sr-16234 and Breast-Neoplasms

Selective estrogen receptor modulators (SERMs) and selective estrogen down regulators (SERDs) act as estrogen receptor (ER) agonists or antagonist depending on the targeted tissue and the specific configuration of the used SERM or SERD. Effects on bone, endometrium and breast cancer are of interest. Endocrine treatments have been used in breast cancer since the end of the 19th century. In the second part of the last century different compound of SERMs and SERDs have been developed and we will discuss them mainly as used in the treatment and prevention of breast cancer. Tamoxifen is the widely investigated and most used representative of these drugs and has been introduced in the advanced disease, in the neoadjuvant and adjuvant setting and for prevention of the disease. Its role has been challenged in the last years by the introduction of third generation aromatase inhibitors that have proven a higher activity than tamoxifen and a different toxicity pattern. Several other SERMs have been investigated, but none of them was clearly superior to tamoxifen. The main interest in different SERMs has to be seen in the slightly different safety profile between the different compounds. SERDs act as pure estrogen antagonist. They have been used in the treatment of advanced breast cancers and their role in other settings still needs further investigation. The increased use of aromatase inhibitors as first line endocrine therapy raises new questions on the role that tamoxifen and other SERMs or SERDs may play in breast cancer. The sequencing of endocrine therapies and the combination of endocrine therapies with new targeted therapies in hormone sensitive breast cancer remains a very important research issue. Polymorphisms in genes coding for tamoxifen metabolizing enzymes, as for instance, the CYP2D6 genotype, have the potential of becoming clinically useful predictive marker for tamoxifen response. With this meaningful newer knowledge it is possible that the place of tamoxifen in the treatment of breast cancer will be redefined in the future.

Topics: Anastrozole; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Chemotherapy, Adjuvant; Clinical Trials as Topic; Combined Modality Therapy; Cytochrome P-450 CYP2D6; Estradiol; Estrogen Receptor Modulators; Female; Fulvestrant; Genotype; Humans; Neoadjuvant Therapy; Nitriles; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Tamoxifen; Triazoles

TAS-108 is a novel steroidal antiestrogen 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. Its molecular mechanisms of actions are different from those of tamoxifen and fulvestrant. TAS-108 showed tissue-selective agonist activity in the bone and cardiovascular systems and, in preclinical and phase I studies, did not show any effect on the endometrium. In a phase I study, TAS-108 was well tolerated at doses ranging from 40 to 160 mg/d with no maximum tolerated dose. Toxicities included hot flashes, headache, and nausea and vomiting. The drug has linear pharmacokinetics. In the phase I study, there was evidence of biological antitumor activity, with stable disease noted in several patients. A phase II study is ongoing, and phase III studies are being planned with the drug.

Topics: Breast Neoplasms; Clinical Trials, Phase I as Topic; Estradiol; Estrogen Receptor Modulators; Female; Humans

The objective of this study was to evaluate 3 different doses of (7α)-21-(4-[(diethylamino)methyl]-2 methoxyphenoxy)-7 methyl-19 norpregna-1,3,5(10)-trien-3-ol 2-hydroxy-1,2,3-propanetricarboxylate (TAS-108) in patients with recurrent, hormone-responsive breast cancer.. In this randomized, double-blind, multicenter study, TAS-108 was administered daily at a dose of 40 mg, 80 mg, or 120 mg to postmenopausal patients with locally advanced, or inoperable, or metastatic hormone-receptor positive breast cancer. The primary efficacy outcome was clinical benefit (CB), defined as the total number of patients who achieved a complete response, a partial response, or stable disease for ≥24 weeks. The study was a 2-stage design in which 19 patients per dose group were planned in the first stage. If at least 3 patients in any dose group achieved a CB, then that dose group was to be allowed to continue enrolling for the second stage, and the group could include up to a total of 60 patients.. The 40-mg and 80-mg groups met the criterion and enrolled patients into the second stage. In the 40-mg group, there were 13 CB events in 60 patients (21.7%); and, in the 80-mg group, there were 12 CB events in 60 patients (20%). The 120-mg daily dose was stopped early, because it failed to achieve the criterion. For the 40-mg and 80-mg groups, the median time to progression was 15.0 weeks and 15.9 weeks, respectively. Only 1 drug-related serious adverse event (grade 3 hyperglycemia) was reported.. TAS-108 at 40 mg and 80 mg daily demonstrated clinical activity with an encouraging duration of benefit. Because of its superior safety profile, TAS-108 40 mg daily is recommended for further development.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Breast Neoplasms; Disease-Free Survival; Double-Blind Method; Estradiol; Estrogen Receptor Modulators; Female; Humans; Middle Aged; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Postmenopause

This randomized phase II study was intended to identify the optimal dose of TAS-108, a novel steroidal antiestrogen, for the treatment of breast cancer in postmenopausal Japanese women. The potential clinical effects of TAS-108 on the uterus, bone, serum lipids, and hormones were also investigated. Postmenopausal women with hormone receptor-positive metastatic breast cancer who had previously received one or two endocrine therapies were randomly assigned to one of the three possible dose levels of TAS-108 (40, 80 or 120 mg/day). Oral TAS-108 was given daily, and the efficacy and safety of the three doses were evaluated. A total of 97 patients (33, 32, and 32 in the 40-, 80-, and 120-mg groups, respectively) were treated with TAS-108. The clinical benefit rate was 30.3% for the 40-mg, 25.0% for the 80-mg, and 25.0% for the 120-mg group. The 40-mg group achieved the prespecified target threshold. TAS-108 at all dose levels was well tolerated and appeared to have no harmful effects in terms of the variables examined in this study. We conclude that the optimal dose of TAS-108 among the three doses is 40 mg, once daily, for further studies. JAPIC Clinical Trials Information number: Japic CTI - 121754.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Breast Neoplasms; Estradiol; Female; Humans; Middle Aged; Neoplasm Metastasis; Postmenopause; Treatment Outcome

The potential of TAS-108 for the treatment of breast cancer has been shown by preclinical studies. We therefore investigated the safe dosage, tolerability, and effectiveness on hormone levels and bone metabolism markers and the pharmacokinetics of TAS-108 administered in postmenopausal Japanese women with metastatic breast cancer.. The subjects had previously undergone standard endocrine therapeutic modalities. TAS-108 was given repeatedly to five patients each, at three dose levels (40, 80, and 120 mg p.o.) once a day after the first daily meal for a scheduled 8 weeks. Plasma concentrations of TAS-108 and its metabolites were measured at the scheduled time points.. Fifteen patients received TAS-108 treatment. Orally administered TAS-108 was well tolerated at doses up to 120 mg and did not cause notable changes either in hormone levels or bone metabolism markers. Pharmacokinetic results indicated dose-dependent increases in plasma levels of TAS-108 and its metabolites. A steady state was achieved by 2 weeks at all dose levels, suggesting no marked accumulation. Clinical benefits were confirmed in 5 of 15 patients.. Repeated oral administration of TAS-108 at doses up to 120 mg was well tolerated, and the plasma level of this compound increased dose-dependently.

Topics: Administration, Oral; Aged; Bone Remodeling; Breast Neoplasms; Drug Administration Schedule; Estradiol; Estrogen Receptor Modulators; Female; Humans; Japan; Middle Aged; Neoplasm Metastasis; Postmenopause; Time Factors; Treatment Outcome

TAS-108 is a novel steroidal anti-oestrogen, expected to be useful for the treatment of breast cancer. The present study was conducted to investigate the safety, tolerability and pharmacokinetics of TAS-108 following the administration at a single oral dose of 40 mg to up to 120 mg in 12 post-menopausal women and the effect of food on the pharmacokinetics of the drug. All adverse events were mild and involved transient symptoms that resolved without therapeutic intervention. TAS-108 was readily absorbed and plasma levels of TAS-108 steadily declined, apparently in a multi-exponential manner. C(max) and AUC(0-12) were proportionally increased with increasing dose of TAS-108. The C(max) and AUC(0-t) of TAS-108 and its metabolite, deEt-TAS-108, were significantly increased to approximately 150% when TAS-108 was administered after a meal. Food did not affect the elimination half-life of TAS-108 or its metabolites. In this escalating dose-study of TAS-108, the drug was well tolerated by healthy post-menopausal Japanese women. The pharmacokinetics of TAS-108 indicated dose proportionality, and its bioavailability was significantly increased by food intake.

Topics: Administration, Oral; Biological Availability; Breast Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Estradiol; Estrogen Antagonists; Estrogens; Female; Humans; Japan; Middle Aged; Postmenopause

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.. 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.. 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 C(max) ranged from 2.8 to 21.0 ng/mL and AUC(0-t) from 15.1 to 148.7 ng.h/mL, this showed a linear correlation with the dose.. 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.

Topics: Administration, Oral; Aged; Breast Neoplasms; Dose-Response Relationship, Drug; Estradiol; Female; Half-Life; Humans; Middle Aged; Neoplasm Metastasis; Postmenopause; Survival Analysis

(7Alpha)-21-[4-[(diethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-trien-3-ol 2-hydroxy-1,2,3-propanetricarboxylate (TAS-108) is a novel steroidal antiestrogen, modulating the differential recruitment of transcriptional cofactors by liganded estrogen receptors and representing a promising agent for the treatment of breast cancer. To understand better the relationships between the drug exposure and the efficacy or toxicity of TAS-108, we investigated the metabolism and distribution of TAS-108 after oral administration of [14C]TAS-108 to rats bearing a 7,12-dimethylbenz(alpha)anthracene-induced mammary carcinoma. The metabolites (7alpha)-21-[4-[(ethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-trien-3-ol (deEt-TAS-108), (7alpha)-21-[4-[(diethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-trien-3-ol-N-oxide (TAS-108-N-oxide), and 3-methoxy-4-[(7alpha)-7-methyl-19-norpregna-1,3,5(10)-trien-3-ol-21-yl]oxybenzoic acid (TAS-108-COOH) were identified as the major metabolites in the plasma, and in addition, (7alpha)-21-[4-[(ethylamino)methyl]-2-methoxyphenoxy]-3-methoxy-7-methyl-19-norpregna-1,3,5(10)-triene (O-Me-deEt-TAS-108) was identified as a novel metabolite in this study. The time-concentration profiles of TAS-108 and its metabolites in the plasma were compared with those in the tumor and uterus of the rats. Radioactivity was found at a high level in various organs including lung, liver, spleen, ovary, and many glands at 12 h and was relatively higher in tumor tissue than in plasma. On the other hand, the levels of radioactivity in the brain and eyeball were very low or not detectable. TAS-108, deEt-TAS-108, and O-Me-deEt-TAS-108 were extensively distributed in the rat tissues and the tumor, with corresponding tissue/plasma ratios for Cmax and area under the curve in the range of 7 to 100. In contrast, TAS-108-COOH and TAS-108-N-oxide were hardly distributed to the tissues and thus may not contribute to the efficacy or toxicity of TAS-108. Thus, TAS-108, deEt-TAS-108, and O-Me-deEt-TAS-108, being distributed highly in tumor tissue, may be more important for the efficacy and toxicity of TAS-108 in vivo than TAS-108-COOH and TAS-108-N-oxide.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Oral; Animals; Autoradiography; Breast Neoplasms; Carbon Radioisotopes; Carcinoma; Estradiol; Estrogen Antagonists; Female; Liver; Neoplasms, Experimental; Rats; Rats, Sprague-Dawley; Tissue Distribution; Uterus