Search

Purpose: The activity of the novel antitumor agent tasquinimod (TASQ) with S100A9 as a molecular target was investigated in men with metastatic castration-resistant prostate cancer (CRPC) and minimal symptoms., Patients and Methods: We conducted a randomized, double-blind, placebo-controlled phase II trial in men assigned (at a ratio of two to one) to either oral once-daily TASQ 0.25 mg/d escalating to 1.0 mg/d over 4 weeks or placebo. The primary end point was the proportion of patients without disease progression at 6 months, defined by Response Evaluation Criteria in Solid Tumors Group, Prostate Cancer Working Group (PCWG2), or pain criteria, excluding prostate-specific antigen., Results: Two hundred one men (134 assigned to TASQ; 67 to placebo) were evaluable, and baseline characteristics were well balanced. Six-month progression-free proportions for TASQ and placebo groups were 69% and 37%, respectively (P < .001), and median progression-free survival (PFS) was 7.6 versus 3.3 months (P = .0042). In PCWG2 CRPC clinical subgroups, PFS in months was as follows: nodal metastases, 6.1 versus 3.1; bone metastases, 8.8 versus 3.4; and visceral metastases, 6.0 versus 3.0 for patients receiving TASQ versus placebo, respectively. Bone alkaline phosphatase levels were stabilized in the TASQ group, whereas the impact on PSA kinetics was less pronounced. Adverse events (AEs) occurring more frequently in the TASQ arm included GI disorders, fatigue, musculoskeletal pains, and elevations of pancreatic and inflammatory biomarkers. Grade 3 to 4 AEs, including asymptomatic elevations of laboratory parameters, were reported in 40% of patients receiving TASQ versus 10% receiving placebo; deep vein thrombosis (4% v 0%) was more common in the TASQ arm., Conclusion: TASQ significantly slowed progression and improved PFS in patients with metastatic CRPC with an acceptable AE profile.

Purpose: We have identified a subset of patients exhibiting extended survival with metastases from androgenindependent prostate cancer of which the principal site of progression was the tumor primary. The purpose of this study was to evaluate the expression of selected biomarkers to characterize this subset of prostate cancer patients., Experimental Design: A 105 core tissue microarray was constructed from primary tumor samples from 16 patients, with matched lymph node metastases in 5 cases. Immunohistochemistry was used to evaluate selected biomarkers associated with prostate cancer progression. Standard statistical methodologies were used to compute the distribution of time to progression and overall survival associations between pairs of biomarkers. Hierarchical clustering was done between groups of biomarkers, and we devised new methods to assess homogeneity of biomarker expression., Results: The median interval from diagnosis to salvage surgery was 65 months. The profile of biomarker expression was notable for virtual absence of neuroendocrine features, high CD10, low matrix metalloproteinase (MMP)-9, high E-cadherin expression, and high membranous beta-catenin. The mean proliferative index was 12.1 +/- 10.1%, and the mean apoptotic index was 3.48 +/- 2.22%, and there was a significant correlation between these indices. Expression of the epidermal growth factor receptor was associated with phospho-AKT and proliferative index but inversely associated with phospho-STAT3., Conclusions: The cohort of prostate cancer patients, characterized by locally aggressive disease rather than lethal metastatic progression, was associated with a distinctive biomarker signature. The biomarker profile was, in general, more consistent with low-grade prostate cancer exhibiting local growth rather than metastatic progression. Ongoing studies will establish whether this unique subset of patients can be identified prospectively.

Close to 30,000 men will die from prostate cancer in the United States in 2003. Hormonal ablation, the basis of systemic therapy, will invariably fail to control the progression of metastatic prostate cancer in the long run. For many years the only available therapeutic modalities for patients with metastatic androgen independent prostate cancer have been second-line hormonal maneuvers with estrogens or steroids and chemotherapy. So far, chemotherapy has been shown to confer adequate palliation but no overall survival benefit in prospective randomized controlled trials, and the only chemotherapy drugs approved by the US Food and Drug Administration are mitoxantrone and estramustine. Novel treatment strategies that aim at specific signaling pathways, apoptosis, differentiation, or specific membranous targets are being developed. Such new therapeutic modalities, along with recent data on immunotherapy and bone targeting strategies, will be reviewed here.

Third-generation aromatase inhibitors (anastrozole, letrozole, and exemestane) have emerged as an alternative first-line endocrine treatment for postmenopausal breast cancer patients with hormone-responsive disease. Their clinical efficacy, excellent tolerability, and safety profile compare favorably with that of tamoxifen, which has been the cornerstone of endocrine therapy for years. This review will discuss the findings of recently published randomized clinical trials comparing this new class of drugs with tamoxifen as first-line treatment for advanced disease. We will also present the design and rationale of ongoing trials looking into the use of third-generation aromatase inhibitors in the adjuvant setting and review data regarding their possible role in premenopausal women., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

Background: Tamoxifen has been shown to promote the growth of human endometrial tumors implanted in athymic mice, and it has been associated with a twofold to threefold increase in endometrial cancer. Toremifene, a chlorinated derivative of tamoxifen, and ICI 182,780, a pure antiestrogen, are two new antiestrogens being developed for the treatment of breast cancer. The effects of these drugs on endometrial cancer are currently unknown. Our objective was to evaluate the effects of toremifene and ICI 182,780 on the growth of human endometrial cancer in athymic mice., Methods: Athymic, ovariectomized mice were implanted with human endometrial tumors and treated with estrogen, tamoxifen, or the new antiestrogens., Results: The effects of tamoxifen and toremifene on the growth of either tamoxifen-stimulated or tamoxifen-naive endometrial tumors in athymic mice were not substantially different. ICI 182,780 inhibited the growth of tamoxifen-stimulated endometrial cancer, in both the presence and the absence of estrogen., Conclusions: Toremifene and tamoxifen produce identical effects in our endometrial cancer models. Therefore, it is possible that toremifene, like tamoxifen, may be associated with an increased incidence of endometrial cancer. In contrast, ICI 182,780 inhibited tamoxifen-stimulated endometrial cancer, both in the presence and in the absence of estrogen, suggesting that this drug may be safe with regard to the endometrium, even if it is used following tamoxifen, and that it may not result in an increased incidence of endometrial cancer. Indeed, it is even possible that ICI 182,780 may prove useful as an adjuvant agent in early stage endometrial cancer.

It is clear that growth of the MCF-7 breast cancer cell line is stimulated by estrogen and when estrogen is removed, growth slows. We have observed a tumor derived from MCF-7 cells that grows in athymic mice in the absence of estrogen stimulation. We hypothesized that a mutation in the estrogen receptor (ER) could be responsible for this constitutive growth. Using single stranded conformational polymorphism (SSCP) and DNA sequencing analysis, we have identified an ER containing a point mutation at position 415 (gly to val) within the hormone binding domain. The functional activity of this mutant was assessed in vitro and in vivo. Using transient transfection into an ER negative breast cancer cell with an ERE luciferase reporter gene, we found that both the wild-type and mutant receptors have similar efficacy. Additionally, the estrogenic responses were blocked by antiestrogens in a concentration related manner. We also found that tumors with the mutant receptor show similar growth response in athymic mice as wild-type: stimulation with estradiol and inhibition with antiestrogens. We conclude that the point mutation at position 415 (gly to val) is not responsible for constitutive growth.

Tamoxifen is the most widely prescribed endocrine therapy for breast cancer, with more than 7.5 million woman-years of clinical experience. Tamoxifen has both antiestrogenic and estrogenic activity. The antiestrogenic activity accounts for its efficacy against breast cancer, while the estrogenic activity is considered to be associated with positive effects on bone mineral density and lipid profiles and a proliferative effect on the endometrium in some women. Tamoxifen has a good tolerability profile and has demonstrated benefits for breast cancer patients in prolonging overall and disease-free survival and reducing the incidence of contralateral breast cancer. These known benefits of tamoxifen far outweigh the risk of endometrial cancer in tamoxifen-treated patients with breast cancer.

We have cloned and characterized a 77-kDa oestrogen receptor (ER) from an oestrogen-independent subclone of the MCF-7 human breast cancer cell line. This receptor contains an in-frame, tandem duplication of exons 6 and 7, located in the steroid-binding domain of the ER. This mutation has abrogated ligand binding, but not DNA binding, in this mutant ER. We previously described the partial structure of a unique oestrogen receptor (ER) that is expressed in an oestrogen-independent MCF-7:2A subclone of the breast cancer cell line MCF-7 (Pink JJ, Wu SQ, Wolf DM, Bilimoria MM, Jordan VC 1996a, Nucleic Acids Res 24 962-969). Sequence analyses determined the molecular weight of this 80-kDa ER to be 77 kDa, and hereafter this protein will be designated as ER77. Examination of the entire coding sequence of the ER77 mRNA indicates that it contains a tandem duplication of exons 6 and 7. Using a coupled transcription/translation system, a 77-kDa ER, which corresponds to the protein observed in the MCF-7:2A cells, was expressed. The ER77 protein does not bind the ligands [3H] oestradiol or [3H]tamoxifen aziridine. In DNA binding gel shift assays, the in vitro synthesized ER77 binds to a consensus vitellogenin A2 oestrogen-response element. In transient transfection experiments, the mutant ER, alone or in combination with the wild-type ER, does not induce expression of an oestrogen-responsive luciferase reporter construct. In fact, expression of the ER77 in the ER-positive T47D:A18 cell line inhibits E2-induced luciferase expression. Overexpression of wild-type ER in T47D:A18 cells leads to elevated constitutive expression of the luciferase reporter, which was inhibited by co-transfection with ER77. These data suggest that the ER77 can interfere with normal ER activity and does not act as a constitutive activator of oestrogen-independent growth in MCF-7:2A cells. Consequently, the constitutive growth observed in MCF-7:2A cells is probably the result of other ER-mediated pathways.

The majority (60-70%) of endometrial cancers express estrogen receptor. Typically, estrogen-receptor-positive endometrial tumors are associated with a more favorable outcome. Despite this, there is often a discrepancy between estrogen receptor expression and clinical outcome of the disease. Although little is known about the exact role of the estrogen receptor in endometrial malignancies, in breast cancer, where such information is abundant, a number of mutations of the estrogen receptor have been identified. To investigate whether mutations of the estrogen receptor gene occur in endometrial cancers we performed single-stranded conformational polymorphism analysis (SSCP) on 35 human endometrial tumors. We detected four point mutations in three different patients. Interestingly, all the mutations were detected in patients who had aggressive endometrial tumors (grade 3). Although we found the incidence of mutations of the estrogen receptor to be low (8.5%) and thus unlikely to be associated with the majority of endometrial cancers, further investigation is needed to elucidate the role of aberrant estrogen receptor expression in the progression of endometrial malignancies.

Tamoxifen has been the endocrine treatment of choice for all stages of breast cancer for nearly a decade. Millions of women are currently receiving tamoxifen worldwide, while large-scale randomised trials have been launched aiming to investigate the drug's merit as a preventive agent. However, there are now concerns about tamoxifen's potential carcinogenicity. The goal of this review is to address these concerns, re-evaluate the available data from laboratory biological models and those from clinical reports and put the whole issue into perspective. Our focus is the association between tamoxifen and the increased frequency of endometrial tumours, while key issues, such as the role of duration of tamoxifen therapy, are also addressed. Finally, we discuss the various monitoring strategies for early detection of endometrial lesions and pertinent problems most likely to be encountered by clinicians taking care of patients who are receiving tamoxifen.

The estrogen receptor (ER) contains two transcriptional activation domains: AF-1 and AF-2. AF-2 is dependent on a highly species-conserved region of the ER. It has been shown that site-directed point mutations of conserved hydrophobic amino acids within this region reduce estrogen-dependent transcriptional activation. In addition, when these mutated ERs are transfected into HeLa cells, both tamoxifen and ICI 164,384 become strong agonists. The implication is that mutations in this region could account for the tamoxifen-stimulated tumors seen clinically. We performed single stranded conformational polymorphism (SSCP) analysis spanning the entire ER along with DNA sequencing of the AF-2 region of the ER isolated from two different tamoxifen-stimulated breast cancers, MCF-7/TAM and MCF-7/MT2, and a tamoxifen-stimulated endometrial cancer, EnCa 101. In addition, a tamoxifen-stimulated endometrial carcinoma cell line, the Ishikawa cell line, was also studied. There were no mutations found by SSCP analysis and sequencing of all four AF-2 regions also revealed no mutations. Mutations within the AF-2 region of the human ER do not appear to account for the growth of human breast and endometrial carcinomas that are used as reproducible laboratory models of tamoxifen-stimulated growth observed clinically.

Toxifen, a nonsteroidal antiestrogen, is currently the most widely used adjuvant therapy for the treatment of breast cancer. Though the efficacy of tamoxifen has been well documented in clinical trials, the certainty over the duration of therapy is less clear. Clinical and laboratory evidence suggests that longer therapy is better; however, whether this means 5 years, 10 years, or indefinite therapy has not been established in clinical trials. Essential to any study of long-term tamoxifen therapy is consideration of its effects not only on breast cancer but also on other estrogen target tissues. The estrogenic effect of tamoxifen that lowers serum lipids results in fewer hospital admissions for heart disease and a reduction in fatal myocardial infarction. Similarly, tamoxifen maintains bone mass that may ultimately result in fewer fractures. The effects of tamoxifen appear to parallel the effects of estrogen, so results from clinical trials of estrogen replacement therapy will provide a useful guide of what to expect with tamoxifen. The negative aspect of the therapy is a modest increase in the incidence of endometrial cancer. However, the incidence of endometrial cancer after stopping either estrogen or tamoxifen remains elevated for at least 5 years after the drug is stopped. Nevertheless, it is important to stress that the overall prognosis remains unaffected. We conclude that it will be difficult to demonstrate survival differences between 5 and 10 years of tamoxifen in clinical trials unless significant tamoxifen-stimulated recurrences occur with continued therapy. The benefits of tamoxifen must be calculated using estimates of the decreased rates of heart disease, contralateral cancers, decreased hospitalizations for fractures, and reduced cancer relapses.

Tamoxifen has been used as an adjuvant therapy for breast cancer for nearly two decades. The benefits of adjuvant tamoxifen therapy in prolonging disease-free and overall survival have been shown in randomized clinical trials. Despite this, some developing evidence suggests that tamoxifen causes a 2- to 3-fold increase in endometrial cancer. This paper reviews the reports of endometrial carcinoma in tamoxifen-treated patients. Two hundred fifty cases of endometrial carcinoma are reported, but only one case is identified in a premenopausal woman. When documented, 77% (n=127) of the cases are good-grade (grade 1 or 2) and 80% (n=125) are stage-I disease. Since the distribution of good grade (79%) and stage I (74%) from the Surveillance, Epidemiology and End Results (SEER) data are comparable, concerns about more aggressive or late-stage disease appear to be unwarranted. The modest increase in the incidence of early-stage, good-grade endometrial carcinoma described during tamoxifen therapy suggests that it would be unreasonable to institute an aggressive detection strategy of endometrial biopsies. This approach would only lead to further detection bias and would not be cost-effective. Physicians should ensure that patients do not have pre-existing endometrial cancer prior to adjuvant tamoxifen therapy for breast cancer and, furthermore, they should educate patients about signs and symptoms of early endometrial carcinoma and when reported these should be followed up with a gynecologic examination.

During the past 5 years, a number of case reports and clinical trial results have associated tamoxifen therapy with an increased incidence of endometrial carcinoma. A review of the literature shows that there are over 200 cases of endometrial carcinoma reported in tamoxifen-treated women. Most cases are Stage I (82%), grade 1-2 disease (80%), which is consistent with the Surveillance Epidemiology and End Results Reporting data of 74 and 79% for Stage I and grade 1-2 endometrial carcinoma. We conclude that there is a modest increase in endometrial carcinoma incidence during tamoxifen therapy (i.e., 2/1000 tamoxifen treated women per year versus 1/1000 women per year for Surveillance Epidemiology and End Results Reporting), that there is no strong association with duration of therapy, and that tamoxifen is not associated with a high-grade, poor prognosis disease. The benefits of tamoxifen in lives saved exceeds the incidence of endometrial carcinoma.