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Originally published as JCO Early Release 10.1200/JCO.2005.66.130 on June 13 2005 © 2005 American Society of Clinical Oncology. Phase II Study of Temsirolimus (CCI-779), a Novel Inhibitor of mTOR, in Heavily Pretreated Patients With Locally Advanced or Metastatic Breast Cancer
From the Nottingham City Hospital, Nottingham; Royal Marsden Hospital, London, United Kingdom; Innere Klinik und Poliklinik (Tumorforschung), Universitätsklinikum Essen, Essen; Frauenklinik Rotes Kreuz, Munich; Klinik für Tumorbiologie, Freiburg; Stadtische Kliniken Oldenburg, Oldenburg; Albert Ludwigs-Universität Freiburg, Freiburg, Germany; Institut Jules Bordet, Brussels, Belgium; Ludwig Boltzmann-Institute for Applied Cancer Research, Kaiser-Franz-Josef-Spital, Vienna, Austria; Kantonsspital St. Gallen, St. Gallen; Inselspital Bern, Bern; Universitätsspital Basel, Basel, Switzerland; N.N. Petrov Research Institute of Oncology, St Petersburg, Russia; Institute of Oncology, Vilnius University, Vilnius, Lithuania; Wyeth Research, Paris, France, Collegeville, PA, and Cambridge, MA; and Central European Society for Anticancer Drug Research-EWIV (CESAR) Address reprint requests to Stephen Chan, MD, Department of Clinical Oncology, Nottingham City Hospital, Hucknall Rd, Nottingham N65 1PB, United Kingdom; e-mail: schan2{at}ncht.trent.nhs.uk.
PURPOSE: In this study, two doses of temsirolimus (CCI-779), a novel inhibitor of the mammalian target of rapamycin, were evaluated for efficacy, safety, and pharmacokinetics in patients with locally advanced or metastatic breast cancer who had been heavily pretreated. PATIENTS AND METHODS: Patients (n = 109) were randomly assigned to receive 75 or 250 mg of temsirolimus weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, adverse events, and pharmacokinetics of temsirolimus. RESULTS: Temsirolimus produced an objective response rate of 9.2% (10 partial responses) in the intent-to-treat population. Median time to tumor progression was 12.0 weeks. Efficacy was similar for both dose levels but toxicity was more common with the higher dose level, especially grade 3 or 4 depression (10% of patients at the 250-mg dose level, 0% at the 75-mg dose level). The most common temsirolimus-related adverse events of all grades were mucositis (70%), maculopapular rash (51%), and nausea (43%). The most common, clinically important grade 3 or 4 adverse events were mucositis (9%), leukopenia (7%), hyperglycemia (7%), somnolence (6%), thrombocytopenia (5%), and depression (5%). CONCLUSION: In heavily pretreated patients with locally advanced or metastatic breast cancer, 75 and 250 mg temsirolimus showed antitumor activity and 75 mg temsirolimus showed a generally tolerable safety profile.
Approximately 400,000 women globally died of breast cancer in 2002.1 Women with metastatic breast cancer have a median survival of 2 to 3 years.2 For the majority of patients, metastatic breast cancer is a chronic disease with periods of relapse and remission requiring multiple treatment regimens.3 Treatment decisions are based on site of metastasis/urgency of symptoms and whether tumors are positive for estrogen or progesterone receptors and overexpression of the HER2/neu receptor. All current treatments for advanced breast cancer have shortcomings.4-7 Temsirolimus (CCI-779; Wyeth Pharmaceuticals, Collegeville, PA) is a novel inhibitor of the mammalian target of rapamycin (mTOR). mTOR is a member of the phosphoinositide-kinase-related kinase family and a central component of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway that mediates eukaryotic cell growth and proliferation.8,9 Temsirolimus binds to the immunophilin FK506/rapamycin-binding protein10 and this complex binds to mTOR and inhibits its function. This inhibition then results in inhibition of phosphorylation of downstream proteins, including the eukaryotic translation initiation factor 4E binding protein-1 and the 40S ribosomal protein p70 S6 kinase,11-13 which ultimately results in growth arrest of cells in the G1 phase of the cell cycle.14 It has been proposed that the p70 S6 kinase could be used as a biologic marker to measure mTOR inhibition.15,16 However, sensitivity to mTOR inhibitors did not correlate with decreased p70 S6 kinase activity for all cell types11,17,18 so it may not be a useful marker. In preclinical studies, temsirolimus inhibited the proliferation of breast cancer cell lines that were estrogen dependent, overexpressed the HER2/neu receptor, or were deficient in the PTEN tumor suppressor.11 In a nude mouse xenograft model, temsirolimus inhibited growth of PTEN-deficient breast tumor cells but not PTEN-expressing breast tumor cells.11 These results suggest that temsirolimus might be a useful treatment for breast cancer with specific phenotypes. In a phase 1 study of patients with advanced solid tumors (n = 24),19 temsirolimus was administered over a wide range of doses as a weekly 30-minute infusion. Temsirolimus was generally well tolerated; dermatologic toxicity (71%) and mucositis (71%) were the most frequently occurring related adverse events. Partial responses were observed in one patient with advanced renal cell carcinoma and in one patient with metastatic breast cancer. In a phase 2 study of heavily pretreated patients with advanced refractory renal cell carcinoma (n = 111),20 temsirolimus (25, 75, or 250 mg) was administered as a weekly 30-minute infusion and an objective response rate of 7.2% was observed with maculopapular rash (76%) and mucositis (70%) as the most frequently occurring related adverse events. We report here the results of a phase II study of temsirolimus administered to heavily pretreated patients with locally advanced or metastatic breast cancer.
Trial Design This was a randomized, two–dose level, open-label, Simon two-stage21 trial of temsirolimus in patients with locally advanced or metastatic breast cancer. Eligible patients were randomly assigned in a 1:1 ratio to receive 75 or 250 mg temsirolimus once weekly for 6 months or until evidence of disease progression, provided that the drug was well tolerated. The study protocol was approved by the institutional review boards of the participating institutions and all patients gave written informed consent. The study was conducted according to the Declaration of Helsinki and its amendments.
Patients Patients were excluded from the study if they had CNS metastases or bone metastases when no other measurable disease was present. They also were excluded if they had received cancer chemotherapy, radiation therapy, or any investigational agent within 4 weeks before starting temsirolimus treatment or had prior hematopoietic stem cell transplantation; prior malignancy other than breast cancer, cervical carcinoma-in-situ, basal cell carcinoma, or squamous cell carcinoma of the skin; or systemic therapy for a prior malignancy within 5 years before starting temsirolimus treatment. Patients with an active severe infection; known infection with HIV, hepatitis B virus, or hepatitis C virus; unstable angina; myocardial infarction within 6 months before starting temsirolimus treatment; therapy for life-threatening ventricular arrhythmia; or life-threatening visceral disease or other severe concurrent disease were ineligible. Patients who were pregnant, breastfeeding, or of childbearing potential without using dual forms of effective contraception were excluded. Estrogen, progesterone, and HER2/neu receptor status in tumors was obtained from patient histories when available. HER2/neu receptor status could be determined by immunohistochemical analysis or fluorescence in situ hybridization.
Drug Administration
Tumor Response The primary objective was the objective response rate, the proportion of patients who had confirmed CR and PR after at least 8 weeks of treatment. Secondary objectives included (1) clinical benefit rate (the proportion of patients who had confirmed CR and PR and SD for at least 24 weeks); (2) time to response (the interval from the date of the first temsirolimus dose to the date of the initial documentation of CR or PR); (3) duration of response (the interval from the first report of CR or PR to the date of PD or death); and (4) time to tumor progression (TTP; measured from the first dose of temsirolimus until the first date of documented PD or date of censoring because of last tumor assessment, last drug dose, or discontinuation from the study). Results for TTP were analyzed by Kaplan-Meier estimates. The data cut-off date was March 26, 2004.
Safety Assessment
Specific temsirolimus-related TEAEs resulted in dose reductions. A 25% dose reduction was made if the ANC was < 1,000/µL and
Statistical Analysis Fifty eligible patients were to be enrolled in each treatment arm for the entire study, with 16 eligible patients to be enrolled in each treatment arm for the first stage. Each treatment arm was treated independently. In the first stage, if at least two of 16 patients in a treatment arm had an objective response, approximately 34 additional patients were to be enrolled in the second stage. If fewer than two of 16 patients had a response, consideration was given to stopping enrollment in that treatment arm.
Pharmacokinetic Assessment
Patients A total of 109 patients were enrolled from October 2000 to February 2002; in this intent-to-treat (ITT) population, 55 and 54 patients were randomly assigned to receive 75 and 250 mg temsirolimus per week, respectively. One patient withdrew consent before undergoing baseline assessments. Two additional patients did not receive temsirolimus because they were found to be ineligible after screening. A total of 106 patients received at least one dose and were evaluated for safety (55 and 51 in the 75- and 250-mg dose groups, respectively). One patient in the 75-mg dose group completed 24 weeks of temsirolimus treatment without continuing into follow-up. The other 105 patients discontinued from the study because of disease progression (n = 78), temsirolimus-related adverse events (n = 15), temsirolimus-unrelated adverse events (n = 3), and withdrawal of consent (n = 9). The median age of the 108 patients was 56 years; 94% of patients had an ECOG PS of 0/1; 81% of patients were heavily pretreated and had at least three regimens of chemotherapy, immunotherapy, or hormonal therapy in the adjuvant, locally advanced, or metastatic setting (Table 1). Receptor status was reported by investigators. Thirty-eight percent of patients had tumors that were positive for estrogen and/or progesterone receptors and 36% had tumors of unknown status. On the basis of immunohistochemical or fluorescence in situ hybridization analysis, 35% of patients had tumors that were positive for the HER2/neu receptor and 17% had tumors of unknown status. Cancer characteristics were similar between the two treatment groups.
Summary of Exposure to Temsirolimus Patients in the 250-mg dose group received fewer doses of temsirolimus than those in the 75-mg dose group because of dose reductions and delays. Patients in the 75-mg dose group received a median of nine doses of temsirolimus over a median of 11 weeks (Table 2). Patients in the 250-mg dose group received a median of nine doses of temsirolimus over a median of 12 weeks. The relative dose-intensity (actual dose/assigned dose) was 0.9 for the 75-mg dose group and 0.8 for the 250-mg dose group (Table 2). In the 75-mg and 250-mg dose groups, 31% and 51% of patients, respectively, had at least one dose reduction and 47% and 61%, respectively, had at least one delay.
Efficacy Six patients in the 75-mg dose group and four patients in the 250-mg dose group achieved PR (Table 3) and, as no patients had CR, the objective response rate was 9.2% for all patients in the ITT population. Five patients (4.6%) had SD for at least 24 weeks and the clinical benefit rate (PR + SD  24 weeks) was 13.8%.
For the 10 patients with PR, the median time to response was 1.9 months (75-mg dose group, 1.9 months; 250-mg dose group, 1.8 months; range, 1.5 to 3.2 months). The median duration of response was 6.0 months for these 10 PR patients (75-mg dose group, 6.7 months; 250-mg dose group, 5.4 months; range, 3.7 to 8.7 months). Median TTP was 12.0 weeks for all patients in the ITT population, 9.9 weeks for the 75-mg dose group, and 14.3 weeks for the 250-mg dose group (Fig 1).
Relationships Between Objective Responses and Prognostic Factors Patients with objective responses and all patients in the ITT population were classified into subgroups based on prognostic factors including number of metastatic sites, dominant site of metastasis, and types of prior chemotherapy (Table 4). There were about three-fold more patients with one or two metastatic sites who had objective responses (13.6%) than patients with more than two metastatic sites who had objective responses (4.1%).
Safety At least one temsirolimus-related TEAE occurred in each of the 106 patients treated in the study (Table 5). Mucositis, maculopapular rash, and nausea occurred in 70%, 51%, and 43% of patients, respectively (Table 6). At least two-fold more patients in the 250-mg dose group than in the 75-mg dose group had epistaxis, dry skin, and dry mouth. At least one grade 3 or 4 temsirolimus-related TEAE occurred in 55% of patients (Table 6). Grade 3 or 4 mucositis, leukopenia, hyperglycemia, increased levels of gamma-glutamyl transpeptidase, somnolence, thrombocytopenia, and depression occurred in 5% to 9% of patients (Table 6). Of these patients, more than two-fold-in the 250-mg dose group than in the 75-mg dose group had grade 3 or 4 mucositis and somnolence. Five patients in the 250-mg dose group and no patients in the 75-mg dose group had grade 3 or 4 depression.
The most common reasons for dose reductions and delays were thrombocytopenia (reductions, 21 patients; delays, 27 patients) and mucositis (reductions, 10 patients; delays, 13 patients). The most frequent adverse events that led to discontinuation were depression and/or somnolence (75-mg dose group, two patients; 250-mg dose group, five patients); three patients in the 250-mg dose group discontinued because of a temsirolimus-related allergic reaction. One patient with advanced disease at study entry (ECOG PS = 2) received 75 mg temsirolimus, was hospitalized on day 7, and died as a result of pneumonia on day 9. The treating investigator considered the occurrence of pneumonia to be possibly related to temsirolimus administration. An additional 25 patients died on study because of disease progression.
Pharmacokinetics As described previously,24 a three-compartment model was used to characterize temsirolimus disposition. In this study, factors for effect of dose on clearance (Appendix, Equation 1), dose number on central volume of distribution (Equation 2), and weight on intercompartmental clearance (Equation 3) significantly explained exposure variability for temsirolimus. A two-compartment model with first-order metabolite formation was used to characterize sirolimus disposition. Factors for effect of dose on central volume of distribution (Equation 4), hematocrit on intercompartmental clearance (Equation 5), and dose number on both peripheral volume (Equation 6) and formation rate (Equation 7) were identified as significant covariates explaining variability in sirolimus exposure. Observed versus individual Bayesian-predicted concentrations of temsirolimus and sirolimus from these models are depicted in Figures 2A and 2B.
The population pharmacokinetic analysis indicated that weight and hematocrit were significant covariates associated with intercompartmental clearance for temsirolimus and sirolimus, respectively, and therefore, the effect of each on the corresponding concentration versus time profile was analyzed. At the end of week 4, at steady-state, for the 75-mg dose, higher body weight was associated with higher temsirolimus trough concentrations and higher hematocrit was associated with higher sirolimus trough concentrations (Fig 3). Exposure was long-lived, with concentrations in whole blood ranging from 1.7 to 4.9 ng/mL for temsirolimus and 9.3 to 14 ng/mL for sirolimus. Steady-state concentrations were 1.5- to 1.9-fold higher for temsirolimus (less than proportional) and 3.4-fold higher for sirolimus (proportional) for the 250-mg dose than for the 75-mg dose (data not shown).
As predictor variables for pharmacodynamic correlation, various forms of drug exposure were considered. To minimize bias, the average AUC of temsirolimus and average AUCsum through 8 weeks of treatment were determined for all patients. The average parameters were considered more appropriate than discrete AUC values because a significant fraction of patients had dose reductions or delays during this 8-week period. The association of drug exposure to tumor response did not exhibit a discernible trend (Fig 4).
The results of this phase II study indicate that temsirolimus, a novel mTOR inhibitor, has antitumor activity in heavily pretreated patients with locally advanced or metastatic breast cancer. Partial responses were observed both in patients with visceral-dominant and soft tissue-dominant metastases. The objective response rate was 9.2%, the clinical benefit rate was 13.8%, and median TTP was 12.0 weeks for all patients in the ITT population. This antitumor activity was comparable for the two dose levels and suggests that both 75 and 250 mg temsirolimus produce the required biologic activity. Differences in tolerability to 75 and 250 mg temsirolimus were observed. The most common, clinically important grade 3 or 4 temsirolimus-related TEAEs were mucositis (9%), leukopenia (7%), hyperglycemia (7%), somnolence (6%), thrombocytopenia (5%), and depression (5%). More patients in the 250-mg than in the 75-mg dose group had grade 3 or 4 mucositis (250 mg, 7; 75 mg, 3), somnolence (250 mg, 5; 75 mg, 1) and depression (250 mg, 5; 75 mg, 0). More patients in the 250-mg dose group than in the 75-mg dose group had dose reductions and delays and discontinuations because of temsirolimus-related adverse events. Thus, based on the results of this study, 75 mg temsirolimus administered weekly by intravenous infusion is a safe and efficacious dose for use as a single agent in the treatment of advanced breast cancer. Similar efficacy and safety results were obtained in the phase II study in which heavily pretreated patients with advanced renal cell carcinoma were treated with temsirolimus weekly by intravenous infusion.20 An objective response rate of 7.2% was observed and temsirolimus was generally well tolerated, with hyperglycemia (17%), hypophosphatemia (13%), anemia (9%), and hypertriglyceridemia (6%) as the most common grade 3 or 4 related TEAEs. Safety and efficacy were similar for the 3 dose levels tested (25, 75, and 250 mg). Thus, temsirolimus may be useful for the treatment of at least two types of cancer. The standard treatment for women with anthracycline-resistant metastatic breast cancer is a taxane in the presence or absence of trastuzumab, depending on whether the tumor overexpresses HER2/neu. When heavily pretreated advanced breast cancer patients were treated with trastuzumab or docetaxel as single agents, objective response rates of 15% and 30%, respectively, and median TTP of 3.1 and 4.8 months were reported.5,25 In this study, the median TTP of 3.0 months for heavily pretreated advanced breast cancer patients treated with temsirolimus was similar to that for the patients treated with trastuzumab or docetaxel, but the objective response rate of 9.2% for temsirolimus was lower. Although the antitumor activity of single-agent temsirolimus was modest in this study, it may be useful in combination therapy. Preclinical data indicated that antitumor activity was additive when temsirolimus was used in combination.26 The favorable safety profile of 75 mg temsirolimus in this study suggests that an effective dose of temsirolimus in a combination therapy may cause few severe adverse events. Thus, temsirolimus should be studied in combination with other agents as a treatment for breast cancer. The results of a study of temsirolimus used in combination with letrozole in breast cancer patients has been reported.27 Studies of temsirolimus used in other combinations are also underway. In conclusion, in heavily pretreated patients with locally advanced or metastatic breast cancer, temsirolimus, a novel mTOR inhibitor, had clinical activity at doses of 75 and 250 mg and a generally tolerable safety profile at the 75-mg dose. On the basis of these results, studies with temsirolimus in combination with other agents are being conducted in patients with breast cancer to evaluate antitumor activity and safety and to identify prognostic factors or biomarkers that would allow a specific population to be targeted for therapy.
Definition of parameters in the temsirolimus three-compartment model.
Remaining parameters for the temsirolimus three-compartment model include Q2 (intercompartmental clearance between compartments 1 and 2) with a value of 46.1 L/hour ; V2 (volume of distribution of compartment 2) of 190 L, and V3 (volume of distribution of compartment 3) of 4360 L.
Definition of parameters in the sirolimus two-compartment model.
The remaining parameter for the sirolimus two-compartment model includes CL (apparent clearance) with a value of 8.09 L/hour.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Co-investigators in this study were C. Oberhoff, Klinik für Frauenheilkunde und Geburtshilfe, Universitätsklinikum Essen, Essen, Germany; S. Steinbild, Klinik für Tumorbiologie, Freiburg, Germany; M. Piccart, Institut Jules Bordet, Brussels, Belgium; M. Gneist, Ludwig Boltzmann-Institute for Applied Cancer Research, Kaiser-Franz-Josef-Spital, Vienna, Austria, and CESAR-EWIV; G. Raab, Frauenklinik Rotes Kreuz, Munich, Germany; and V.D. Ivanov, N.N. Petrov Research Institute of Oncology, St. Petersburg, Russia. We thank all patients and clinical personnel who participated in this study, and A. Gronfier for data management, Y.Z. Zhang for clinical programming, and S. Leinbach for manuscript preparation.
Supported by research funding from Wyeth Research, Collegeville, PA. Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology (ASCO), Orlando, FL, May 18-21, 2002, and the 39th Annual Meeting of ASCO, Chicago, IL, May 31-June 1, 2003. Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. GLOBOCAN 2002. World Health Organization, International Agency for Research on Cancer. http://www-dep.iarc.fr/. 2. Dickson RB, Lippman ME: Cancer of the breast, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles & Practice of Oncology. Philadelphia, PA, Lippincott, Williams & Wilkins, 2001, pp 1633-1717 3. Piccart MJ, Bernard MC, Cardoso F: Non-endocrine systemic therapies in advanced breast cancer. Eur J Cancer 1:287-298, 2003 (suppl)
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12. Dudkin L, Dilling MB, Cheshire PJ, et al: Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin Cancer Res 7:1758-1764, 2001
13. Neshat MS, Mellinghoff IK, Tran C, et al: Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA 98:10314-10319, 2001 14. Gibbons JJ, Discafani C, Peterson R: The effect of CCI-779, a novel macrolide anti-tumor agent, on growth of human tumor cells in vitro and in nude mouse xenografts in vivo. Proc Am Assoc Cancer Res 40:301, 1999 (abstr 2000)
15. Peralba JM, DeGraffenried L, Friedrichs W, et al: Pharmacodynamic evaluation of CCI-779, an inhibitor of mTOR, in cancer patients. Clin Cancer Res 9:2887-2892, 2003
16. Boulay A, Zumstein-Mecker S, Stephan C, et al: Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 64:252-261, 2004
17. Hosoi H, Dilling MB, Liu LN, et al: Studies on the mechanism of resistance to rapamycin in human cancer cells. Mol Pharmacol 54:815-824, 1998
18. Brennan P, Babbage JW, Thomas G, et al: p70(s6k) integrates phosphatidylinositol 3-kinase and rapamycin-regulated signals for E2F regulation in T lymphocytes. Mol Cell Biol 19:4729-4738, 1999
19. Raymond E, Alexandre J, Faivre S, et al: Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol 22:2336-2347, 2004
20. Atkins MB, Hidalgo M, Stadler WM, et al: Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22:909-918, 2004 21. Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1-10, 1989[Medline]
22. Punt C, Boni J, Bruntsch U, et al: Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors. Ann Oncol 14:931-937, 2003 23. Beal SL, Sheiner LB: NONMEM User's Guides. NONMEM Project Group, University of California at San Francisco, San Francisco, CA, 1992 24. Boni JP, Leister C, Bender G, et al: Population pharmacokinetics of CCI-779: Correlations to safety and pharmacogenomic responses in patients with advanced renal cancer. Clin Pharmacol Ther 77:76-89, 2005[CrossRef][Medline]
25. Nabholtz JM, Senn HJ, Bezwoda WR, et al: Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy: 304 Study Group. J Clin Oncol 17:1413-1424, 1999
26. Geoerger B, Kerr K, Tang CB, et al: Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy. Cancer Res 61:1527-1532, 2001 27. Baselga J, Fumoleau P, Gil M, et al: Phase II, 3-arm study of CCI-779 in combination with letrozole in postmenopausal women with locally advanced or metastatic breast cancer: Preliminary results. J Clin Oncol 22:13S, 2004 (abstr 544) Submitted December 23, 2004; accepted April 25, 2005. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
1.5x upper limit of normal [ULN], bilirubin 
