Endocrine Therapy Options Research Articles

Difference of opinion - Radical prostatectomy in metastatic prostate cancer: is there enough evidence? | Opinion: Yes.

Prostate cancer (PCa) is the most frequent and the second ranked cause of cancer deaths among men each year. The vast majority of patients are diagnosed with localized disease, however it is estimated that 35,000 American men were diagnosed with locally advanced or metastatic prostate cancer (mPCa) in 2015 (1). During the last few years we have seen notable advances in the treatment of mPCa with the introduction of several second-line hormonal therapy options, immunotherapy and cytotoxic chemotherapy in hormone sensitive disease (2). With newer therapies that prolong survival in patients re-lapsing with mPCa and the increasingly widespread use of prostate-specific antigen (PSA) testing, men with metastatic disease might have lower disease burden at diagnosis than in the past decades (3). Although recent data suggest a relative improvement in 2-year overall survival in mPCa patients treated with systemic therapy, the long-term survival still remains disappointing. Actually, patients with mPCa and non-metastatic PCa present 5-year cancer-specific survival (CSS) rates of 28% and 99%, respectively (4). Thus, there is clearly room for improvement in the treatment of mPCa patients.The concept of cytoreductive surgery is well established in a number of tumors such as ovarian (5) and kidney cancer (6). Cytoreduction is still a largely unexplored subject in PCa, however recent evidences have shown its importance in the mPCa scena-rio. Possible theoretical advantages of cytoreductive prostatectomy (CP) include primary tumor debulking and improved response to systemic therapies. Kadmon et al. described one of the first studies addressing this issue in 1982. In an animal model, the authors used a PCa cell line that uniformly resulted in metastatic lung colonies. The mice were treated with either single-dose chemotherapy, surgical excision of the primary tumor, or a combination of tumor excision and postoperative single-dose chemotherapy. Tumor excision followed by postoperative chemotherapy resulted in a decrease in the number of metastatic sites in the lungs and prolonged survival. Of the combined group, 42% were long-term survivors (tumor-free >180 days), which was not seen in the non-surgery group (7). One additional potential mechanism of action for CP is based on the concept of tumor self-seeding. It is known that circulating tumor cells (CTCs) have the potential to seed metastases in distant organs in a unidirectional process. CTCs can also seed and then colonize their own tumors of origin, which accelerates tumor growth, angiogenesis and stromal recruitment through seed-derived factors (8). CTCs detected by the CellSearch®

Palbociclib (PAL) in combination with fulvestrant (F) in pre-/peri-menopausal (PreM) women with metastatic breast cancer (MBC) and prior progression on endocrine therapy – results from Paloma-3.

524Background: Standard endocrine therapy options for PreM women with MBC are limited and better options are needed. PALOMA-3 is the first large registrational study to include PreM women with HR+ ...

A novel compound, NK150460, exhibits selective antitumor activity against breast cancer cell lines through activation of aryl hydrocarbon receptor.

Antiestrogen agents are commonly used to treat patients with estrogen receptor (ER)-positive breast cancer. Tamoxifen has been the mainstay of endocrine treatment for patients with early and advanced breast cancer for many years. Following tamoxifen treatment failure, however, there are still limited options for subsequent hormonal therapy. We discovered a novel compound, NK150460, that inhibits 17β-estradiol (E2)-dependent transcription without affecting binding of E2 to ER. Against our expectations, NK150460 inhibited growth of not only most ER-positive, but also some ER-negative breast cancer cell lines, while never inhibiting growth of non-breast cancer cell lines. Cell-based screening using a random shRNA library, identified aryl hydrocarbon receptor nuclear translocator (ARNT) as a key gene involved in NK150460's antitumor mechanism. siRNAs against not only ARNT but also its counterpart aryl hydrocarbon receptor (AhR) and their target protein, CYP1A1, dramatically abrogated NK150460's growth-inhibitory activity. This suggests that the molecular cascade of AhR/ARNT plays an essential role in NK150460's antitumor mechanism. Expression of ERα was decreased by NK150460 treatment, and this was inhibited by an AhR antagonist. Unlike two other AhR agonists now undergoing clinical developmental stage, NK150460 did not induce histone H2AX phosphorylation or p53 expression, suggesting that it did not induce a DNA damage response in treated cells. Cell lines expressing epithelial markers were more sensitive to NK150460 than mesenchymal marker-expressing cells. These data indicate that NK150460 is a novel AhR agonist with selective antitumor activity against breast cancer cell lines, and its features differ from those of the other two AhR agonists.

Clinical implications for a treatment algorithm and differential indication to hormone therapy and chemotherapy options in metastatic castrate-resistant prostate cancer: a personal view

Although docetaxel is still considered a mainstay of treatment in metastatic castrate-resistant prostate cancer (mCRPC), in the last few years, new agents have been developed to improve survival in this setting and reach a possible optimal personalized treatment strategy. In this paper, we provide a personal view and an algorithm for mCRPC patients, according to available evidence, personal opinion and experience. Abiratone acetate, cabazitaxel, radium-223, sipuleucel-T and enzalutamide, together with docetaxel, have demonstrated a survival benefit in these patients. The use of rechallenge with docetaxel in mCRPC patients with disease progression after a first response has been considered. These new agents complicated the scenario and posed the challenge to move from the old sequential to a new algorithm-based approach. At this stage, the algorithm is necessarily based on experts’ opinion, since the efficacy of a single agent in a specific setting has not been validated by sequential trials.

Adjuvant Endocrine Therapy of Perimenopausal and Recently Postmenopausal Women With Hormone Receptor-Positive Breast Cancer

Although 5 years of tamoxifen has been the standard adjuvant endocrine therapy for premenopausal women with hormone receptor-positive breast cancer for more than 2 decades, emerging results suggest that either switching to an aromatase inhibitor after 5 years of tamoxifen when postmenopausal or continuing tamoxifen for an additional 5 years can further decrease relapse risk. As a result, more premenopausal breast cancer patients will be continuing adjuvant endocrine therapy through the menopause transition. In this setting, questions arise regarding continued tamoxifen use through 10 years and/or the timing and appropriateness of switching to an aromatase inhibitor. In addition, it is now recognized that estrogen levels substantially decline for approximately 2 years after the last menstrual period and that chemotherapy and/or tamoxifen-induced amenorrhea preclude reliable ovarian function determination. Because aromatase inhibitors are only effective in a low estrogen environment without ovarian estrogen production, determination of the optimal endocrine adjuvant therapy for perimenopausal women and those recently postmenopausal represent a challenge requiring understanding of current clinical study results and the potential for interactions among therapeutic interventions, ovarian function, and clinical outcome. Available options include tamoxifen for 10 years, tamoxifen for 5 years followed by aromatase inhibitors, tamoxifen with a luteinizing hormone-releasing hormone (LHRH) agonist, aromatase inhibitor with an LHRH agonist or aromatase inhibitor with bilateral oophorectomy. Although completed (Austrian Breast Cancer Study Group [ABCSG]-12) and ongoing (SOFT [Suppression of Ovarian Function Trial], TEXT [Tamoxifen and Exemestane Trial]) clinical trials are addressing some issues, many questions will remain requiring individualized clinical judgement. Rationale supporting the available endocrine therapy options in this setting and recommendations for clinical management follow.

The Role of Mammalian Target of Rapamycin (mTOR) Inhibition in the Treatment of Advanced Breast Cancer

Endocrine therapy (ET) with aromatase inhibitors (AIs) has become the standard of care for postmenopausal women with hormone-receptor-positive (HR(+)) advanced breast cancer (ABC); however, progression following initial treatment remains a major clinical challenge given the large patient population, many of whom develop progressive disease. There is an unmet need for treatment strategies that can overcome endocrine resistance. Growth factor-mediated signaling pathways, such as the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, contribute to estrogen-independent growth that may lead to endocrine resistance. Preclinical studies have demonstrated that the use of mTOR inhibitors, such as everolimus and temsirolimus, is a promising strategy to potentially enhance endocrine sensitivity in ABC. This review will focus on the current ET options for women with HR(+) ABC who have progressed on prior AI therapy, the role of mTOR-mediated signaling in breast cancer, and the clinical evidence supporting the use of mTOR inhibitors.

Evolution of postmenopausal hormone therapy between 2002 and 2009

The results of the Women's Health Initiative led to a sharp decline in postmenopausal hormone therapy use. Subsequently, treatment guidelines were revised to recommend hormone therapy at the lowest effective dose for the shortest possible duration. The objective of this analysis was to assess trends in nationwide hormone therapy prescription claims from 2002 to 2009. This study was a retrospective database analyses of pharmacy claims from MedImpact Healthcare Systems Inc. Data from women with claims for oral or transdermal hormone therapy were analyzed to assess trends in hormone therapy claims, including route of administration, dose, and physician specialty. By the end of 2002, the total number of hormone therapy claims dropped approximately 30% from 2002 second quarter claims. This trend continued during the next 7 years, and by 2009, hormone therapy claims were reduced by more than 70%. The proportion of low--dose oral claims rose fourfold, whereas the proportion of standard/high-dose claims decreased 30%. The proportion of claims for transdermal formulations more than doubled, and the proportion of claims for low-dose transdermal hormone therapy increased 10-fold. Although reductions in overall claims, routes of administration, and dose categories were similar between physician specialties, obstetrician/gynecologists prescribed transdermal hormone therapy nearly twice as often as all other types of providers. Since the publication of the Women's Health Initiative results, there has been a sustained decrease in hormone therapy claims. The proportional use of low-dose oral and transdermal formulations has increased, but as of 2009, claims for these formulations accounted for approximately one in four total hormone therapy claims.

The evolving paradigm of second-line hormonal therapy options for castration-resistant prostate cancer

The review examines recent advances in second-line hormonal therapy for the treatment of castrate-resistant prostate cancer (CRPC). Recent data highlight the continued importance of androgen signaling in CRPC. These findings have spurred the development of novel inhibitors of adrenal and intra-tumoral androgen synthesis and novel androgen signaling inhibitors with activity in CRPC. In the past year abiraterone acetate, a CYP17 (17α-hydroxylase/17, 20 lyase) inhibitor, received US FDA approval for use in the treatment of metastatic CRPC in patients previously treated with docetaxel. Additionally, the novel androgen signaling inhibitor MDV3100 has been reported to confer a survival advantage compared to placebo in the same patient population. Here we review the scientific rationale for targeting androgen signaling in CRPC and the recent pivotal trials that support the use of novel second-line hormonal therapies. Additionally, we summarize ongoing preclinical and clinical efforts to ascertain and overcome mechanisms of resistance. Novel inhibitors of extra-gonadal androgen synthesis and androgen receptor function demonstrate the continued importance of androgen signaling in CRPC. These agents have improved clinical outcomes for patients with metastatic CRPC.

Abstract 3654: Prognostic role of androgen receptor in bladder cancer

Abstract Aims: Hormone receptors are the prototype predictive marker in breast and prostate cancer. Hormone receptor positive cancers have a better prognosis, increased tropism to metastasize into the bones and respond to endocrine treatment options. The prognostic value of hormone receptor in urothelial carcinoma of the bladder (UCB) is less established. This may in part result from technical limitations of immunhistochemical detection methods. Interestingly, female gender has recently been identified as strong adverse factor in advanced UCB (May et al., 2011). By analyzing whole genome expression data from non-muscle invasive bladder cancer patients, we have evaluated the potential of top candidate genes (ESR1, PGR, AR, CYP19, HER2, RACGAP1) commonly used to stratify breast cancer patients to predict bladder cancer progression. In view of the gender specific effects, we have focused on the prognostic role of androgen receptor expression on tumor invasion, disease progression and survival. Methods: Affymetrix microarray data from 41 non-metastatic bladder cancer patients undergoing curative surgery were analyzed. Prognostic value of androgen receptor mRNA expression was analyzed by unsupervised Cluster analysis, partitioning tests, Mann Whitney tests and Kaplan Meier estimates of cancer specific survival. Results: Cluster analysis in the microarray date of the superficial UCB cohort identified a hormone receptor positive subtype and a proliferation dominated subtype of equal size. Androgen receptor expression was negatively associated with cancer specific death (r=−0,42; p=0,005), while proliferation correlated with increased risk of cancer specific death (r=0,46; p=0,003). In addition, low androgen receptor expression was associated with higher tumor stage (pTa vs pT1-4; p=0,017). In Kaplan Meier analysis, the cancer specific survival was significantly better in tumors exhibiting high androgen receptor levels (80% vs. 20 %; p<0,0001). Discussion: Resembling to some extent the situation in other cancer types, hormone receptors are prognostic factors in early stage bladder cancer. These results may also explain the recently described gender specific effects in bladder cancer. Moreover, these results raise the possibility, that UCB patients may be stratified according to their androgen receptor status in view of prognosis and putative endocrine therapy options. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3654. doi:1538-7445.AM2012-3654

Current approaches to the management of Her2-negative metastatic breast cancer

While metastatic breast cancer (MBC) remains incurable, a vast array of active therapeutic agents has provided the opportunity for long-term disease control while maintaining quality of life and physical function. Optimal management of MBC balances a multitude of factors, including a woman's performance status, social support, symptoms, disease burden, prior therapies, and surrogates for tumor biology. Choosing the most appropriate initial therapy and subsequent sequence of treatments demands flexibility as goals and patient preferences may change. Knowledge of the estrogen receptor (ER), progesterone receptor (PR), and Her2 receptor status of the metastatic tumor has become critical to determining the optimal treatment strategy in the metastatic setting as targeted therapeutic approaches are developed. Patients with ER+ or PR+ breast cancer or both have a wide array of hormonal therapy options that can forestall the use of cytotoxic therapies, although rapidly progressive phenotypes and the emergence of resistance may ultimately lead to the need for chemotherapy in this setting. So-called 'triple-negative' breast cancer - lacking ER, PR, and Her2 overexpression - remains a major challenge. These tumors have an aggressive phenotype, and clear targets for therapy have not yet been established. Chemotherapy remains the mainstay of treatment in this group, but biologically based clinical trials of new agents are critical to developing a more effective set of therapies for this patient population.

Nuclear Hormone Receptor Signals as New Therapeutic Targets for Urothelial Carcinoma

Unlike prostate and breast cancers, urothelial carcinoma of the urinary bladder is not yet considered as an endocrine-related neoplasm, and hormonal therapy for bladder cancer remains experimental. Nonetheless, there is increasing evidence indicating that nuclear hormone receptor signals are implicated in the development and progression of bladder cancer. Androgen-mediated androgen receptor (AR) signals have been convincingly shown to induce bladder tumorigenesis. Androgens also promote the growth of AR-positive bladder cancer cells, although it is controversial whether AR plays a dominant role in bladder cancer progression. Both stimulatory and inhibitory functions of estrogen receptor signals in bladder cancer have been reported. Various studies have also demonstrated the involvement of other nuclear receptors, including progesterone receptor, glucocorticoid receptor, vitamin D receptor, and retinoid receptors, as well as some orphan receptors, in bladder cancer. This review summarizes and discusses available data suggesting the modulation of bladder carcinogenesis and cancer progression via nuclear hormone receptor signaling pathways. These pathways have the potential to be an extremely important area of bladder cancer research, leading to the development of effective chemopreventive/therapeutic approaches, using hormonal manipulation. Considerable uncertainty remains regarding the selection of patients who are likely to benefit from hormonal therapy and optimal options for the treatment.

Are All Estrogens Created Equal? A Review of Oral vs. Transdermal Therapy

To compare oral and transdermal delivery systems in domains of lipid effects; cardiovascular, inflammatory, and thrombotic effects; effect on insulin-like growth factor, insulin resistance, and metabolic syndrome; sexual effects; metabolic effects including weight; and effects on target organs bone, breast, and uterus. Review of the literature 1990-2010. Studies selected on basis of applicability, quality of data, and relationship to topic. Data applicable to the comparisons of oral versus transdermal delivery systems for postmenopausal estrogen therapy were utilized to perform a review and formulate conclusions. Significant differences appear to exist between oral and transdermal estrogens in terms of hormonal bioavailability and metabolism, with implications for clinical efficacy, potential side effects, and risk profile of different hormone therapy options, but neither results nor study designs are uniform. Bypassing hepatic metabolism appears to result in more stable serum estradiol levels without supraphysiologic concentrations in the liver. By avoiding first-pass metabolism, transdermal hormone therapy may have less pronounced effects on hepatic protein synthesis, such as inflammatory markers, markers of coagulation and fibrinolysis, and steroid binding proteins, while oral hormone therapy has more pronounced hyper-coagulant effects and increases synthesis of C-reactive protein and fibrinolytic markers. Both oral and transdermal delivery systems have beneficial effects on high-density lipoprotein cholesterol to low-density lipoprotein cholesterol ratios (oral>transdermal), while the transdermal system has more favorable effects on triglycerides. Incidence of metabolic syndrome and weight gain appears to be slightly lower with a transdermal delivery system. Oral estrogen's significant increase in hepatic sex hormone binding globulin production lowers testosterone availability compared with transdermal delivery, with clinically relevant effects on sexual vigor.

Commentary on “Expression of dopamine 2 receptor subtypes mRNA in clinically nonfunctioning pituitary adenomas”

In the paper by Su et al. [1], in this issue, expression of mRNA for the two subtypes of dopamine 2 receptor has been evaluated by RT-PCR in operative samples from 72 patients (21 with prolactinomas, 25 with gonadotropinoma, 21 with null cell adenoma, 3 with oncocytoma, and 2 with silent corticotroph adenoma). Two normal pituitaries were also assessed. The results showed a lower expression of D2L and D2S mRNA in NFPAs as compared with prolactinomas, but a minority of the patients (21.6%), mostly gonadotropinomas and null cell adenomas, displayed relatively high mRNA levels. The very recently published study by Gabalec et al. [2] lends support to the observations of Su et al. confirming the preferential expression of D2R mRNA in gonadotropinomas, however, with significant interindividual variability. The standard approach to the treatment of NFPAs consists of trans-sphenoidal surgery; however, the management of postoperative residual tumor is debated, and no evidence-based indications are present (with both watch and wait and radiotherapy and hormonal therapy options being present) [3]. The observations by Su and Gabalec support future prospective controlled studies aimed at evaluating the differential response to these treatment options (and possibly also to innovative molecules) [4] stratified according to DR2 mRNA expression.

Breast Cancer Series: Hormone Therapy

Breast Cancer Series: Hormone Therapy (FCS8836/FY906) Women who are at high risk of getting breast cancer and women who have had breast cancer may be prescribed daily oral medications to block the estrogen receptor site or decrease the production of estrogen. This 2-page fact sheet describes various hormone therapy options. It is part of a 12-part Breast Cancer series. Written by Karen C. Daily and Martha C. Monroe and published by the UF Department of Family Youth and Community Sciences, June 2011. http://edis.ifas.ufl.edu/fy906 Minor Revision February 2015.

Parenteral administration of progestins for hormonal replacement therapy

New options for hormonal replacement therapy (HRT) include non-oral, low-dose sustained delivery of progestins in different formulations. Since the Women's Health Initiative (WHI) study, prescription trends were observed selecting progesterone over other progestins, or delivering the progestin parenterally, in order to reach low systemic levels of the steroid. Such modalities include progesterone vaginal rings or gels, and intra-uterine systems (IUSs). When given via the transdermal and intranasal routes, the hormones are delivered systemically although the first liver impact is by-passed. Of the progestins selected for delivery of low doses by means of an IUS, or transdermally, only very active molecules can be used. An IUS approved for HRT in several countries delivers very low doses of levonorgestrel (LNG) in the uterine cavity. Nestorone® is well absorbed transdermally from a gel as well as from a metered dose transdermal system (MTDS) that sprays an invisible film on the skin. Transdermal patches combining oestradiol with either norethisterone acetate or LNG have been available for several years. Although parenteral administration of progesterone or low-dose progestins should in theory be associated with fewer side-effects than oral therapy, the long-term safety of the newer systems warrants further evaluation.

Increasing protection after tamoxifen: insights from the extended adjuvant aromatase inhibitor trials

For disease-free postmenopausal women with hormone-responsive breast cancer, a risk for relapse remains following 5 years of adjuvant therapy with tamoxifen. Additional therapy with tamoxifen beyond 5 years is not indicated due to a demonstrated lack of efficacy beyond this time frame. Thus, there is a need for other endocrine therapy options in the period beyond 5 years. The third-generation aromatase inhibitors (anastrozole, letrozole, and exemestane) have emerged as at least as effective and somewhat better tolerated alternatives to tamoxifen. Three trials were initiated to evaluate the efficacy and tolerability of aromatase inhibitors in the extended adjuvant setting. Among these, the large, double-blind, randomized, placebo-controlled MA.17 trial has already demonstrated a significant benefit of letrozole when compared with placebo on disease-free survival in postmenopausal women previously treated for 4.5-6 years with tamoxifen. A smaller open-label trial, the Austrian Breast and Colorectal Cancer Study Group 6a has reported a significant benefit for anastrozole on recurrence when used as extended adjuvant therapy when compared with no treatment, and similar results have been seen with extended adjuvant exemestane in the National Surgical Adjuvant Breast and Bowel Project B-33 trial. The results of these trials have important clinical implications for the future of extended adjuvant hormonal therapy for breast cancer.

Care of the menopausal patient: A nurse practitioner’s view

To evaluate the benefits and risks of hormone therapy (HT) and other treatment options for early postmenopausal women. Published clinical trials, selected peer-reviewed literature, and recent clinical practice guidelines. Results of the Women's Health Initiative (WHI) studies on HT may not be directly applicable to healthy, early postmenopausal women suffering from hot flushes. HT is the most effective treatment for menopausal symptoms. The benefits of HT in relieving menopausal symptoms are likely to exceed the risks in this population. The results of the WHI reinforce the importance of individualized care based on a woman's medical history, medical needs, and desired outcomes. Nurse practitioners can help their patients put recent results into perspective. When HT is used, nurse practitioners should consider using lower doses and reevaluate the need for therapy annually.

HER2/neu in systemic therapy for women with breast cancer: a systematic review

Amplification and/or overexpression of the HER2/neu gene is associated with a poor prognosis in breast cancer. Many studies have suggested that this gene may be associated with the relative efficacy of chemotherapy and endocrine therapy options. A systematic review of the evidence was conducted. MEDLINE, EMBASE, the Cochrane Library, the American Society of Clinical Oncology annual meeting proceedings, and the San Antonio Breast Cancer Symposia proceedings were all searched to November 2006 for reports of analysis by HER2/neu status of the relative efficacy of the treatment arms in randomized controlled trials. Thirty-five trials were identified. A meta-analysis of trials of tamoxifen versus observation found no significant interaction between treatment and HER2/neu status, although one trial not included in the meta-analysis did find interaction. A meta-analysis of adjuvant anthracycline-based chemotherapy trials found a significant interaction (difference in disease-free survival log-hazard ratios -0.31, 95% confidence interval -0.50 to -0.13; difference in overall survival log-hazard ratios -0.34, 95% confidence interval -0.53 to -0.14). Significant interaction was also found in a meta-analysis of disease-free survival in trials of adjuvant taxane therapy versus non-taxane therapy (difference in disease-free survival log-hazard ratios -0.36, 95% confidence interval -0.68 to -0.04). HER2/neu overexpression and/or amplification was associated with greater efficacy of the anthracycline or taxane regimen. Current evidence supports the conclusion that the benefit of both anthracycline-based and taxane-based adjuvant chemotherapy is associated on HER2/neu status, with patients with HER2/neu-positive cancers benefiting more from these therapies than those with HER2/neu-negative cancers.

Eliciting patient preferences for hormonal therapy options in the treatment of metastatic prostate cancer

Treatment choices for metastatic prostate cancer are complex and can involve men balancing survival versus quality of life. The present study aims to elicit patient preferences with respect to the attributes of treatments for metastatic prostate cancer through a discrete choice experiment (DCE) questionnaire. Men with recently diagnosed localized prostate cancer were asked to envisage that they had metastatic disease when completing a survey. As expected, men with prostate cancer placed considerable importance on gains in survival; however, avoiding side effects of treatment was also clearly important. Survival gains should be considered alongside side effects when discussing treatment options in metastatic disease.

Improvement in survival of breast cancer patients with synchronous metastases

1063 Background: Less than 10% of breast cancer patients are diagnosed with metastatic disease upon initial diagnosis. Once metastases are detected, median survival ranges between 18 and 24 months. Many new chemotherapy agents, hormonal therapy, monoclonal antibodies and supportive care options were presented during the last decade. Although a few randomized trials have demonstrated improvement in survival for various agents, it has not been clear whether the overall survival of these patients has improved. In this study, we analyzed the survival of patients diagnosed with metastatic breast cancer in during the 1990’s Methods: We have analyzed 874 patients diagnosed with breast cancer at our Institute in the years 1991–1994 and 1102 patients in 1996–1999. Tumor characteristics, treatments, and the outcomes of these patients were compared. We used Kaplan-Meier, Wilcoxon test and Cox proportional hazard in order to investigate variants between the 2 groups. Results: After excluding all women with no evidence of metastatic disease at diagnosis, we analyzed 96 patients. No major difference in tumor characteristics was found between the group of patients diagnosed in the early 1990’s and the group diagnosed in the late 1990’s. We found a significant relationship between the period of diagnosis of metastatic breast cancer and survival: median survival was 19 months for the first group and 35 months for the second group (p=0.0398, 95% C.I), with 5-year overall survival rates 8% for patients diagnosed in the early 1990’s and 25% for patients diagnosed in the late 1990’s, p=0.0497. Two years survival was 25% and 60% respectively, although insignificant, p = 0.0941. Although there was no significant difference in number of chemotherapy courses given in the 2 groups, many more new generation treatments were used for the late 90th group. The Hazard of death within 5 years for patients treated with at least one new generation protocol was 0.53, p= 0.004. Conclusions: This study suggests that there has been significant survival improvement in breast cancer patients diagnosed with synchronous metastasis during the second half of the 1990’s. This improvement can be explained by the introduction of new treatments agents and strategies during the last decade No significant financial relationships to disclose.