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 Buzdar, A. Articles by Hudis, C. Search for Related Content PubMed PubMed Citation Articles by Buzdar, A. Articles by Hudis, C. Social Bookmarking                            What's this?

Phase II, Randomized, Double-Blind Study of Two Dose Levels of Arzoxifene in Patients With Locally Advanced or Metastatic Breast Cancer

Aman Buzdar, Joyce A. O’Shaughnessy, Daniel J. Booser, John E. Pippen, Jr., Stephen E. Jones, Pamela N. Munster, Patrick Peterson, Allen S. Melemed, Eric Winer, Clifford Hudis

From the M.D. Anderson Cancer Center and US Oncology Research, Houston, and Baylor-Sammons Cancer Center and Texas Oncology, Dallas, TX; Memorial Sloan-Kettering Cancer Center, New York, NY; Eli Lilly and Company, Indianapolis, IN; and Dana-Farber Cancer Institute, Boston, MA.

Address reprint requests to Aman Buzdar, MD, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 424, Houston, TX 77030; email: abuzdar{at}mdanderson.org.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Purpose: To select a daily dose of arzoxifene (LY353381), a selective estrogen receptor modulator, for use in future studies in women with locally advanced or metastatic breast cancer who are either potentially tamoxifen sensitive (TS) or tamoxifen refractory (TR).

Patients and Methods: This trial was a randomized, double-blind, phase II study of arzoxifene 20 mg (n = 55) and 50 mg (n = 57) in women with advanced or metastatic breast cancer. Patients were randomly assigned to balance for number of metastatic disease sites, prior tamoxifen therapy, and estrogen receptor status. The primary end point was tumor response rate (RR). Secondary end points included clinical benefit rate (CBR), time to progression (TTP), and toxicity.

Results: Forty-nine patients were TS and 63 were TR. According to independent review, among TS patients, RR was higher in the 20-mg arm than the 50-mg arm (26.1% v 8.0%), with a longer TTP (8.3 v 3.2 months; P > .05). Among the TR patients, response rate was the same in the 20-mg and 50-mg arms (10.3%) with similar TTP (2.7 and 2.8 months, respectively; P > .05). CBR was higher in the 20-mg arm than in the 50-mg arm among TS patients (39.1% v 20.0%) and TR patients (13.8% v 10.3%). Arzoxifene was well tolerated. Dose-dependent toxicity was not demonstrated. There were no deaths during study.

Conclusion: Arzoxifene is effective in the treatment of TS and TR patients with advanced or metastatic breast cancer at the 20-mg and 50-mg dose levels. Toxicities are minimal, and the therapy is tolerated. The 20-mg dose seems to be at least as effective as the 50-mg dose. Accordingly, arzoxifene 20 mg/d was selected for further study in patients with breast cancer.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
BREAST CANCER is the most common malignancy among women in the Western hemisphere and the second most common cause of cancer-related mortality. A substantial body of experimental, clinical, and epidemiologic evidence indicates that steroid hormones play a major role in the etiology of breast cancer.¹ The effects of steroid hormones on breast epithelium are mediated through estrogen and progesterone receptors (ER and PgR, respectively).² Tamoxifen has been the drug of choice for endocrine manipulation of both early and advanced stages of breast cancer.³ Its biologic effects are mediated primarily by inhibiting the actions of estrogen through its binding to the ER. Although tamoxifen is generally a well-tolerated drug, it does have significant side effects. These include hot flashes (20% to 80%), thromboembolism (1% to 3%), and a variety of ocular toxicities and endometrial cancer. The risk of developing endometrial cancer with tamoxifen is estimated to increase two- to seven-fold in postmenopausal women receiving long-term treatment.^4–9 Moreover, there are concerns that long-term use (> 5 years) in the treatment of early-stage breast cancer is associated with the development of tamoxifen-dependent breast cancer.⁶

Given the above concerns, considerable attention has been paid to developing more selective antiestrogens. The nonsteroidal benzothiophene selective ER modulator arzoxifene was designed to have potent ER antagonistic activity in the breast and endometrium while maintaining beneficial estrogen agonist activity on bone and lipids. In preclinical studies, both arzoxifene and its desmethyl metabolite bound to the ER with high affinity and inhibited estrogen-dependent growth of MCF-7 cells.¹⁰ Arzoxifene does not stimulate the uterine endometrium in ovariectomized rats; however, it does block estrogen-induced stimulation of the endometrium.¹¹ It also demonstrated favorable effects on bone and lipids in preclinical studies.¹²

A phase I study of four doses of arzoxifene (10, 20, 50, and 100 mg) was conducted in 32 patients with previously treated breast cancer.¹³ The most common side effect was hot flashes (56%). Prospective evaluation of uterine safety, performed at baseline and after 12 weeks of treatment, showed no evidence of endometrial stimulation. Although responses were not seen, six patients had stable disease lasting for 6 months or longer. As no dose-dependent toxicity was identified in that study, this study was conducted to further evaluate the safety and efficacy of arzoxifene 20 mg and 50 mg in patients with advanced or metastatic breast cancer, and to determine the dose of arzoxifene to be used in future phase III trials.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Study Design
This was a randomized, double-blind, phase II study of arzoxifene. Each participating institutions’ independent review board gave approval to the study design before enrolling patients. After providing informed consent, patients were randomly assigned to receive either 20 or 50 mg of arzoxifene (Eli Lilly and Company, Indianapolis, IN), taken as a single tablet daily with meals. Treatment was continued until disease progression or unacceptable toxicity occurred or informed consent was withdrawn. Patients experiencing disease progression at the 20-mg dose were eligible to receive further open-label arzoxifene treatment at a dose of 50 mg daily, at the investigator’s discretion. Treatment was discontinued for any study drug–related grade 4 toxicity. Randomization was performed using the Pocock and Simon method¹⁴ to maximize baseline treatment group balance according to three important prognostic factors: number of metastatic disease sites (< three or three sites), prior tamoxifen therapy (yes or no), and degree of ER expression (high, low, or unknown). High ER expression was defined as 50 fmol/mg of ER (biochemical) or 50% cells positive (immunohistochemistry), and low ER expression was defined as less than 50 fmol/mg of ER (biochemical) or less than 50% cells positive (immunohistochemistry).

Eligibility Criteria
The study population consisted of women who were potentially tamoxifen sensitive (TS), defined as no prior exposure to tamoxifen or patients who experienced relapse more than 12 months after cessation of adjuvant tamoxifen therapy, or tamoxifen refractory (TR), defined as patients who experienced relapse during adjuvant tamoxifen treatment (provided at least 1 year had elapsed between initiation of tamoxifen and development of metastatic disease) or patients treated with tamoxifen as first-line therapy for metastatic disease whose disease was at least stable for 6 months on tamoxifen and then progressed. All patients were women at least 18 years old with a pathologic diagnosis of locally advanced or metastatic breast cancer. Patients had an Eastern Cooperative Oncology Group performance status (PS) of 0 or 1, estimated life expectancy of 24 weeks, and tumors that were assessable or bidimensionally measurable and were ER- and/or PgR-positive. Patients with inoperable, locally advanced breast cancer were enrolled only if they were not good candidates, in the investigator’s judgment, for primary chemotherapy. Patients whose ER/PgR status was unknown were eligible if they were older than 50 years. Prior neoadjuvant or adjuvant chemotherapy was permitted if completed at least 6 months before diagnosis of metastatic disease. Patients who had received prior adjuvant hormonal therapy (including oophorectomy or ovarian irradiation) were enrolled, provided there was an interval of at least 12 months between completion of therapy and diagnosis of metastatic disease. Concomitant medications such as bisphosphonates, hematopoietic growth factors, and palliative radiotherapy were permitted. Patients with child-bearing potential were required to use a barrier contraceptive method during and for 3 months after the trial.

Patients were excluded from the study per investigator’s discretion if they had rapidly progressive disease, a serious concomitant systemic disorder, or predisposition to thromboembolic disorder; inadequate end-organ function (eg, serum creatinine 1.5 times the upper limit of normal [ULN], bilirubin 1.5 times the ULN, and ALT or AST > 2.5 times the ULN); hypercalcemia; tumor known to be ER- and PgR-negative; or untreated brain metastases or were pregnant, breast-feeding, or had used any investigational agent within 4 weeks before study enrollment.

The study was conducted in accordance with the principles of the Declaration of Helsinki. The protocol and consent process was approved by all relevant ethics boards, and all patients gave written consent before enrollment.

Baseline Evaluations
A complete history and physical examination including PS assessment, blood pressure, pulse, height, and weight were performed at baseline and at each subsequent physician visit. Assessment of tumor markers (eg, carcinoembryonic antigen, CA15–3, and CA-125), urinalysis, and an ECG were also performed at baseline. Measurements of palpable lesions and tumor markers that were elevated at baseline were subsequently obtained monthly for 3 months, then every 2 to 3 months. Additional testing included complete blood cell count, chemistry analysis, serum osteocalcin, sex hormones (luteinizing hormone [LH], follicle-stimulating hormone [FSH], estradiol, and sex-hormone–binding globulin [SHBG]), and plasma levels of LY353381 and its desmethyl metabolite LY335562, which were obtained monthly for 3 months, then every 2 to 3 months. Radiologic tumor assessments were obtained at day 85 and then every 2 to 3 months while patients were enrolled on the study. All patients who received at least 4 weeks of treatment, had prestudy staging and tumor measurements, and had at least one tumor measurement while receiving treatment were considered assessable for the efficacy analysis. Toxicities were evaluated at each physician visit using the National Cancer Institute Common Toxicity Criteria grading system (version 1.0).¹⁵ All patients who received at least one dose of LY353381 were considered assessable for the safety analysis.

Uterine Evaluations
Uterine safety was prospectively evaluated in this trial for patients with an intact uterus. Transvaginal ultrasounds (TVUs) were performed no more than 4 weeks before initiation of treatment, at day 85 (± 7 days), or sooner for those discontinuing from study for any reason. For patients who continued treatment beyond 12 weeks, a TVU was performed at least every 6 months in the first year and at least yearly thereafter. Endometrial thickness was considered significant, warranting further evaluation if it was more than 8 mm at baseline or at subsequent evaluation or if the increase from baseline was 5 mm at a subsequent evaluation; follow-up occurred either with saline-infused sonohysterography, hysteroscopy/guided biopsy, or dilatation and curettage (D&C). If inadequate tissue was obtained by blind biopsy or D&C, further attempts to obtain endometrial tissue were required. Slides of endometrial tissue were reviewed centrally by Covance Inc (Princeton, NJ).

Efficacy Assessments
Tumor response rate (RR) was assessed by the investigator and independent review panel using standard World Health Organization response criteria.¹⁶ Clinical benefit rate was prospectively defined as the sum of patients with complete response (CR), partial response (PR), or stable disease (SD) lasting 6 months during the study. An independent review panel consisting of three independent radiologists reviewed the data for all patients with a response or SD according to the investigator. There was no independent review for patients whose disease was assessed by physical examination alone. Tumor response data collected during the open-label dose-escalation phase were not included in the primary analysis of tumor response.

Time to progression (TTP) was measured from the time of randomization until the time of documented progressive disease (PD), including death by any cause. The duration of response is identical to TTP but is only defined for patients who exhibit tumor response. Survival was defined as the time from randomization until death by any cause. Analyses of secondary end points were based on investigator-determined assessments.

Pharmacokinetics
Concentrations of LY353381 and its desmethyl metabolite LY335562 in plasma were evaluated monthly for the first 3 months, then every 2 to 3 months while patients were enrolled on the study. The desmethyl metabolite, LY335562, is referred to in the protocol as unconjugated dihydroxy metabolite, LY335563. LY335563 is the hydrochloride salt of LY335562. Samples were collected at any time during each visit. Heparinized plasma collected from patients was analyzed for LY353381 and LY335562 using validated high-performance liquid chromatography/mass spectrometry (MS)/MS method.

Statistical Methods
The study was designed to enroll 37 patients per dose cohort, with the primary goal of selecting the better of two doses of arzoxifene.¹⁷ An early stopping rule was included in case one or both doses proved to be inactive. The selection procedure was simply to choose the dose with the higher observed response rate between treatment groups. Assuming the true response rate is at least 15% higher on the better dose, this design has a 90% probability of selecting the better dose. Note that the selection design does not control for type I errors in the comparison of response rates between the dose cohorts, so the question of whether there was a statistically significant difference in response rate was not addressed. Exact 95% binomial confidence intervals (CIs) were computed for response rates, but only for purposes of illustrating the precision of the point estimates.

For end points other than response rate, standard statistical analysis methods were used to summarize and compare cohorts. Kaplan-Meier¹⁸ estimation and the log-rank test were used to evaluate TTP. The Mantel-Haenszel ² test was used to compare incidence of toxicities accounting for severity. Changes from baseline in various end points (eg, hormones, bone-related markers, and physical examinations) were assessed within study arms using the nonparametric sign test to allow for nonsymmetrical distributions, and between study arms using the Wilcoxon rank sum test. All significance tests for secondary end points were performed at the .05 level, whereas all CIs used the 95% level.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patient Characteristics
Between May 1998 and February 2001, 121 patients were entered onto the study, which was conducted at six study centers in the United States. Nine patients were not assigned to treatment because they either did not meet eligibility criteria (seven patients) or decided not to enter (two patients). One hundred twelve women were enrolled; 55 were randomly assigned to receive 20 mg of arzoxifene, and 57 patients were randomly assigned to receive 50 mg. Table 1 lists the baseline patient and disease characteristics of all randomized patients. Of note, there were more PS 0 patients in the 50-mg arm than in the 20-mg arm (42% v 31%). Also, there were more ER-positive patients in the 50-mg arm than in the 20-mg arm (91% v 84%). Sixty-three patients were defined as TR and 49 were considered TS. Overall, the characteristics were well matched when comparing the 20- and 50-mg cohorts, regardless of tamoxifen sensitivity.

View larger version (18K): [in this window] [in a new window]   Fig 1. Kaplan-Meier18 estimate for time to progression (months) in tamoxifen-sensitive patients.

View larger version (14K): [in this window] [in a new window]   Fig 2. Kaplan-Meier18 estimate for time to progression (months) in tamoxifen-refractory patients.

A survival analysis was not performed because more than 80% of the enrolled patients were still alive at the time of the final analysis.

Toxicity
One patient with a prior diagnosis of cholelithiasis on the 20-mg arm experienced grade 3 transaminase and grade 3 bilirubin elevations. Overall, grade 2 laboratory aberrations were reported in less than 5% of patients, with only 7% of patients experiencing grade 1 aberrations. There were no investigator-determined grade 4 laboratory abnormalities.

Table 6 presents clinical toxicities reported in at least 2% of patients treated with arzoxifene. There were no statistically significant differences in the toxicities observed between the treatment arms. The most common grade 2 clinical toxicities were hot flashes and nausea. Seven patients (6%) reported with grade 3 toxicities, including nausea/vomiting, rash, neuromotor toxicity (defined as fatigue and asthenia; n = 2), neuromood toxicity (defined as depression), headache, neurocerebellar toxicity (defined as dizziness), and pulmonary toxicity (defined as dyspnea). These events did not result in drug discontinuation. There were no grade 4 clinical toxicities.

There were five deaths that all occurred within 5 weeks of study discontinuation. Four patients died as a result of PD and one died as a result of unspecified natural causes that were not disease related.

Effects on the Endometrium
All enrolled patients with an intact uterus underwent a baseline TVU evaluation. Because of the natural and potentially complex variations in endometrial thickness in menstruating women, only postmenopausal women are discussed in this report. Ninety-three of the 112 patients were postmenopausal; 33 of the 93 patients had undergone hysterectomy before enrollment. Sixty patients underwent baseline TVU evaluations, 21 in the 20-mg arm and 39 in the 50-mg arm. Forty-six of the 60 patients had at least one follow-up TVU. Although none of the postmenopausal patients in the 20-mg arm experienced significant endometrial thickness increases (see Patients and Methods, under Uterine Evaluations), one patient did experience vaginal bleeding attributed to atrophic vaginitis. Five patients in the 50-mg arm had a significant increase in endometrial thickness. Four of these five patients did not undergo the study-defined follow-up evaluations; however, two of the four patients had normalization of their endometrial thickness without diagnostic or therapeutic intervention. For the one patient who underwent further evaluation of her increased endometrium, the obtained tissue was insufficient for diagnosis.

Hormone and Bone Biomarker Evaluations
There were no statistically significant differences within or between treatment arms in changes from baseline in serum LH, FSH, estradiol, or SHBG (Table 7). However, when the data are analyzed according to menopausal status, decreases in LH and FSH with a concomitant increase in SHBG in postmenopausal women, consistent with a weak estrogen agonist effect on the pituitary, become evident (data not shown). These findings have been previously reported in postmenopausal women receiving tamoxifen therapy.¹⁹

The serum osteocalcin level was measured at baseline, every 4 weeks for 12 weeks, and then every 2 to 3 months until study discontinuation. The osteocalcin data analysis consisted of a comparison in median change from baseline to last observed value for all randomized patients, as well as a comparison between the two treatment groups. A total of 105 patients had at least two osteocalcin measurements (88 postmenopausal patients; 17 premenopausal patients). Although there was a statistically significant decline in osteocalcin among the postmenopausal patients in the 50-mg arm (median change, -3.5 µg/L), such a decline was not noted in the postmenopausal patients in the 20-mg arm (median change, -1.9 µg/L). The difference between the 20-mg and 50-mg arms in osteocalcin suppression in postmenopausal women did not reach statistical significance. Among the premenopausal patients with serial measurements, osteocalcin was not significantly suppressed by either arzoxifene 20 mg (median change, 0.3µg/L) or 50 mg (median change, -0.6 µg/L); however, the small number of premenopausal patients in this study precludes reliable statistical analysis or interpretation. The observed osteocalcin suppression indicates that arzoxifene exerts an antiresorptive effect on bone in postmenopausal but not premenopausal breast cancer patients.

Pharmacokinetics
The overall mean steady-state plasma concentrations of LY353381 were 2.88 ng/mL and 8.36 ng/mL for the 20-mg and 50-mg doses, respectively. None of the samples obtained were below the limit of LY353381 quantitation (< 0.05 ng/mL) for either dose group. For desmethyl metabolite LY335562, however, approximately 68% and 44% of the samples obtained were below the limit of quantitation (< 0.05 ng/mL) for the 20-mg and 50-mg arms, respectively. For patients who had quantifiable LY335562, the individual observed steady-state concentrations ranged from 0.051 to 1.132 ng/mL for the 20-mg dose and 0.051 to 2.798 ng/mL for the 50-mg dose. These data demonstrate the linear pharmacokinetic profile of arzoxifene and are consistent with data previously observed.¹³

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
This double-blinded, randomized, phase II trial was designed to select an effective dose of arzoxifene for phase III trials. In this phase II study, the efficacy and safety of 20 mg and 50 mg of arzoxifene in patients with advanced or metastatic breast cancer were further investigated. The study indicates that arzoxifene is an effective therapy in patients with advanced or metastatic breast cancer at both the 20-mg and 50-mg doses. There did not seem to be an obvious dose-response curve in this study. Among the TS patients, the 20-mg dose of arzoxifene produced numerically superior RR, CBR, and TTP compared with the 50-mg dose. Among the TR patients, 20 mg of arzoxifene produced RR, CBR, and TTP similar to the 50-mg dose. Safety and toxicity were similar for the two doses in both patient cohorts. Because the efficacy and toxicity were similar in the two dose cohorts, this study supports the use of the 20-mg dose of arzoxifene as the treatment dose for subsequent phase III trials.

Although the between-group CIs for 20 mg and 50 mg of arzoxifene indicate that there is no difference between the doses for either TS or TR patients, the seemingly large difference in RRs and CBRs warrant further scrutiny. There were four imbalances between the 20-mg and 50-mg arms of the TS cohort: PS, receptor status, menopausal status, and length of adjuvant tamoxifen exposure. However, three of the four imbalances that would be anticipated to predict a higher response rate (PS, receptor status, and menopausal status) actually favored the 50-mg arm. The one characteristic that may have favored the 20-mg arm was the shorter length of adjuvant tamoxifen exposure in the TS patients.

As previously noted, there are theoretical and clinical concerns that use of adjuvant tamoxifen for more than 5 years may be associated with the development of tamoxifen-dependent breast cancer.⁶ The activity of arzoxifene has recently been reported in two models of breast cancer in athymic mice: MCF-7 (wild-type p53 mutation) and T47D (nonfunctional p53 mutation).²⁰ In these studies, arzoxifene was found not to be cross-resistant in the T47D model but seemed to be partially cross-resistant with tamoxifen in the tamoxifen-stimulated MCF-7 model. Given the disparate action of arzoxifene in the two models, this may indicate that arzoxifene could be superior to tamoxifen in some patients because of the different cross-resistant patterns. The data in this study in the TR cohort indicate that there is some activity of arzoxifene after disease progression on tamoxifen. The partial cross-resistance with tamoxifen may explain the lower response rate seen in the 50-mg cohort owing to a slight imbalance in randomization, with a longer duration of tamoxifen exposure in the 50-mg arm. The mechanisms of hormonal resistance in breast cancer thus remain an important area of translational research.

It is noteworthy that in a comparable European randomized, phase II study of arzoxifene 20 mg and 50 mg in 92 patients with advanced breast cancer, arzoxifene resulted in investigator-assessed RRs of 40.5% and 36.4%, CBRs of 64% and 61.4%, and TTPs of 10.7 and 8.6 months, respectively (P > .05). There were some differences in the study population that may account for the discrepancies. Compared with the patients in the current study, patients in the European study were older (median age, 70 years), had newly diagnosed breast cancer (median time from breast cancer diagnosis to study entry, 1.2 months), and were treatment-naive (85% of patients had received no prior chemotherapy, and 91% had received no prior tamoxifen therapy; Baselga J, Llombart A, manuscript submitted for publication).

Overall, toxicities of arzoxifene were minimal, and there were no statistical differences in toxicities between the 20-mg and 50-mg cohorts. Although hot flashes and nausea were the most common toxicities in both arms, there was no evidence of dose-dependent toxicity. The phase I trial of arzoxifene in patients with metastatic breast cancer found little estrogenic effects on uterine tissue.¹³ In this study, an increased endometrial thickness was reported in five of the 60 postmenopausal patients, all of whom were treated at the 50-mg dose. Further data indicating that there is minimal estrogenic effect on uterine tissue come from a phase II study in patients with progestagen-sensitive, metastatic endometrial cancer.²¹ This study treated 30 patients with progestagen-sensitive, metastatic endometrial cancer with 20 mg of arzoxifene and reported an overall RR of 28% and a median TTP of 5.5 months.

In conclusion, arzoxifene is an effective agent in the treatment of advanced or metastatic breast cancer and seems to be safe and well tolerated. Arzoxifene 20 mg daily is currently being compared with tamoxifen 20 mg daily in TS patients with advanced breast cancer in a multinational phase III trial.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Principal investigators for the study (in addition to listed authors) were as follows: University of Chicago, Chicago, IL, G. Fleming; and Kenneth Norris Jr Comprehensive Cancer Center, Los Angeles, CA, C.A. Russell.

	NOTES

 
This work was sponsored by Eli Lilly and Company.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
1. Henderson BE, Bernstein L: The international variation in breast cancer rates: An epidemiological assessment. Breast Cancer Res Treat 18:S11–S17, 1991 (suppl)

2. Wakeling AE: Similarities and distinctions in the mode of action of different classes of antioestrogens. Endocr Relat Cancer 7:17–28, 2000[CrossRef][Medline]

3. Jaiyesimi IA, Buzdar AU, Decker DA, et al: Use of tamoxifen for breast cancer: Twenty-eight years later. J Clin Oncol 13:513–529, 1995[Abstract/Free Full Text]

4. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371–1388, 1998[Abstract/Free Full Text]

5. Early Breast Cancer Trialists’ Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351:1451–1467, 1998[CrossRef][Medline]

6. Fisher B, Dignam J, Bryant J, et al: Five versus more than five years of tamoxifen for lymph node-negative breast cancer: Updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 93:684–690, 2001[Abstract/Free Full Text]

7. Barakat RR: The effect of tamoxifen on the endometrium. Oncology 9:129–134, 1995

8. van Leeuwen FE, Benraadt J, Coebergh JW, et al: Risk of endometrial cancer after tamoxifen treatment of breast cancer. Lancet 343:448–452, 1994[CrossRef][Medline]

9. Jordan VC, Assikis VJ: Endometrial carcinoma and tamoxifen: Clearing up a controversy. Clin Cancer Res 1:467–472, 1995[Abstract]

10. Bryant HU, Glasebrook AL, Knadler MP, et al: LY353381.HCl: A highly potent selective estrogen receptor modulator with oral activity in vivo. Endocrine Society Annual Meeting, Minneapolis, MN, July 1997 (abstr P3–446)

11. Bryant HU, Wilson PK, Adrian MD, et al: Selective estrogen receptor modulators: Pharmacological profile in the rat uterus. J Soc Gynecol Invest 3:152A, 1996 (abstr 188)

12. Rowley E, Adrian MD, Bryant H, et al: LY353381.HCl is a new SERM with potent bone and lipid effects without stimulation of uteri. J Bone Miner Res 12:S348, 1997 (abstr F490)

13. Münster P, Buzdar A, Dhingra K, et al: Phase I study of a third generation selective estrogen receptor modulator (SERM, LY353381. HCl) in metastatic breast cancer. J Clin Oncol 19:2002–2009, 2001[Abstract/Free Full Text]

14. Pocock SJ, Simon R: Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 31:103–115, 1975[CrossRef][Medline]

15. National Cancer Institute: Common Toxicity Criteria Manual (version 1.0). Bethesda, MD, National Cancer Institute, National Institute of Health, United States Department of Health and Human Services, 1982

16. World Health Organization: WHO Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland, World Health Organization publication no. 48, 1979

17. Gibbons JD, Olkin I, Sobel M: Selecting and Ordering Populations: A New Statistical Methodology. New York, NY, Wiley, 1977

18. Kaplan EL, Meier P: Nonparametric estimation of incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef]

19. Sunderland MC, Osborne CK: Tamoxifen in premenopausal patients with metastatic breast cancer: A review. J Clin Oncol 9:1283–1297, 1991[Abstract]

20. Macgregor-Shafer J, Lee E-S, Dardes RC, et al: Analysis of cross-resistance of the selective estrogen receptor modulators arzoxifene (Ly353381), and LY117018 in tamoxifen-stimulated breast cancer xenografts. Clin Cancer Res 7:2505–2512, 2001[Abstract/Free Full Text]

21. Klijn JGM, Rosenberg P, Scambia G, et al: Multicentre phase II study of the selective estrogen receptor modulator (SERM) LY353381 in advanced or recurrent endometrial cancer: Objective responses in progestagen sensitive patients (PTS). Proc Am Soc Clin Oncol 19:386a, 2000 (abstr 1527)

Submitted June 18, 2002; accepted December 9, 2002.

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

This article has been cited by other articles:

				W. Zwart, M. Rondaij, K. Jalink, Z. D. Sharp, M. A. Mancini, J. Neefjes, and R. Michalides Resistance to Antiestrogen Arzoxifene Is Mediated by Overexpression of Cyclin D1 Mol. Endocrinol., September 1, 2009; 23(9): 1335 - 1345. [Abstract] [Full Text] [PDF]

				M. Bolognese, J. H. Krege, W. H. Utian, R. Feldman, S. Broy, D. L. Meats, J. Alam, M. Lakshmanan, and M. Omizo Effects of Arzoxifene on Bone Mineral Density and Endometrium in Postmenopausal Women with Normal or Low Bone Mass J. Clin. Endocrinol. Metab., July 1, 2009; 94(7): 2284 - 2289. [Abstract] [Full Text] [PDF]

				Z. Qin, I. Kastrati, R. T. Ashgodom, D. D. Lantvit, C. R. Overk, Y. Choi, R. B. van Breemen, J. L. Bolton, and G. R. J. Thatcher Structural Modulation of Oxidative Metabolism in Design of Improved Benzothiophene Selective Estrogen Receptor Modulators Drug Metab. Dispos., January 1, 2009; 37(1): 161 - 169. [Abstract] [Full Text] [PDF]

				V. Deshmane, S. Krishnamurthy, A. S. Melemed, P. Peterson, and A. U. Buzdar Phase III Double-Blind Trial of Arzoxifene Compared With Tamoxifen for Locally Advanced or Metastatic Breast Cancer J. Clin. Oncol., November 1, 2007; 25(31): 4967 - 4973. [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]

				G. J. Kelloff, S. M. Lippman, A. J. Dannenberg, C. C. Sigman, H. L. Pearce, B. J. Reid, E. Szabo, V. C. Jordan, M. R. Spitz, G. B. Mills, et al. Progress in Chemoprevention Drug Development: The Promise of Molecular Biomarkers for Prevention of Intraepithelial Neoplasia and Cancer--A Plan to Move Forward Clin. Cancer Res., June 15, 2006; 12(12): 3661 - 3697. [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]

				L. Wu and I. F. Tannock Effect of the Selective Estrogen Receptor Modulator Arzoxifene on Repopulation of Hormone-Responsive Breast Cancer Xenografts between Courses of Chemotherapy Clin. Cancer Res., November 15, 2005; 11(22): 8195 - 8200. [Abstract] [Full Text] [PDF]

				C. J. Fabian and B. F. Kimler Selective Estrogen-Receptor Modulators for Primary Prevention of Breast Cancer J. Clin. Oncol., March 10, 2005; 23(8): 1644 - 1655. [Full Text] [PDF]

				M. B. Sporn Arzoxifene: A Promising New Selective Estrogen Receptor Modulator for Clinical Chemoprevention of Breast Cancer: Commentary re C. J. Fabian et al., Breast Cancer Chemoprevention Phase I Evaluation of Biomarker Modulation by Arzoxifene, a Third Generation Selective Estrogen Receptor Modulator. Clin Cancer Res 2004;10:5403-17. Clin. Cancer Res., August 15, 2004; 10(16): 5313 - 5315. [Full Text] [PDF]

				C. J. Fabian, B. F. Kimler, J. Anderson, O. W. Tawfik, M. S. Mayo, W. E. Burak Jr., J. A. O'Shaughnessy, K. S. Albain, D. M. Hyams, G. T. Budd, et al. Breast Cancer Chemoprevention Phase I Evaluation of Biomarker Modulation by Arzoxifene, a Third Generation Selective Estrogen Receptor Modulator Clin. Cancer Res., August 15, 2004; 10(16): 5403 - 5417. [Abstract] [Full Text] [PDF]

				S. Detre, S. Riddler, J. Salter, R. A'Hern, M. Dowsett, and S. R. D. Johnston Comparison of the Selective Estrogen Receptor Modulator Arzoxifene (LY353381) with Tamoxifen on Tumor Growth and Biomarker Expression in an MCF-7 Human Breast Cancer Xenograft Model Cancer Res., October 1, 2003; 63(19): 6516 - 6522. [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 Buzdar, A. Articles by Hudis, C. Search for Related Content PubMed PubMed Citation Articles by Buzdar, A. Articles by Hudis, C. Social Bookmarking                            What's this?