrozole with that of tamoxifen as a function of age, the results demonstrate that letrozole is effective in both elderly and younger patients and it provides antitumor efficacy that is superior to that of tamoxifen in both age groups.

The primary results and the final analysis of the overall study by Mouridsen et al. [5, 10] demonstrated the advantages of letrozole over tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women. The cut off date for the primary analysis was March 2000, with a follow-up of approximately 18 months. The cut off date for the final analysis was 18 months later, at a median follow-up of 32 months, with a total observation period up to 57 months. The final report confirmed the superiority of letrozole over tamoxifen for all previously reported end points, including TTP, time to treatment failure, ORR, and rate of overall clinical benefit. These mature data confirm that letrozole’s efficacy is superior to that of tamoxifen, which was maintained throughout the study, and, in this analysis by age, the reliability of letrozole’s beneficial effects was further reinforced, as letrozole outperformed tamoxifen in regard to TTP and ORR in both older and younger patients.

In both age groups, TTP was significantly longer in patients treated with letrozole, with the observed benefit more dramatic in patients ≥70 years. The median TTP in those patients taking letrozole was 12.2 months, versus a median TTP of 5.8 months for those patients assigned tamoxifen. In patients <70 years of age, the median TTP was 8.8 months with letrozole, versus 6.0 months with tamoxifen.

The most impressive demonstration of superiority for letrozole was observed in patients aged ≥70. The overall ORR in older patients was more than twice as high in patients who received letrozole (38%) than in those who received tamoxifen (18%), a statistically significant difference. In patients younger than 70, the difference between treatments in ORR was not statistically significant; however, letrozole was favored (26%) over tamoxifen (22%).

Overall survival times were similar in both treatment arms in patients younger than 70. In patients aged 70 years or older, median survival was significantly longer for those in the randomized letrozole arm than for those in the randomized tamoxifen arm.

The data show similar benefits with tamoxifen in patients <70 and ≥70 years of age for both TTP (6.0 versus 5.8 months) and ORR (22% versus 18%). Thus, the benefit with tamoxifen appeared to be independent of age, whereas TTP as well as ORR were significantly better in older patients treated with letrozole than in younger patients treated with letrozole. The reasons for these relationships cannot be attributed to differences in demographics or patient characteristics, as these were well balanced between treatment groups within each age group.

BMIs were similar in the two patient groups, and there were no significant relationships between TTP or ORR and BMI for either of the two treatment groups in patients younger than 70 or ≥70 years of age (data not shown).

A previous analysis of the subset of patients with baseline serum marker measurements, at a median follow-up of around 18 months, demonstrated that positive serum HER-2 status predicted a shorter TTP, higher risk of progression, and lower response rate [11]. In this subanalysis, in patients younger than 70 years, HER-2+ tumors were similarly distributed in the two treatment arms (35% for letrozole, 26% for tamoxifen). Independent of age, treatment and HER-2 expression significantly influenced TTP: compared with patients treated with tamoxifen, patients treated with letrozole had a significantly lower risk for progression, and patients with elevated HER-2 levels had a significantly greater risk for progression than those with normal HER-2 expression levels. However, patient age did not significantly affect TTP after consideration of treatment and HER-2 expression. Similarly, letrozole, again independent of age, significantly influenced ORR compared with tamoxifen, and patients with elevated HER-2 levels had a significantly lower response rate than those with normal HER-2 expression levels. However, after considering treatment and HER-2 expression, the age of patients did not significantly influence ORR. As HER-2+ tumors occurred more often in the tamoxifen arm (32%) than in the letrozole arm (18%) in patients aged 70 or older, the observed differences in distribution according to HER-2 status cannot explain the difference in efficacy with letrozole according to age.

In the multivariate analysis of the subset of patients with baseline serum marker measurements, updated at a median follow-up of 32 months [12], exactly the same baseline covariates as for the main study were prognostic for both TTP and ORR, with the addition of serum HER-2. The profile of a patient with a long TTP and with an objective response was that she should have a normal serum HER-2 level, no liver metastasis, a KPS score of at least 90, and be treated with letrozole; the effect of prior adjuvant antiestrogen therapy when followed by letrozole treatment for advanced disease appeared to be different from the effect of this variable when followed by treatment with tamoxifen for advanced disease. The median TTP for a profiled patient without prior adjuvant antiestrogen therapy was 14.4 months and, with prior adjuvant antiestrogen therapy, it was 21.4 months. For the "opposite" profile, that is, a patient with an elevated serum HER-2 level, with liver metastasis, and with a KPS score ≤80, treated with tamoxifen and having received prior adjuvant antiestrogen therapy, the median TTP was 2.9 months. It seems likely, therefore, that HER-2 status could have accounted for some of the treatment differences in elderly patients, given that, in the subset with baseline serum marker measurements, more elderly patients assigned to tamoxifen than assigned to letrozole had HER-2+ tumors.

In existing data, age has repeatedly been shown to have no significant effect on letrozole plasma trough levels [13] or on steady-state kinetics [14]. Further research to generate data on pharmacokinetics, pharmacodynamics, and molecular-biological characterization of tumors, including an analysis of aromatase activity, is needed to explain the phenomenon of potential age-related differences.


   CONCLUSION
Top
 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
This subanalysis by age indicates that the efficacy of letrozole as first-line endocrine therapy is superior to that of tamoxifen, regardless of age group. These findings are important, as differences in biological and clinical patterns of breast cancer in the elderly are not clearly defined, due to a paucity of data subsequent to the historical underenrollment of elderly patients in clinical trials. Age is an important determinant of the type of treatment selected for breast cancer patients, and these findings indicate that letrozole may be more effective than tamoxifen in treating both older and younger postmenopausal women with locally advanced or metastatic breast cancer who are candidates for hormonal therapy. The reliability of results established by the primary findings and final analysis of the overall study emphasize the consistently superior effects of first-line letrozole in patients with advanced breast cancer and, in the context of this subanalysis by age, the results demonstrate that letrozole is effective in both elderly and younger patients and provides superior antitumor efficacy, versus tamoxifen, in both age groups.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Supported by Novartis Pharma AG, Basel, Switzerland. Dr. Mouridsen has served as a consultant for Novartis Pharmaceuticals Corporation.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

  1. Yancik R, Ries LA. Aging and cancer in America: demographic and epidemiologic perspectives. Hematol Oncol Clin North Am 2000;14:17–23.[CrossRef][Medline]
  2. Kimmick GG, Balducci L. Breast cancer and aging: clinical interactions. Hematol Oncol Clin North Am 2000;14:213–234.[CrossRef][Medline]
  3. Alghanem AA, Hussain S. The effect of age on estrogen and progesterone receptor in primary breast cancer. J Surg Oncol 1985;30:29–32.[Medline]
  4. Elwood JM, Godolphin W. Oestrogen receptors in breast tumours: associations with age, menopausal status and epidemiological and clinical features in 735 patients. Br J Cancer 1980;42:635–644.[Medline]
  5. 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 Breast Cancer Group. J Clin Oncol 2001;19:2596–2606.[Abstract/Free Full Text]
  6. Bonneterre J, Thurlimann B, Robertson JF 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 2000;18:3748–3757.[Abstract/Free Full Text]
  7. Nabholtz JM, 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. Arimidex Study Group. J Clin Oncol 2000;18:3758–3767.[Abstract/Free Full Text]
  8. Ragaz J. Status of aromatase inhibitors in relation to other breast cancer treatment modalities. Endocr Relat Cancer 1999;6:277–291.[Abstract]
  9. Mouridsen H, Chaudri-Ross HA. Correspondence. J Clin Oncol 2002;20:877–8.
  10. Mouridsen H, Gershanovich M, Sun Y et al. 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 2003;21:2101–2109.[Abstract/Free Full Text]
  11. Lipton A, Mouridsen H, Ali S et al. Serum HER-2/neu and response to the aromatase inhibitor letrozole versus tamoxifen. Breast Cancer Res Treat 2001;69:210.
  12. Suhail A, Leitzel K, Demers L et al. Predictive factors and response to letrozole vs tamoxifen. Accepted for presentation at 25th San Antonio Breast Cancer Symposium, San Antonio, Dec 11–14, 2002.
  13. Data on file. Novartis Pharma AG, Basel, Switzerland.
  14. Pfister CU, Martoni A, Zamagni C et al. Effect of age and single versus multiple dose pharmacokinetics of letrozole (Femara) in breast cancer patients. Biopharm Drug Dispos 2001;22:191–197.[CrossRef][Medline]
Received December 2, 2002; accepted for publication March 23, 2004.




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