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The Oncologist, Vol. 9, No. 5, 489-496, September 2004; doi:10.1634/theoncologist.9-5-489
© 2004 AlphaMed Press

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Superiority of Letrozole to Tamoxifen in the First-Line Treatment of Advanced Breast Cancer: Evidence from Metastatic Subgroups and a Test of Functional Ability

H. Mouridsena, Y. Sunb, M. Gershanovichc, R. Perez-Carriond, D. Becquarte, H.A. Chaudri-Rossf, R. Langf

a Rigshospitalet, Copenhagen, Denmark; b Chinese Academy of Medical Sciences, Beijing, China; c Petrov Research Institute, St. Petersburg, Russia; d Hospital Universitario de la Princesa, Madrid, Spain; e Z.A. Middelheim, Antwerpen, Belgium; f 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
Top
 Learning Objectives
Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
After completing this course, the reader will be able to:

  1. Identify which advanced breast cancer patients in the three subsets studied (with nonvisceral metastases, with visceral metastases without liver involvement, and with liver metastases) responded most favorably to first-line therapy.
  2. Describe the limitations of first-line treatment in the three subsets of patients with advanced breast cancer.
  3. Explain how KPS assessment correlates with overall survival in patients with advanced breast cancer with different sites of metastatic lesions.

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. The letrozole study 025 is a large (n = 907), international, double-blind, randomized, phase III trial in postmenopausal women with advanced breast cancer. This subanalysis compares the efficacies of letrozole and tamoxifen as first-line therapy in postmenopausual women with advanced breast cancer according to site of metastatic lesions and Karnofsky Performance Status (KPS).

Materials and Methods. Nine hundred seven patients with advanced breast cancer were randomly assigned to once-daily oral letrozole (2.5 mg; Femara®; Novartis Pharma AG; Basel, Switzerland) or tamoxifen (20 mg; Tamofen®; Leiras OY; Turku, Finland). Time to progression (TTP) was estimated using the Kaplan-Meier product-limit method. Treatments were compared by Cox proportional hazards regression models.

Results. Letrozole treatment significantly prolonged TTP in all subsets of patients: those with nonvisceral metastases, those with visceral metastases without liver involvement, and those with liver metastases. The reduction in risk of progression ranged from 25%, for patients with nonvisceral metastases, to 36%, for patients with liver metastases. The distributions of baseline KPS scores for both treatment groups were similar (57% had KPS scores ≥90). Time to worsening of 20 points or more in KPS score was significantly longer with letrozole than with tamoxifen, but modest numbers of patients experienced such deterioration (letrozole, 20%, tamoxifen, 22%, in patients without visceral metastases; 23%–24% in patients with liver metastases; and letrozole, 14%, tamoxifen, 30%, in patients with visceral metastases without liver involvement).

Conclusion. These data demonstrate the consistent superiority of letrozole over tamoxifen and support the use of letrozole as a new standard of endocrine therapy in postmenopausal women with advanced breast cancer.

Key Words. Letrozole • Tamoxifen • Breast neoplasms • Postmenopause • Aromatase inhibitors • Karnofsky performance status


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
The third-generation aromatase inhibitors, letrozole (Femara®; Novartis Pharmaceuticals Corporation; East Hanover, NJ), anastrozole (Arimidex®; AstraZeneca Pharmaceuticals; Wilmington, DE), and exemestane (Aromasin®; Pfizer; New York, NY), have displaced aminoglutethimide and megestrol acetate as second-line treatments for hormone-sensitive, advanced breast cancer in postmenopausal women [1–4]. This success has encouraged their testing as first-line therapy in phase III clinical trials, where the current standard therapy for the past 20 years has been tamoxifen. Letrozole was shown, in study 025, to be superior to tamoxifen in terms of time to progression (TTP) and overall response rate (ORR) [5, 6].

Advanced breast cancer presents a range of pathologic conditions and clinical outcomes. Nearly all patients are likely to develop bone metastases, and more than 50% of patients will have some liver involvement [7, 8]. Bone metastases account for a substantial amount of disability, while liver metastases are associated with a higher mortality. To further evaluate the efficacy of letrozole in advanced breast cancer, we performed a subset analysis of study 025 according to whether patients had nonvisceral metastases, visceral metastases without liver involvement, or liver metastases.

Another outcome variable that can be used to evaluate treatment in cancer patients is maintenance of functional ability. For patients with metastatic disease, palliative treatment is usually the only option, and the goal is to keep patients as active and independent for as long as possible. While quality of life (QOL) assessments can provide additional information, a functional assessment such as that of the Karnofsky Performance Status (KPS) scale has widespread use and is highly correlated with overall survival [9, 10]. Using this scale, tamoxifen has been shown to maintain good functional ability for longer than other treatments in advanced breast cancer patients [11]. Here, we present data relating to KPS assessments made during study 025 for the previously mentioned subsets of patients with metastatic disease.


   MATERIALS AND METHODS
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 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Study Design
The study followed a randomized, double-blind, double-dummy design and was conducted at 201 centers in 29 countries. Patients were assigned once-daily treatment of either 2.5 mg letrozole or 20 mg tamoxifen, with placebos to match the complementary treatment (double-dummy technique). Patients remained on first-line treatment until progression or discontinuation for any other reason, if recommended by the site investigator. Provided they remained eligible for further endocrine therapy, patients could be switched, at the investigator’s discretion, to the alternative treatment on progression. All patients were followed for overall survival.

Eligibility Criteria
The trial was open to postmenopausal women with either metastatic disease or locally advanced disease that was confirmed by histologic or cytologic tests (stage IIIB according to American Joint Committee on Cancer [1992] criteria) and not amenable to treatment by surgery or radiotherapy. Previous chemotherapy (one regimen) for advanced disease was permitted when there was objective evidence that progression had occurred within 3 months before the start of the study. Prior adjuvant endocrine therapy was allowed provided it had been discontinued at least 12 months prior to study entry. A KPS score of at least 50 (World Health Organization grade 0–2) was required. The major exclusion criteria were evidence of central nervous system (CNS) metastasis, bilateral diffuse lymphangitis carcinomatosa of the lung with more that 50% involvement, and metastasis of the liver that exceeded 33% of volume.

Assessment of Efficacy
The primary end point was TTP (defined as the interval between the date of randomization and the earliest date of disease progression). Secondary end points were ORR (taken as the percentage of patients with complete responses [CRs] or partial responses [PRs], as confirmed by a second evaluation 3 months later), duration of overall response, rate of clinical benefit (CR, PR, or stabilization of disease/no change [NC], lasting at least 24 weeks), duration of clinical benefit, time to treatment failure (TTF), time to response, and overall survival. Patient assessments that included physical and hematological examinations and a performance status evaluation were made every 3 months.

Statistical Methodology
Median time to event was estimated by the Kaplan-Meier product-limit method. Treatments were compared by Cox proportional hazards regression models (time to event data), testing the influence of baseline covariates on the treatment difference as well as testing the effect of each covariate in the presence of the other covariates. Differences between treatments in discrete data, such as response, clinical benefit, and deteriorating/improving KPS score were compared using logistic regression models. The protocol prospectively planned that these analyses be undertaken.


   RESULTS
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 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Patients
Demographic data were fully presented previously [5] and are summarized in Table 1Go. Baseline characteristics of the 907 patients in the two study arms were well balanced, with a median age of 64.5 years. Most patients (93%) had metastatic disease. Only 167 (19%) had previously received adjuvant tamoxifen, and the majority of these (126) had stopped adjuvant treatment at least 2 years before enrollment into the study. Soft-tissue disease occurred in only 25%, but soft-tissue lesions were present in 62% of the study population. Bone lesions were dominant (i.e., bone disease only or bone disease plus soft-tissue disease) in 30%, but present in 52%, of patients. Visceral lesions were dominant in 44% of patients (i.e., viscera dominant in the presence of any visceral site regardless of involvement of bone or soft tissue). Baseline KPS scores between 80 and 100 were recorded for 92% of patients [5]. The median follow-up at the cut off date for the updated analysis [6] was approximately 32 months.


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  		Table 1. Core baseline data of trial patients
 
Efficacy
The updated results of study 025 [6] confirmed the previously reported results [5]. Median TTP was 9.4 months for letrozole and 6.0 months for tamoxifen, representing an almost 30% lower risk for progression (hazard ratio 0.72; 95% confidence interval [CI] = 0.62–0.83; p < 0.0001) (Table 2Go) [6].


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  		Table 2. Number of patients progressing, TTP, and hazard ratios for TTP according to type of metastasis
 
In patients without visceral disease, the median TTPs were 10.9 months with letrozole and 6.3 months with tamoxifen (hazard ratio 0.75; 95% CI = 0.62–0.91; p = 0.004) (Table 2Go, Fig. 1AGo). For those with visceral disease without liver involvement (most had lung involvement), the median TTPs were very similar at 11.9 and 6.1 months, respectively (hazard ratio 0.66; 95% CI = 0.51–0.86; p = 0.002) (Table 2Go, Fig. 1BGo). In patients with liver metastases, the benefit of letrozole over tamoxifen was smaller, but still significant. The median TTPs for patients with liver metastases were 3.8 months with letrozole and 3.0 months with tamoxifen (hazard ratio 0.64; 95% CI = 0.43–0.94; p = 0.02) (Table 2Go, Fig. 1CGo).



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  		Figure 1. Kaplan-Meier estimates for TTP. Solid line denotes letrozole, dashed line denotes tamoxifen. A) Patients with nonvisceral metastases: median TTPs were 10.9 months (95% CI = 9.1–13.6) for letrozole (n = 258) and 6.3 months (95% CI = 5.8–9.0) for tamoxifen (n = 246). B) Patients with visceral metastases without liver involvement: median TTPs were 11.9 months (95% CI = 8.6–14.7) for letrozole (n = 135) and 6.1 (95% CI = 4.6–9.0) for tamoxifen (n = 153). C) Patients with liver metastases: median TTPs were 3.8 months (95% CI = 3.1–6.1) for letrozole (n = 60) and 3.0 months (95% CI = 3.0–3.2 months) for tamoxifen (n = 55).

 
KPS was relatively insensitive to change in these first-line patients. A worsening of KPS score by 20 points or more occurred in similarly modest numbers of patients in both treatment arms in the subsets of nonvisceral metastases (letrozole 20%, tamoxifen 22%) and liver metastases (letrozole 23%, tamoxifen 24%). In the subset of patients with visceral metastases without liver involvement (mostly lung), significantly fewer letrozole patients (14%) than tamoxifen patients (30%) experienced deteriorations in their KPS scores of 20 points or more (Table 3Go). In that subset of patients, time to worsening was significantly longer for letrozole than for tamoxifen patients (p = 0.0001), but "delay" has little meaning in view of the modest numbers of patients experiencing deterioration. Generally, median time to worsening was not estimable.


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  		Table 3. KPS score: worsening and improvement
 
Improvement in KPS score by at least 20 points sustained for at least 6 months occurred in very modest numbers of patients. In the subset of patients with nonvisceral disease, it was observed in 11% of patients given letrozole and in 8% of patients given tamoxifen. In patients with liver metastases, improvement in KPS score was observed in 6% of patients treated with letrozole and in 7% of patients treated with tamoxifen. In patients with visceral metastases without liver involvement, improvement in KPS score occurred in 20% of those treated with letrozole compared with 9% of those treated with tamoxifen (p = 0.06) (Table 3Go).

Overall Survival
The final overall survival analysis of study 025 (median follow-up period of 32 months) has been reported [6]. The median overall survival time was slightly longer in the letrozole arm (34 months) than in the tamoxifen arm (30 months). Although this difference in overall survival was not statistically significant (by the protocol-specified overall log-rank test), there was a significant early survival benefit for patients in the letrozole arm over the first 2 years of the study. In the subset of patients with nonvisceral metastases, 54% in each treatment arm switched treatments on progression. The median survival time in both treatment arms was 3 years. In the subset of patients with visceral metastases without liver involvement, 49% in each treatment arm crossed over. The median overall survival times were 34 months for letrozole and 31 months for tamoxifen. In the subset of patients with liver metastases, 51% in the letrozole arm were able to switch to tamoxifen on progression, compared with only 36% in the tamoxifen arm switching to letrozole on progression. The median overall survival times were 19 months for patients initially randomized to letrozole and 11.5 months for patients initially allocated to the tamoxifen arm (p = 0.07, data not shown).

Safety
The safety analysis of the two monotherapies included a total of 910 patients (455 in each arm). Although at least one adverse event (including worsening of tumor-related symptoms) was reported in most patients [5], there were differences among subgroups in the nature of adverse events reported. In the subset of patients without visceral metastases (i.e., with bone and/or soft-tissue disease), the five most frequent complaints were: bone pain, back pain, hot flushes, nausea, and arthralgia in both treatment arms (Table 4Go). In the subset of patients with visceral metastases without liver involvement (i.e., mainly lung), the five most frequently reported adverse events were: dyspnea, cough, arthralgia, back pain, and hot flushes. In the tamoxifen arm, nausea was the third most frequently reported adverse event (Table 4Go). In the subset of patients with liver metastases (several of whom also had lung involvement), the five most common adverse events were: bone pain, nausea, hot flushes, dyspnea, and arthralgia for patients treated with letrozole but bone pain, fatigue, back pain, nausea, and constipation and dyspnea (equally often) with tamoxifen (Table 4Go).


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  		Table 4. Most frequently reported adverse events (reported for ≥10% patients) irrespective of relationship to study drugs
 
The frequencies and nature of reported adverse events suspected to be related to the study drug were similar for the letrozole and tamoxifen treatment arms [5]. An overall 7% of patients discontinued the study due to adverse events, withdrawal of consent, or death. Progression of disease was associated with discontinuations due to adverse events [5] and, for this reason, it is difficult to distinguish discontinuations primarily due to adverse events. It is estimated that 2%–3% of patients in each treatment arm discontinued first-line treatment primarily because of adverse events.


   DISCUSSION
Top
 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
The present data build on the already published results of study 025 and demonstrate the superiority of the aromatase inhibitor letrozole over tamoxifen in the first-line treatment of advanced breast cancer in postmenopausal women.

  • Letrozole resulted in a significantly longer TTP compared with tamoxifen in all subgroups of patients with metastatic lesions.
  • Patients with nonvisceral or visceral, but not liver, metastases had longer TTPs than patients with liver lesions. In patients with nonvisceral metastases, the risk for progression was 25% lower with letrozole than with tamoxifen. In patients with visceral metastases without liver involvement (mainly lung), the risk for progression with letrozole was 34% less than with tamoxifen, and the median TTP was almost twice as long with letrozole. In patients with liver metastases, although the median TTPs were similar for both treatments, the risk for progression was 36% lower with letrozole than with tamoxifen.
  • TTP was shortest for patients with liver lesions. Letrozole afforded a significant benefit over tamoxifen.
  • Although the time to worsening of KPS was significantly longer with letrozole than with tamoxifen, KPS was relatively insensitive to change in this population receiving first-line endocrine therapy. While deterioration of at least 20 points in KPS score occurred in 20%–22% of patients with nonvisceral metastases, similar results occurred in patients with liver metastases (23%–24%), although progression occurred much earlier in the latter patients. In patients with mainly lung metastases (visceral without liver involvement), deterioration in KPS occurred in twice as many patients with tamoxifen (30%) as with letrozole (14%).
  • These results were generally mirrored by improvements of at least 20 points in KPS score sustained for at least 6 months, particularly in the subset of patients with visceral metastases without liver involvement (20% improved with letrozole, compared with 9% for tamoxifen).

For more than 20 years, tamoxifen has been the standard first-line therapy for hormone-sensitive breast cancer in postmenopausal women. The third-generation aromatase inhibitors have now challenged the position of tamoxifen with favorable outcomes. Anastrozole was demonstrated in two trials to be at least as effective as tamoxifen [12, 13, 14] and, in the present study, letrozole demonstrated superiority to tamoxifen in TTP, TTF, response rate, and early survival, and demonstrated equivalence in overall survival [5, 6]. In addition, the time to worsening of performance status score was longer with letrozole.

The superiority of letrozole over tamoxifen in TTP was apparent irrespective of site of metastasis: nonvisceral, visceral without liver involvement, and liver; however, in patients with liver metastases, TTPs were only approximately 30%–50% of the TTPs in patients without liver metastases.

It is well known that the presence of liver metastases is a predictor of poor survival, and this was supported by the relatively short TTP seen in these patients, as well as a substantially shorter median overall survival. Generally, postmenopausal patients with receptor-positive metastatic disease are offered endocrine therapy as a first-line systemic approach. Those responsive may be offered a second-line endocrine therapy, whereas those nonresponsive are offered chemotherapy as a second-line systemic option. The relatively short TTP with first-line endocrine therapy in patients with liver metastases calls for the evaluation of the optimal sequence of endocrine therapy and chemotherapy.


   CONCLUSION
Top
 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
In conclusion, this subanalysis by different sites of metastatic lesion and on KPS score indicates that the efficacy of letrozole as first-line endocrine therapy is superior to that of tamoxifen in patients with nonvisceral metastases, with visceral metastases without liver involvement, and with liver metastases. The reliability of results was established by the primary and final findings of the overall study, and data provided by this subanalysis provide further evidence for the consistently superior effects and significant clinical benefit of first-line letrozole in postmenopausal patients with advanced, hormone-sensitive breast cancer.


   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. Buzdar AU, Jonat W, Howell A et al. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Arimidex Study Group. Cancer 1998;83:1142–1152.[CrossRef][Medline]
  2. Gershanovich M, Chaudri HA, Campos D et al. Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Letrozole International Trial Group (AR/BC3). Ann Oncol 1998;9:639–645.[Abstract/Free Full Text]
  3. 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 1998;16:453–461.[Abstract]
  4. Kaufmann M, Bajetta E, Dirix LY et al. Exemestane improves survival compared with megestrol acetate in postmenopausal patients with advanced breast cancer who have failed on tamoxifen. Results of a double-blind randomised phase III trial. Eur J Cancer 2000;36:S86–S87.
  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. 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]
  7. Mundy GR, Guise TA, Yoneda T. Biology of bone metastases. In: Harris JR, Lippman ME, Morrow M et al., eds. Diseases of the Breast. Philadelphia: Lippincott Williams and Wilkins, 2000:911–920.
  8. Talamonti MS. Management of discrete liver metastasis. In: Harris JR, Lippman ME, Morrow M et al., editors. Diseases of the Breast. Philadelphia: Lippincott Williams and Wilkins, 2000:907–910.
  9. Coates A, Gebski V, Signorini D et al. Prognostic value of quality-of-life scores during chemotherapy for advanced breast cancer. Australian New Zealand Breast Cancer Trials Group. J Clin Oncol 1992;10:1833–1838.[Abstract]
  10. Maltoni M, Amadori D. Prognosis in advanced cancer. Hematol Oncol Clin North Am 2002;16:715–729.[CrossRef][Medline]
  11. Mouridsen HT, Rose C, Engelsman E et al. Combined cytotoxic and endocrine therapy in postmenopausal patients with advanced breast cancer. A randomized study of CMF vs CMF plus tamoxifen. Eur J Cancer Clin Oncol 1985;21:291–299.[CrossRef][Medline]
  12. 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]
  13. Bonneterre J, Thuerlimann 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]
  14. 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 2001;92:2247–2258.[CrossRef][Medline]
Received November 26, 2002; accepted for publication March 23, 2004.




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