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Clinical Cancer Research Vol. 10, 5425-5431, August 15, 2004
© 2004 American Association for Cancer Research

Clinical Trials

A Phase I and Pharmacokinetic Study of TAS-108 in Postmenopausal Female Patients with Locally Advanced, Locally Recurrent Inoperable, or Progressive Metastatic Breast Cancer

L. Johnetta Blakely1, Aman Buzdar1, Hsiu-Yin Chang1, Debra Frye1, Richard Theriault1, Vicente Valero1, Edgardo Rivera1, Daniel Booser1, Jun Kuritani2 and Masuhiro Tsuda2

1 Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; and 2 Taiho Pharmaceutical Co., Ltd., Tokyo, Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: TAS-108 is a novel steroidal anti-estrogen compound that has a strong binding affinity to the estrogen receptor and, in preclinical studies, has antitumor activity against tamoxifen-resistant breast cancer cell lines. The objective of this study was to investigate the safety and the pharmacokinetics in patients with previously treated advanced breast cancer.

Experimental Design: TAS-108 was administered orally once daily starting at 40 mg/day, with dose escalations of 60, 80, 120, and 160 mg/day. A minimum of three patients were enrolled in each dose level, and, if no drug-related grade 3 or higher adverse events were seen in the first 14 days, the next cohort of patients was treated at the next level. Pharmacokinetic data were obtained on day 1, 2, 15, and 28 of the first course.

Results: A total of 16 patients were enrolled, and most had received six to seven prior therapies. Clinical toxicities included nausea, vomiting, hot flashes, headache, weakness and fatigue; all were grade 1–2. TAS-108 had no effect on endometrial thickness based on trans-vaginal ultrasound evaluation. The average duration of therapy was 17.4 weeks (range, 4–60 weeks). The mean terminal half-life ranged from 8.0 to 10.7 hour in the interval of 12 to 24 hours postdose. The mean Cmax ranged from 2.8 to 21.0 ng/mL and AUC0-t from 15.1 to 148.7 ng·h/mL, this showed a linear correlation with the dose.

Conclusions: TAS-108 was well tolerated in the doses studied with no maximum tolerated dose. The drug has linear pharmacokinetics, and in this heavily treated patient population, there was evidence of biological antitumor activity. A multi-institutional phase II study is planned.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
There are 217,440 cases of new breast cancer estimated this year with ~40,110 deaths (1) . Many chemotherapeutic and hormone therapies have been used to treat breast cancer in the neo-adjuvant and adjuvant setting as well as to prevent breast cancer. Tamoxifen is a selective estrogen receptor modulator (SERM) that has been shown to be effective in treating metastatic disease in women with estrogen receptor-positive breast cancer regardless of menopausal status (2 , 3) . Tamoxifen is also used in the adjuvant setting in postmenopausal women with estrogen receptor-positive breast cancer after surgery (2 , 3) . Recently tamoxifen has also been shown as an effective agent in the prevention for breast cancer in high-risk populations (4) . Tamoxifen has an agonistic activity that is beneficial for protection against bone loss (5) ; however, this agonistic effect also can be harmful with an increase in the incidence of endometrial cancer and thromboembolic events seen with the use of tamoxifen (6 , 7) .

Many have begun to investigate aromatase inhibitors and selective estrogen receptor down-regulator (SERD) to overcome the clinical limitations of tamoxifen. Aromatase inhibitors have been shown to be clinically superior to tamoxifen with time to progression for postmenopausal women with estrogen receptor-positive breast cancer (8, 9, 10, 11, 12) . These drugs do not have agonistic properties and, therefore, do not have the same risk of endometrial cancer with long-term use as does tamoxifen. What is unclear is whether the steroidal aromatase inhibitors and SERD will have the same protective effect on bone mineral density as does tamoxifen, because nonsteroidal aromatase inhibitors are associated with an increased risk of bone loss (13 , 14) . Also, aromatase inhibitors, although superior clinically to tamoxifen, cannot be used in premenopausal women without complete estrogen blockade with luteinizing hormone-releasing hormone.

TAS-108 was developed to find a ligand for estrogen receptor {alpha} and/or ß, which might be clinically more beneficial than tamoxifen, aromatase inhibitors, and SERD. TAS-108, (7{alpha})-21-[4-[(diethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-trien-3-ol 2-hydroxy-1,2,3-propanetricarboxylate, is a novel steroidal molecule developed in collaboration between Taiho Pharmaceutical Co., Ltd., and SRI International. TAS-108 has been shown to be a strong binding ligand to estrogen receptor with recruitment of a specific cofactor to estrogen receptor ß (15) . It was shown that TAS-108 acts with molecular mechanisms that are different from those of tamoxifen or SERD (16) . TAS-108 showed tissue-selective agonist activity in the bone and cardiovascular systems (17) .

In preclinical studies, TAS-108 was shown to have antitumor activity with increased binding affinity when compared with tamoxifen and fulvestrant. TAS-108 was found to be active in the tamoxifen-sensitive MCF-7 cell line and resistant cell lines FST-1, KPL-1, and LY-2. TAS-108 was shown to inhibit the decrease in bone mineral density in estrogen-deprived rat models, which suggests agonistic activity; however, when tested, TAS-108 was found to have antagonistic activity in estrogen-stimulated uterine tissue in animal models. TAS-108 was found to have no serious toxicities in animal studies and, in a phase I study that was made in healthy postmenopausal women, showed no serious adverse events or dose-dependent increases in adverse events. Side effects from that study included mild nausea, arthralgia, muscle cramps, and moderate back and limb pain.3 The data of that study indicated that most patients treated at the 10- and 20-mg dose levels had levels of TAS-108 below the limit of quantifications, but at the 40-mg dose level, TAS-108 levels were detectable. The 40-mg dose was the starting dose for the phase I study reported here; preliminary results of this study were reported at the 94th Annual Meeting of the American Association of Cancer Research (18) .


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection.
Postmenopausal women over the age of 18 were eligible for this study. "Postmenopausal" was defined as no spontaneous menses for a total of 5 years, amenorrheic for at least 12 months with serum estrogen level <30 pg/mL, and both luteinizing hormone and follicle-stimulating hormone values >20 IU/L, chemotherapy induced amenorrhea for at least 12 months, bilateral oophorectomy, or radiation castration and amenorrheic for at least 3 months (except for luteinizing hormone–releasing hormone agonist-induced amenorrhea). Other eligibility criteria included the following: histologically or cytologically confirmed breast cancer; locally advanced or locally recurrent inoperable or metastatic breast cancer; laboratory documentation of positive estrogen receptor and/or progesterone receptor status or previous endocrine therapy for advanced disease with biological antitumor activity; Zubrod performance status of 0 to 2; life expectancy ≥12 weeks; measurable and/or evaluable disease; adequate bone marrow function; adequate liver function (defined as absolute granulocyte count >1500/µL; platelet count >75,000/µL; and hemoglobin >10.0 g/dl), and adequate renal function (defined as bilirubin and creatinine <1.5 times the upper limit of normal; transaminases <2.5 times the upper limit of normal (if liver metastasis was present then transaminases needed to be <5 times the upper limit of normal)].

Patients were required to have received and failed at least two or more prior systemic antitumor therapies with at least one of these therapies having been an endocrine therapy. Patients who had received previous investigational therapies had to be off those therapies for at least 4 weeks before treatment with TAS-108. Patients also had to have recovered from all previous anticancer treatment-related toxicities to at least grade 1. It was preferred that patients be off prior chemotherapy for at least 4 weeks and prior endocrine therapy for at least 3 weeks. Patients with inflammatory breast cancer were excluded from the study, as were patients with symptomatic brain metastasis, extensive liver involvement, or lymphangitic lung involvement. Patients who had been taking supplemental estrogen or progesterone within 3 weeks of the start of the study were also excluded. All of the patients gave written informed consent as per institutional and federal regulatory requirements. The institutional review board approved the study.

Study Design.
This was a phase I, open-label, nonrandomized, dose-finding study of TAS-108. The study evaluated the safety and the pharmacokinetics of TAS-108 when administered orally in postmenopausal women with advanced breast cancer. Taiho Pharmaceutical Co., Ltd., Tokyo, Japan, supplied TAS-108. Patients were enrolled in five escalating dose groups: 40 mg, 60 mg, 80 mg, 120 mg, and 160 mg dosages (Table 1)Citation . The study drug was given orally and once daily in each of the five dose levels.


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  		Table 1 Dose levels for TAS-108

 
A minimum of three patients were enrolled in each dose level. If there were no drug related grade 3 or higher toxicities in the first 14 days of treatment in the first three patients, escalation to the next dose started. If grade 3 or higher drug-related toxicities were seen in one of the first three patients, three more patients were planned to be enrolled in that dose level. The maximum tolerated dose of TAS-108 was defined as one dose level below the dose at which two or more of the first three patients or of the total of six patients experienced grade 3 or higher drug-related toxicities. NCI CTC version 2.0 (National Cancer Institute Common Toxicity Criteria, NIH, Bethesda, MD) was used for grading drug-related toxicities. Patients remained on TAS-108 at their designated dose level until disease progression or until unacceptable toxicity occurred.

Pharmacokinetics.
Blood samples (3 ml) were collected in heparinized tubes before the first dose of TAS-108 and at 2, 4, 6, 8, 10, 12, 14, and 24 h thereafter on day 1. Blood samples were also collected at day 15 before the dose of TAS-108 and on day 28 before and at 6 and 12 h after TAS-108 during course 1 to determine the pharmacokinetic data for TAS-108 and the active metabolite, deEt-TAS-108. These samples were placed on ice and transported to the laboratory at which the samples were centrifuged and the plasma stored at –70°C. The samples were then shipped to Northwest Bioanalytical in Salt Lake City, Utah, where the plasma concentrations of TAS-108 and deEt-TAS-108 were determined. TAS-108 and deEt-TAS-108 plasma concentrations were analyzed using noncompartmental techniques. For each patient consenting to pharmacokinetic blood sampling, the maximum observed plasma concentration (Cmax), time to maximum plasma concentration (tmax), area under the curve from hour 0 to last measurable plasma concentration (AUC0-t), area under the plasma concentration-time curve extrapolated to infinity (AUC0-{infty}), plasma terminal elimination half-life (t1/2), and apparent oral clearance (CL/F) were obtained. Because the concentration-time profile showed a multiphasic elimination process, the elimination half-life were computed for 6- to 12-hour and 12- to 24-hour intervals. One patient underwent a tumor biopsy on day 28 of the fifth course, and two pieces of tumor tissue were obtained. The tumor samples were stored at –70°C, and the samples were shipped to the laboratory of Taiho Pharmaceutical Co., Ltd., Tokushima, Japan. There, tumor samples were pretreated for analysis and then were shipped to Toray Research Laboratory, Kanagawa, Japan, where the concentrations of TAS-108 and deEt-TAS-108 were determined in both the tumor and the blood samples in this patient. In a preclinical study, 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumor-bearing rats were given [14C]TAS-108 orally, synthesized by Daiichi Pure Chemicals Co., Ltd., at a dose of 10 mg/kg. Plasma and tumor were collected at the scheduled time from the rats. Composition of TAS-108 and its metabolite in the plasma and tumor was determined by those radioactivities in high-performance liquid chromatography analysis.

Patient Evaluation.
A complete medical history was obtained from all of the patients, and all underwent a physical examination before enrollment into the study. Patients had repeat physical examinations at the end of each course of treatment during their follow-up clinic visits. Laboratory analyses such as complete blood count, serum electrolytes (total protein, albumin, calcium, phosphorus, glucose, blood urea nitrogen, creatinine, bilirubin, lactate dehydrogenase, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, sodium potassium, chloride, total cholesterol, and triglycerides), urinalysis, serum hormone levels (testosterone, follicle-stimulating hormone, thyroid-stimulating hormone, cortisol, prolactin, estrone, 17ß-estradiol, estriol, luteinizing hormone, and sex hormone-binding globulin), tumor markers [carcinoembryonic antigen (CEA) and CA15–3], and bone markers (serum osteocalcin and type I collagen fragments) were performed before enrollment. Imaging studies such as chest radiographs, computed tomography scans, transvaginal ultrasound, and electrocardiogram were also performed before patients enrolled on study. Tests for complete blood counts, serum chemistries, urinalysis, tumor markers, and bone markers were repeated at the end of each course (defined as four weeks of treatment with TAS-108) before the start of the subsequent course. Imaging studies were done at the discretion of the investigator at the end of courses 1 and 2; however, they were done in all cases at the end of course 3 to evaluate tumor response. Likewise, a transvaginal ultrasound was performed at the end of course 3. For patients who continued treatment after course 3, a transvaginal ultrasound was performed after every four courses of treatment starting at course 3, and the same radiographic method used initially to demonstrate measurable or evaluable disease was repeated every two courses after the third course to evaluate response to TAS-108. Patients achieving a partial or complete response were to have undergone repeat imaging to confirm response 4 weeks after initial documentation.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics.
A total of 16 patients were enrolled in the five dose levels (Table 2)Citation . Most patients (81%) had bone as their site of disease, performance status was 1 or 2, and median age was 57 years. Most patients were heavily pretreated, with the majority of patients receiving three or more prior chemotherapy regimens (62.5%) and three or more endocrine therapies (75%) before starting to receive TAS-108 (see Table 3Citation ). All but one patient participated in the pharmacokinetic analysis, and toxicity and response data were obtained in all 16 patients.


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  		Table 2 Patient characteristics

 

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  		Table 3 Prior chemotherapy, endocrine therapy, and weeks of treatment with TAS-108

 
Safety Profile.
Table 4Citation summarizes the toxicity seen with TAS-108. No maximum tolerated dose was observed during the study.


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  		Table 4 Number of patients reporting toxicities at each dose level

 
Nine patients experienced grade 1 or 2 hot flashes. Seven patients experienced grade 1 or 2 nausea, and four patients had grade 1 or 2 vomiting; one patient experienced grade 3 nausea. Four patients experienced grade 1 or 2 sweating and 11 patients had grade 1 or 2 headache. One patient had grade 1 dizziness, and one patient had grade 2 dizziness. Three patients experienced grade 1 or 2 fatigue, and one patient had grade 3 fatigue. One patient experienced grade 3 tinnitus, and one patient had a seizure while on TAS-108; however, this patient was also receiving other medications known to lower the seizure threshold.

Transvaginal ultrasounds were performed in the eight patients who had not had previous hysterectomy (Table 5)Citation . The ultrasounds measured the endometrial thickness at baseline and then 4 to 12 weeks posttreatment. There was no difference between the baseline and posttreatment endometrial thickness, suggesting that TAS-108 has no effect on the endometrial lining.


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  		Table 5 Endometrial safety data

 
TAS-108 had no effect on liver function tests, cholesterol, thyroid function tests, or electrolytes. There were no hematologic effects seen with TAS-108.

Pharmacokinetics.
All but one patient consented to pharmacokinetic blood testing. All pharmacokinetic data were obtained during course 1 of therapy with TAS-108. Table 6Citation summarizes the pharmacokinetic data for TAS-108 and its metabolites. TAS-108 was rapidly absorbed and reached a mean tmax at 2.7 to 5.3 hours after the dose. The concentration-time profile showed a multiphasic elimination process. The mean terminal half-life ranged from 8.0 to 10.7 hours in the interval of 12 to 24 hours after the dose. The mean Cmax ranged from 2.8 to 21.0 ng/mL and AUC0-t from 15.1 to 148.7 ng·h/mL; this showed a linear correlation with the dose (Fig. 1)Citation . There was no unusual accumulation after multiple-day dosing. Plasma and tumor concentration comparisons were available for one patient who underwent a biopsy after administration of TAS-108. This showed that concentrations in the tumor were higher in the tumor than in plasma, which was similar to what was seen in preclinical animal studies (Fig. 2Citation ; Table 7Citation ).


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  		Table 6 Single-dose pharmacokinetic parameters of TAS-108 and its metabolite

 


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  		Fig. 1. Relationship between Cmax and dosage of TAS-108 in human plasma.

 


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  		Fig. 2. Plasma and tumor concentrations. For human data, the plasma concentrations were determined on day 28 of the first course, and the tissue concentrations on day 28 of the fifth course. Rat (single dose, 10 mg/kg) {permzspch154} TAS-108 in plasma, {permzspch157} TAS-108 in tumor, {permzspch156} deEt-TAS-108 in plasma, {permzspch159} deEt-TAS-108 in tumor. Human (day 28, 60 mg/body) {permzspch154} TAS-108 in plasma, • TAS-108 in tumor, {permzspch156} deEt-TAS-108 in plasma, {blacktriangleup} deEt-TAS-108 in tumor.

 

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  		Table 7 Tumor to plasma ratios after oral administration of TAS-108 (parent) and deEt-TAS-108 (metabolite) in rats and humans

 
Tumor Response.
Response data were available for all patients, and response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Table 8Citation summarizes the responses seen with TAS-108. No patients had partial or complete response. Eight patients treated had stable disease for 11–60 weeks on study, and of those, one patient maintained stable disease for 33 weeks on therapy and another had stable disease for a total of 60 weeks on therapy with TAS-108 (Table 3)Citation . Eight patients had progressive disease.


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  		Table 8 Response to TAS-108

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Antiestrogens play a major role in the treatment of both early and advanced breast cancer. The limitation of current antiestrogen therapy is that there are also associated agonistic properties with an increased incidence of endometrial cancer and thromboembolic events (6 , 7) . TAS-108 is a novel steroidal anti-estrogen compound that, in preclinical studies, did not show any effect on the endometrium. The present study was the first study performed with TAS-108 with doses ranging from 40 to 160 milligrams to determine the safety and pharmacokinetics of TAS-108 in women who had previously been treated with advanced breast cancer. From preclinical studies it is known that TAS-108 is a strong binding ligand to the estrogen receptor and recruits a specific cofactor to estrogen receptor ß (15) . In animal studies, it was shown that TAS-108 was effective against tamoxifen-sensitive and resistant breast tumors. Furthermore, TAS-108 had a positive effect on bone mineral density and had no pathological effect in endometrial tissue in animal models.

In our study, TAS-108 was well tolerated in the doses studied with no maximum tolerated dose. Some toxicities were seen, mainly hot flashes, headache, and nausea and vomiting. However, the incidences of those toxicities were not correlated with the dosage or exposure. There were no laboratory effects seen with TAS-108. We were also able to demonstrate with transvaginal ultrasound, performed in eight patients, that TAS-108 had no effect on the endometrial lining. The drug has linear pharmacokinetics, which was shown in Fig. 1Citation . Although no patients had complete or partial response, in this heavily treated patient population there was evidence of biological antitumor activity, with stable disease noted in 8 of the 16 patients treated. Because stable disease was seen in all dose levels, it suggests the flat dose-response curve of TAS-108 in the range of the 40-to-160-mg dose.

Because this drug was well tolerated, the toxicity was predictable and there was evidence of antitumor activity in heavily pretreated postmenopausal women, a multi-institutional phase II study for dose finding is planned to determine an optimal dose for phase III studies.

If further evidence is shown during future trials, TAS-108 may become an endocrine therapy for advanced breast cancer without risk of endometrial hyperplasia and may have a benefit for bone mineral density as well. Currently, tamoxifen is one of the few options for hormonal therapy in premenopausal women with advanced breast cancer; however, it is known to cause increased risk for endometrial cancer. If TAS-108 shows a favorable therapeutic index, there may be a role for its use not only in postmenopausal breast cancer patients but also in premenopausal breast cancer patients.


   FOOTNOTES
 
Grant support: This study was partially supported by Taiho Pharmaceutical Co., Ltd., Tokyo, Japan.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Aman Buzdar, Breast Medical Oncology, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 424, Houston, TX 77030. Phone: 713-792-2817; Fax: 713-794-4385; E-mail: abuzdar{at}mdanderson.org

3 Unpublished data from Taiho Pharmaceutical Co., Ltd., Tokyo, Japan. Back

Received 2/19/04; revised 4/13/04; accepted 4/27/04.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Jemal A, Tiwari RC, Murray T, et al Cancer Statistics, 2004. CA Cancer J Clin, 54: 8-29, 2004.[Abstract/Free Full Text]
  2. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet, 339: 71-85, 1992.[Medline]
  3. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet, 351: 1451-67, 1998.[CrossRef][Medline]
  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 (Bethesda), 90: 1371-88, 1998.[Abstract/Free Full Text]
  5. Love RR, Mazess RB, Barden HS, et al Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med, 326: 852-6, 1992.[Abstract]
  6. Kedar RP, Bourne TH, Powles TJ, et al Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial. Lancet, 343: 1318-21, 1994.[CrossRef][Medline]
  7. Fisher B, Costantino JP, Redmond CK, et al Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst (Bethesda), 86: 527-37, 1994.[Abstract/Free Full Text]
  8. Bonneterre J, Buzdar A, Nabholtz JM, et al Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. Cancer (Phila), 92: 2247-58, 2001.
  9. Bonneterre J, Thurlimann B, Robertson JF, et al Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol, 18: 3748-57, 2000.[Abstract/Free Full Text]
  10. Nabholtz JM, Bonneterre J, Buzdar A, et al Anastrozole (Arimidex) versus tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: survival analysis and updated safety results. Eur J Cancer, 39: 1684-9, 2003.
  11. Mouridsen H, Gershanovich M, Sun Y, et al Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol, 21: 2101-9, 2003.[Abstract/Free Full Text]
  12. Mouridsen H, Gershanovich M, Sun Y, et al Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol, 19: 2596-606, 2001.[Abstract/Free Full Text]
  13. The ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists’ Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet, 359: 2131-2139, 2002.[CrossRef][Medline]
  14. Goss PE, Ingle JN, Martino S, et al A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med, 349: 1793-1802, 2003.[Abstract/Free Full Text]
  15. Yamamoto Y, Wada O, Yanagisawa J, et al Molecular mechanism of actions of Tas-108(SR16234), a novel steroidal selective estrogen receptor modulator (SERM) [Abstract 1453]. Proc Am Assoc Cancer Res, 42: 270 2001.
  16. Yamamoto Y, Wada O, Takada I, et al Both N- and C-terminal transactivation functions of DNA-bound ERalpha are blocked by a novel synthetic estrogen ligand. Biochem Biophys Res Commun, 312: 656-62, 2003.[CrossRef][Medline]
  17. Toko T, Shibata J, Sato K, et al Antiestrogenic/estrogenic activities of TAS-108 (SR16234), a new steroidal selective estrogen receptor modulator [Abstract 171]. Br Ca Res Trtmt, 57: 52 1999.
  18. Blakely J, Buzdar A, Chang H, et al A phase I and pharmacokinetic study of TAS-108 in previously treated patients with metastatic breast cancer [Abstract 5338]. Proc Am Assoc Cancer Res, 44: 1227 2003.



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