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 Münster, P. N. Articles by Hudis, C. Search for Related Content PubMed PubMed Citation Articles by Münster, P. N. Articles by Hudis, C.

Phase I Study of a Third-Generation Selective Estrogen Receptor Modulator, LY353381.HCl, in Metastatic Breast Cancer

From the Memorial Sloan Kettering Cancer Center, New York, NY; M.D. Anderson Cancer Center, Houston, TX; and Eli Lilly and Company, Indianapolis, IN.

Address reprint requests to Clifford A Hudis, MD, Chief Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, Box #206, 1275 York Ave, New York, NY 10021.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: We conducted this phase I trial to determine the safety and toxicity profile of LY353381.HCl—a novel, potent, third-generation selective estrogen receptor modulator (SERM)—because this benzothiophene derivative demonstrated an SERM profile in preclinical studies.

PATIENTS AND METHODS: We studied 32 patients with recurrent or metastatic breast cancer. Patients were treated in four cohorts with oral daily doses of 10, 20, 50, and 100 mg. Pharmacokinetic sampling was performed during the first 72 hours following the first dose on day 1 and during the 24 hours after the day 57 dose. Eligibility criteria included Eastern Cooperative Oncology Group performance status of 0 to 2; no significant major organ dysfunction; and at least 3 weeks elapsed since most recent hormonal therapy, chemotherapy, and estrogen replacement therapy.

RESULTS: The median patient age was 56 years (range, 30 years to 76 years). The median number of prior chemotherapies for metastatic disease was one (range, zero to four), while the median number of prior hormone regimens for metastatic disease was two (range, zero to five). Receptor status was estrogen receptor (ER) positive and progesterone receptor (PR) positive, 19 patients; ER positive and PR negative, eight patients; ER positive and PR unknown, two patients; and ER and PR unknown, three patients. Dose-limiting toxicity was not observed. Treatment was well tolerated with mild to moderate hot flashes in 18 of 32 patients (56%) at all dose levels. Transvaginal ultrasound performed at baseline and after 12 weeks of treatment showed no endometrial thickening. Of the 32 patients evaluable for response, six patients had stable disease for at least 6 months with a median duration of 7.7 months (range, 6.2 months to 33.8 months). The pharmacokinetics of LY353381.HCl were generally linear with respect to time and studied dose range.

CONCLUSION: As predicted in preclinical testing, daily oral LY353381.HCl is safe, is well tolerated at all tested dose levels, and may be clinically beneficial in patients with extensively pretreated metastatic breast cancer. Further studies with LY353381 to evaluate the efficacy in patients with or without prior exposure to tamoxifen and fewer overall prior regimens are under way.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Breast cancer is one of the most common cancers in the Western Hemisphere and the second most common cause of cancer deaths in women.¹ Endocrine therapy, including ovarian ablation; estrogen; and, more recently, antiestrogen administration, has been a major component of antitumor therapy in breast cancer for more than a century.² Presently, tamoxifen is the drug of choice not only for previously untreated hormonally responsive metastatic disease but also for adjuvant hormone treatment for primary breast cancer. Unfortunately, its estrogenic effects in selected tissue lead to undesirable side effects. Tamoxifen has been associated with an increased risk of endometrial hyperplasia and cancer.^3-5 Furthermore, the effectiveness of tamoxifen is limited by the emergence of resistance suggested by clinical progression while on the drug.^6-8 In vitro studies suggest that resistance may be partially explained by the development of tamoxifen-dependent clones.^9,10 As a result, emphasis has been placed on finding selective estrogen receptor modulators (SERMs) with increased antiestrogenic activity not only in the breast but also in the endometrium and with more favorable estrogenic effects on bone and lipid metabolism.

Preclinical data for a third-generation SERM, LY353381.HCl, suggest that in mammary and uterine tissue this agent has potent antiestrogenic effects while having estrogenic effects on the bone and cholesterol metabolism.^11,12 In vitro, LY353381.HCl is metabolized to desmethyl-LY353381.HCl (LY335562), and both compounds bind to the estrogen receptor (ER) with high affinity.^13,14 Its antitumor efficacy in MCF-7 cells was found to be significantly higher than tamoxifen. The intrinsic estrogen agonist properties in uterine tissues found with tamoxifen were not seen in preclinical testing of LY353381.HCl.¹⁵ In nude mice xenografts, LY353381.HCI was significantly better at inhibiting tumor progression than raloxifene or tamoxifen when given at equivalent doses.¹⁶

Antiestrogen activity on the endometrium has been suggested by the lack of any stimulation of uterine growth in oophorectomized rats.¹⁶ In oophorectomized rats, treatment with LY353381.HCl compared with placebo controls prevented bone loss.^15,17 Extensive preclinical toxicology has not suggested any serious toxicities. Given its promising antitumor activity and its potentially more desirable side effect profile, LY353381.HCl was selected for clinical testing. The starting dose of the trial was 10 mg per day based on several preclinical and pharmacological observations. A phase I study involving multiple doses in healthy postmenopausal women assessed the effects of LY353381.HCl on coagulation parameters, lipoproteins, hormonal parameters, biochemical bone markers, and gynecological parameters. The lowest dose that resulted in significant reductions in biochemical bone markers (serum osteocalcin, urinary crosslaps), low-density lipoprotein (LDL) cholesterol, and gonadotropin concentrations [follicle-stimulating hormone (FSH) and luteinizing hormone (LH)] was 10 mg per day. Preclinical experiments in a MCF-7 Xenograft model suggested that the lowest concentration of LY353381.HCl that resulted in statistically significant reduction of percent change of tumor volume from the control was 0.2 mg/kg/d. This dose was approximately equal to a 10 mg/d human dose. Another preclinical experiment in a rat chemo-preventive model of mammary carcinogenesis found activity at a similar dose level. In the absence of observed toxicity, the 10-mg/d dose was chosen as the starting dose for this study. (Data on file, Eli Lilly and Company, Indianapolis, IN)

In this paper, we report the safety, toxicity, pharmacology, and response data in women with advanced breast cancer.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility Requirements
Women were required to have histologically confirmed locally advanced or metastatic adenocarcinoma of the breast or endometrium that was measurable or evaluable. Other requirements included 18 years old; an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2; and normal organ function (ie, WBC count 3.0 x 10⁹/L, platelets counts 100 x 10⁹/L, and hemoglobin 9 g/dL). The life expectancy had to be > 12 weeks. Patients had to be off any prior chemotherapy, radiation therapy, or hormone therapy for at least 3 weeks before enrollment; however, there was no limit on prior lines of hormonal therapy, chemotherapy, or radiation therapy. The study excluded patients with inadequate liver function (ie, bilirubin > 1.5, prothrombin time or activated partial thromboplastin time > 1.25, AST or ALT > 2.5 times the upper limit of normal), inadequate kidney functions (ie, serum creatinine 1.5 times the upper limit of normal), hypercalcemia (ie, corrected calcium > 11.0 mg/dL), a history of thromboembolic disorders, or a known predisposition to venous thrombosis. Patients were not allowed to take supplemental estrogen or progesterone within 3 weeks or any investigational agent within 4 weeks before study entry. Women with second primary malignancies (except adequately treated basal cell carcinoma of the skin), known brain metastases, or those who were pregnant or breast feeding or who had any active CNS disorder or active infection were also excluded.

Study Design
A single oral dose of LY353381.HCl was administered on the morning of day 1 after patients had been asked to omit breakfast. Regular once daily dosing began on day 4. Patients were instructed to avoid taking the study drug during the period of 1 hour before and 2 hours after meals to ensure consistency of dosing on an empty stomach. Cohorts of eight patients were to be treated at each of four dose levels (10, 50, 100, and 200 mg) administered in tablet form once daily. To ensure safety, three patients in each dose level were treated and then observed for at least 4 weeks. If no more than one of the first three patients developed National Cancer Institute Common Toxicity Criteria (version 1) grade 3 or higher drug-related toxicity, an additional five patients were enrolled at the same dose level. After these five patients were enrolled, three more patients at the next higher dose level could be enrolled immediately.

Dose-limiting toxicity was defined as any grade 3 or higher nonhematologic or hematological toxicity. The doses were increased from 10 mg to 50 mg and then to 100 mg. The final dose level was initially determined as 200 mg per day. However, this dose was replaced by 20 mg per day, based on the pharmacokinetic profiles of the 10-, 50-, and 100-mg dose levels.

Patient Evaluation
A complete history and physical examination including an ECOG performance status, blood pressure, pulse, height, and weight was performed at baseline and at each subsequent physician visit. Tumor markers (CEA, CA15-3, CA-125), urine analysis, and an electrocardiogram were performed before treatment. Tumor markers were subsequently obtained every 4 weeks for those that were elevated at baseline. Other blood testing included hematology (WBC count with differential, platelet count, and hemoglobin) and chemistry analysis [electrolytes, creatinine, calcium, glucose, phosphorus, albumin, bilirubin, alkaline phosphatase, ALT, AST, gamma-glutamyltransferase, and lactose dehydrogenase (LDH)] as well as coagulation studies (prothrombin time, PTT), hormone levels [FSH, LH, estradiol, sex hormone–binding globulin (SHBG)], and bone markers (serum osteocalcin, fasting urine for calcium, creatinine, and type I collagen fragments). These studies were repeated on study once weekly for 4 weeks, every other week until week 12, and then every 2 to 3 months for patients remaining on study. Transvaginal ultrasound, used to assess endometrial thickness, was performed in all patients with an intact uterus at baseline and again at day 85. Subsequent ultrasound studies were performed every 2 to 3 months as long as patients remained on study. Tumor assessments by radiological evaluation (computed tomography scan of chest, abdomen, and pelvis; bone scan) were performed no more than 4 weeks before enrollment and repeated after 12 weeks of treatment and every 2 months thereafter if patients continued on study. Toxicities were evaluated at each physician visit using the Common Toxicity Criteria.

Response Evaluation
Standard World Health Organization response criteria were used to assess responses. Tumor response was evaluated after 12 weeks of treatment and every 2 months thereafter. Patients were allowed to remain on study if they had either an objective response (partial or complete response) or were judged radiologically or clinically to have stable disease.

Pharmacokinetics
Heparinized blood samples (10 mL) were obtained at 0, 0.5, 1, 2, 4, 6, 8, 24, 48, and 72 hours after the first dose of LY353381.HCl. Additional samples were obtained on day 57 at 0, 0.5, 1, 2, 4, 6, 8, and 24 hours after that day’s dose. Single blood samples for pharmacokinetic studies were also collected on days 8, 15, 22, 29, 43, 71, and 85. The pharmacokinetics of LY353381.HCl and the desmethyl metabolite, LY335562, were obtained.

Statistical Analysis
Time to progression was assessed using the Kaplan-Meier method. Confidence intervals for median time to progression were computed using Greenwood’s formula for standard error. Sign tests were used to assess the significance of changes from baseline for pharmacodynamic parameters within treatment groups, and all P values were two sided.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Treatment Administration and Patient Characteristics
Between September 30, 1997, and March 31, 1998, 32 women were enrolled: 21 at Memorial Sloan-Kettering Cancer Center and 11 at M.D. Anderson Cancer Center. Although the study initially planned for a final dose level of 200 mg per day, this was replaced by a cohort at 20 mg per day, based on the pharmacokinetic profiles of the 10-, 50-, and 100-mg dose levels. All patients had histologically confirmed metastatic breast cancer. Other characteristics of the patient population are listed in Table 1. The median age was 56 years old (range, 30 years to 76 years). Three women were premenopausal as defined by age < 50 years old and baseline FSH < 40 IU/L. Most patients had ECOG performance status of 1 or 2 (85%). All patients had received prior tamoxifen therapy. The median number of prior hormone treatments for metastatic disease was 2 (range, 0 to 5), and 14 of 32 (44%) patients had three or more prior hormonal therapies. The median number of prior chemotherapy regimens for metastatic disease was 1 (range, 0 to 4), and 16 of 32 (50%) patients had one or more prior chemotherapy regimen for metastatic disease. Sixteen of 32 (50%) patients had prior adjuvant chemotherapy; four of 32 (13%) patients had prior high-dose therapy (one as adjuvant treatment and three for metastatic disease).

Toxicity
No dose-limiting toxicities were observed in the enrollment and dose escalation phase of the study. Dose reductions were not required in any patient. Hot flashes, the most commonly seen toxicity (18 of 32, 56%), were noted at all dose levels and did not increase in frequency with increasing dose. Other toxicities were rare. One patient had grade 2 nausea and grade 3 vomiting. One patient suffered from a pulmonary embolus during a hospitalization for surgical repair of a femur fracture. A second patient (at the 10-mg dose level) had a deep vein thrombosis in the leg at 34 months on study. This elderly, obese patient with diabetes and a sedentary lifestyle was taken off study after this event. All other observed toxicities were 2 ( Table 2). Rash occurred in three patients (9%); pruritus occurred in two patients (6%); and constipation, headache, and stomatitis were seen in one patient (3%) each.

View larger version (20K): [in this window] [in a new window]   Fig 1. Mean plasma concentrations of LY353381.HCl versus time following a single dose at visit 1 and multiple doses of LY353381.HCl at visit 3.

Effects on the Endometrium
Transvaginal ultrasounds were performed on all patients who had an intact uterus at baseline, at 12 weeks follow-up, and every 8 to 12 weeks on patients who continued treatment. Endometrial thickness of greater than 8 mm or a change from baseline of > 5 mm was considered abnormal and required further work-up.

Pathological thickening of the endometrial lining was not observed in any of the 15 evaluable patients assessed by serial ultrasounds. Median endometrial thickening from baseline to each patient’s largest postbaseline value was approximately 0 mm (range, -9 mm to +3.4 mm). To evaluate the effect of prior tamoxifen therapy on the distribution of these changes, the correlations between time since prior tamoxifen therapy, duration of prior tamoxifen therapy, baseline endometrial thickness, and the change from baseline in endometrial thickness were evaluated. This analysis showed that the change from baseline in endometrial thickness was highly negatively correlated with the baseline endometrial thickness and that the baseline endometrial thickness was positively correlated with duration of prior tamoxifen therapy.

Antitumor Activity
All patients had received prior tamoxifen therapy. The median number of prior therapies for metastatic disease was four (range, zero to eight). No complete, partial, or minor responses were seen in these 32 patients. For all patients, median time to progression was 2.8 months (95% confidence interval, 2.3 months to 3.0 months).

Stable disease beyond 6 months was seen in six of 32 (19%) patients with a median duration of 7.7 months (range, 6.2 months to 34 months). All patients had been extensively pretreated. In addition to tamoxifen, three of these six patients had progressed during prior therapy with an aromatase inhibitor, and three of six patients had been treated with megestrol. Baseline characteristics for these patients are provided in Table 6.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

SERMs, such as tamoxifen or the new generation SERMs, act through binding to the ER. Hormone binding to the ER initiates a series of molecular events that lead to activation or repression of target genes. Both estradiol and SERMs bind at the same site within the core of the ligand-binding domain but with different binding modes.¹⁸ Each class of ligand induces a distinct conformational change in the transactivation domain of the ligand-binding domain. Furthermore, a recent report has shown that binding of tamoxifen to the receptor exposes a binding site that is occupied by a coactivating protein that is not used by the estrogen-activated receptor.¹⁹ These findings suggest that estradiol as well as SERM bind to the ER. Ligand binding subsequently enables binding of coactivators or corepressors, which may at least partly determine whether the ligand is an agonist or antagonist in a certain tissue.

The SERMs have entered clinical trials for prevention and treatment of osteoporosis and for the prevention and treatment of breast cancer. The SERM raloxifene (Evista, Eli Lilly and Company, Indianapolis, IN) has recently been shown to significantly increase the bone mineral density and to lower the total cholesterol and LDL cholesterol in postmenopausal women compared with a placebo group.²⁰ The effect of raloxifene on reducing the incidence of invasive breast cancer was examined in postmenopausal women with osteoporosis as a secondary objective in the Multiple Outcomes of Raloxifene Evaluation trial. In this study, the risk of invasive breast cancer was decreased by 76% after 3 years of treatment with raloxifene.²¹

Preclinical data of the SERM evaluated in our study, LY353381.HCl, suggested that in mammary and uterine tissue, LY353381.HCl has potent antiestrogenic effects, while it shows estrogenic effects on the bone and cholesterol metabolism.^15,16,22 Stimulation of uterine growth has not been observed in any of the examined animal models. Extensive preclinical toxicology did not suggest any profound toxicities. The lowest dose that was considered to be active in preclinical studies and had estrogenic effects in healthy volunteers was 10 mg/d (Data on file, Eli Lilly and Company, Indianapolis, IN). The original study design of using escalating doses of 10 mg, 50 mg, 100 mg, and 200mg per day was later amended to 10 mg, 20 mg, 50 mg, and 100 mg per day when it became clear that antiestrogenic effects, such as hot flashes, were observed at the 10 mg dose, and some of the women had tumor stabilization at the 10 mg dose. At the same time, the results of a parallel study involving healthy volunteers suggested that doses of 25 mg/d and 100 mg/d were equally effective in lowering fibrinogen, biochemical bone markers, LDL cholesterol, and gonadotropin concentrations. (Data on file, Eli Lilly and Company, Indianapolis, IN)

The toxicities of LY353181.HCl were minimal, and dose-limiting toxicities were not reached. The most common toxicities were hot flashes, and these were seen in about half of our patients. In most cases, these hot flashes were mild with no more than one hot flash per day. None of the patients required treatment for their hot flashes. One patient suffered from a pulmonary embolus during hospitalization for surgical repair of a femur fracture. A second patient suffered from a lower extremity deep vein thrombosis after 34 months on study. This patient also was very obese and led a very sedentary life style. While thromboembolic events are not uncommon in patients with hip fractures and hip surgeries and obesity may be a confounding factor, this observation should prompt close attention to the risk assessment of thromboembolic events in further clinical trials with LY353381.HCl. A slight increase in thromboembolic phenomena has been observed with estrogens, tamoxifen, and other SERMs such as raloxifene.^20,23,24 The toxicity criteria used for this study was the Common Toxicity Criteria version 1. While they were later recognized and adjusted in version 2, thromboembolic events were not listed as toxicities.

In this study, no estrogenic effects were seen on the uterus. The sample size was small, and because the incidence of uterine hyperplasia is low, this study could have failed to detect estrogenic effects on the uterus. Two patients reported mild vaginal spotting. However, these events were not associated with any pathologic findings. The absence of endometrial changes has been shown in studies of the benzothiophene raloxifene that included more than 5,000 patients and more than 40 months follow-up. This suggests that other benzothiophenes, such as LY353381.HCl, should not have an adverse effect on the uterus.²⁵ In fact, correlation analysis in this study seemed to indicate that changes in endometrial thickness were related to baseline values, which in turn were related to the duration of prior tamoxifen therapy. The effects on the endometrium will again be evaluated in the ongoing phase II and upcoming phase III trials. The serum osteocalcin, a marker for bone resorption, was significantly decreased in the patients taking LY353381.HCl, which would suggest that this drug may be beneficial for the bone metabolism. However, given the small sample size, no definite conclusion can be drawn with regard to effects on bone metabolism.

Statistically significant changes from baseline to the last observed value were observed for FSH, LH, and SHBG. Treatment with tamoxifen has caused similar effects in postmenopausal women.^26-28 These changes may be caused by an agonist effect on the hypothalamic-pituitary axis. FSH and LH levels in premenopausal patients were not evaluated because only three premenopausal women participated in the study.

Complete pharmacokinetics of LY353381.HCl were evaluated in 28 patients after receiving single and multiple doses of 10 mg, 20 mg, 50 mg, and 100 mg LY353381. Parameter values after the single dose were predictive of steady-state pharmacokinetics after multiple doses, suggesting that LY353381.HCl pharmacokinetics are linear with respect to time during an approximately 7-week dosing regimen. The mean C_max and area under curve values after the single dose and at steady-state increased proportionally with dose, and values of apparent clearance and apparent volume of distribution were comparable in all dose levels except 20 mg. Concentrations of LY353381.HCl appeared relatively low after the 20-mg dose. This variation in the 20-mg dose has not been observed in animal testing or in healthy volunteers. In addition, this finding was not secondary to a known dosing error and could not be explained by obvious differences in the patients characteristics. A previous study in healthy postmenopausal women has indicated that pharmacokinetics of LY353381.HCl were linear with respect to dose over a range from 5 mg every other day to 100 mg daily.²⁹ Therefore, the pharmacokinetic variability and small sample size at each dose level may account for this finding. These results suggest that the pharmacokinetics of LY353381.HCl are linear over the studied dose range. The half-life values for LY353381.HCl in this study were shorter than those reported previously (approximately 46 hours).²⁹ These values could be underestimated because the pharmacokinetic samples were only collected up to 72 hours after the dose. No clear correlation between toxicity and plasma concentrations was observed.

No complete or partial responses were seen, but a significant number of patients had clinically relevant tumor stabilization up to approximately 34 months. The absence of an objective response is not unexpected given the extensive number of prior regimens that patients had received for metastatic disease and the fact that all patients had received and failed prior treatment with tamoxifen. It is generally believed that agents from the same class of drugs are rarely effective. The observation of clinical stability in 19% of our patients is therefore interesting, and the efficacy of the drug in patients who had failed prior tamoxifen will be reevaluated in the ongoing phase II trials.

In summary, LY353381.HCl is a well-tolerated and safe SERM. It has a favorable toxicity profile and appears to be potentially active over a wide range of doses. Several phase II trials of LY353381.HCl in patients with advanced breast cancer are currently ongoing and are close to conclusion. Preliminary data from the most mature of these trials are encouraging.³⁰ Phase III trials comparing LY353381.HCl with tamoxifen in patients with advanced breast cancer are currently under development.

	ACKNOWLEDGMENTS

 
Submitted May 12, 2000; accepted December 13, 2000.

Supported by Eli Lilly and Company.

We thank Dr Michelle Ginsberg from the Department of Radiology for reviewing the radiographs and Renny Bloch from data management for his excellent support on this clinical trial.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Landis SH, Murray T, Bolden S, et al: Cancer statistics, 1999. CA Cancer J Clin 49: 8-31, 1999[Abstract/Free Full Text]

2. Beatson GT: On the treatment of inoperable cases of carcinomas of the mamma: Suggestions for a new method of treatment, with illustrative cases. Lancet ii: 104-107, 1896

3. Barakat RR: The effect of tamoxifen on the endometrium. Oncology (Huntingt) 9:129-134; discussion 139-134, 1995

4. Bertelli G, Pronzato P, Amoroso D, et al: Adjuvant tamoxifen in primary breast cancer: Influence on plasma lipids and antithrombin III levels. Breast Cancer Res Treat 12: 307-310, 1988[Medline]

5. Powles TJ, Hickish T, Kanis JA, et al: Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol 14: 78-84, 1996[Abstract]

6. Mouridsen H, Palshof T, Patterson J, et al: Tamoxifen in advanced breast cancer. Cancer Treat Rev 5: 131-141, 1978[Medline]

7. Legha SS, Buzdar AU, Hortobagyi GN, et al: Tamoxifen. Use in treatment of metastatic breast cancer refractory to combination chemotherapy. JAMA 242: 49-52, 1979[Abstract]

8. Kuss JT, Muss HB, Hoen H, et al: Tamoxifen as initial endocrine therapy for metastatic breast cancer: Long term follow-up of two Piedmont Oncology Association (POA) trials. Breast Cancer Res Treat 42: 265-274, 1997[Medline]

9. Johnston SR: Acquired tamoxifen resistance in human breast cancer: Potential mechanisms and clinical implications. Anticancer Drugs 8: 911-930, 1997 (review)[Medline]

10. Osborne CK, Fuqua SA: Mechanisms of tamoxifen resistance. Breast Cancer Res Treat 32: 49-55, 1994[Medline]

11. Cole HW, Adrian MD, Shetler PK, et al: Comparative pharmacology of high potency selective estrogen receptor modulators (SERMs): LY353381.HCl and CP336,156. Proc Am Soc Bone Mineral Res A491, 1997 (abstr)

12. Rowley E, Adrian MD, Bryant H, et al: The new SERM LY353381oHCl has advantages over estrogen, tamoxifen, and raloxifene in reproductive and nonreproductive tissues of aged ovariectomized rats. Proc Am Soc Bone Mineral Res A490, 1997 (abstr)

13. Rash T, Knadler MP: The disposition and biotransformation of the selective estrogen receptor for modulator, LY353381, in female Fischer 344 rats following a single oral dose. Proc Am Ass Pharmaceut Science A1223, 1997 (abstr)

14. Lantz R, Knadler MP: The disposition of a selective estrogen receptor modulator, LY353381, and its metabolites in female Cynomolgus monkeys following single oral and intravenous doses of ¹4C-LY353381. Proc Am Ass Pharmaceut Science A1222, 1997 (abstr)

15. Sato M, Turner CH, Wang T, et al: LY353381.HCl: A novel raloxifene analog with improved SERM potency and efficacy in vivo. J Pharmacol Exp Ther 287:1-7, 1998

16. Fuchs-Young R, Iversen P, Shelton P, et al: Preclinical demonstration of specific and potent inhibition of mammary tumor growth by new selective estrogen receptor modulators (SERMs). Proc Am Assoc Cancer Res 38: A3847, 1997 (abstr)

17. Sato M, Zeng GQ, Rowley E, et al: LY353381 x HCl: An improved benzothiophene analog with bone efficacy complementary to parathyroid hormone-(1-34). Endocrinology 139: 4642-4651, 1998[Abstract/Free Full Text]

18. Shiau AK, Barstad D, Loria PM, et al: The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 95: 927-937, 1998[Medline]

19. Norris JD, Paige LA, Christensen DJ, et al: Peptide antagonists of the human estrogen receptor. Science 285: 744-746, 1999[Abstract/Free Full Text]

20. Delmas PD, Bjarnason NH, Mitlak BH, et al: Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 337: 1641-1647, 1997[Abstract/Free Full Text]

21. Cummings SR, Eckert S, Krueger KA, et al: The effect of raloxifene on risk of breast cancer in postmenopausal women: Results from the MORE randomized trial—Multiple Outcomes of Raloxifene Evaluation. JAMA 281: 2189-2197, 1999[Abstract/Free Full Text]

22. Ma L, Palkowitz A, Bryant HU: Long term dosing of LY353381. HCl preserves bone quality, reduces turnover and lowers cholesterol levels in ovariectomized rats. Bone 23: S609, 1998 (suppl)

23. Stolley PD, Tonascia JA, Tockman MS, et al: Thrombosis with low-estrogen oral contraceptives. Am J Epidemiol 102: 197-208, 1975[Abstract/Free Full Text]

24. Lipton A, Harvey HA, Hamilton RW: Venous thrombosis as a side effect of tamoxifen treatment. Cancer Treat Rep 68: 887-889, 1984[Medline]

25. Davies GC, Huster WJ, Shen W, et al: Endometrial response to raloxifene compared with placebo, cyclical hormone replacement therapy, and unopposed estrogen in postmenopausal women. Menopause 6: 188-195, 1999[Medline]

26. Jordan VC, Fritz NF, Tormey DC: Endocrine effects of adjuvant chemotherapy and long-term tamoxifen administration on node-positive patients with breast cancer. Cancer Res 47: 624-630, 1987[Abstract/Free Full Text]

27. Kostoglou-Athanassiou I, Ntalles K, Gogas J, et al: Sex hormones in postmenopausal women with breast cancer on tamoxifen. Horm Res 47: 116-120, 1997[Medline]

28. Lonning PE, Johannessen DC, Lien EA, et al: Influence of tamoxifen on sex hormones, gonadotrophins and sex hormone binding globulin in postmenopausal breast cancer patients [published erratum appears in J Steroid Biochem Mol Biol 57: 149, 1996]. J Steroid Biochem Mol Biol 52: 491-496, 1995[Medline]

29. Ferguson L, Ni L, Knadler MP: Pharmacokinetics of LY353381 in healthy postmenopausal women after multiple dose oral administration. Proc Am Ass Pharmaceut Scient A2015, 1999 (abstr)

30. Baselga J, Llombart-Cussat A, Bellet M, et al: Double-blind randomized phase II study of a selective estrogen receptor modulator in patients with locally advanced or metastatic breast cancer. Breast Cancer Res Treat 57: A25, 1999 (abstr)

This article has been cited by other articles:

				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]

				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]

				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]

				W. Licun and I. F. Tannock Selective Estrogen Receptor Modulators as Inhibitors of Repopulation of Human Breast Cancer Cell Lines after Chemotherapy Clin. Cancer Res., October 1, 2003; 9(12): 4614 - 4618. [Abstract] [Full Text] [PDF]

				J. Baselga, A. Llombart-Cussac, M. Bellet, V. Guillem-Porta, N. Enas, K. Krejcy, E. Carrasco, L. Kayitalire, M. Kuta, A. Lluch, et al. Randomized, double-blind, multicenter trial comparing two doses of arzoxifene (LY353381) in hormone-sensitive advanced or metastatic breast cancer patients Ann. Onc., September 1, 2003; 14(9): 1383 - 1390. [Abstract] [Full Text] [PDF]

				A. Buzdar, J. A. O'Shaughnessy, D. J. Booser, J. E. Pippen Jr., S. E. Jones, P. N. Munster, P. Peterson, A. S. Melemed, E. Winer, and C. Hudis Phase II, Randomized, Double-Blind Study of Two Dose Levels of Arzoxifene in Patients With Locally Advanced or Metastatic Breast Cancer J. Clin. Oncol., March 15, 2003; 21(6): 1007 - 1014. [Abstract] [Full Text] [PDF]

				B. L. Riggs and L. C. Hartmann Selective Estrogen-Receptor Modulators -- Mechanisms of Action and Application to Clinical Practice N. Engl. J. Med., February 13, 2003; 348(7): 618 - 629. [Full Text] [PDF]

				R. C. Dardes, D. Bentrem, R. M. O'Regan, J. M. Schafer, and V. C. Jordan Effects of the New Selective Estrogen Receptor Modulator LY353381.HCl (Arzoxifene) on Human Endometrial Cancer Growth in Athymic Mice Clin. Cancer Res., December 1, 2001; 7(12): 4149 - 4155. [Abstract] [Full Text] [PDF]

				J. M. Schafer, E.-S. Lee, R. C. Dardes, D. Bentrem, R. M. O'Regan, A. De Los Reyes, and V. C. Jordan Analysis of Cross-Resistance of the Selective Estrogen Receptor Modulators Arzoxifene (LY353381) and LY117018 in Tamoxifen-stimulated Breast Cancer Xenografts Clin. Cancer Res., August 1, 2001; 7(8): 2505 - 2512. [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 Münster, P. N. Articles by Hudis, C. Search for Related Content PubMed PubMed Citation Articles by Münster, P. N. Articles by Hudis, C.