Femara scientific update |
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Ann Oncol. 2010 Jul 8. [Epub ahead of print]
Lønning PE.
Section of Oncology, Institute of Medicine, University of Bergen, and Department of Oncology, Haukeland University Hospital, Bergen, Norway.
Analysis of aromatase inhibitors in breast cancer patients [The potency and clinical efficacy of aromatase inhibitors across the breast cancer continuum.]
The strategy of using estrogen suppression to treat breast cancer led to the development of aromatase inhibitors, including the third-generation nonsteroidal compounds anastrozole and letrozole, and the steroidal compound exemestane. Aromatase inhibitors potently inhibit aromatase activity and also suppress estrogen levels in plasma and tissue. In clinical studies in postmenopausal women with breast cancer, third-generation aromatase inhibitors were shown superior to tamoxifen for the treatment of metastatic disease. Studies of adjuvant therapy with aromatase inhibitors include (i) head-to-head studies of 5 years of the aromatase inhibitor versus 5 years of tamoxifen monotherapy; (ii) sequential therapy of 2-3 years of tamoxifen followed by an aromatase inhibitor (or the opposite sequence) versus 5 years of tamoxifen monotherapy; (iii) extended therapy with an aromatase inhibitor after 5 years of tamoxifen; and (iv) sequential therapy with an aromatase inhibitor versus aromatase inhibitor monotherapy. Recent results from the Arimidex, Tamoxifen, Alone or in Combination and Breast International Group 1-98 trials advocate using an aromatase inhibitor upfront. This article examines the clinical data with aromatase inhibitors, following a brief summary of their pharmacology.
J Clin Endocrinol Metab. 2010 Jul 7. [Epub ahead of print]
Drake MT, McCready LK, Hoey KA, Atkinson EJ, Khosla S.
Divisions of Endocrinology and Metabolism (M.T.D., L.K.M., K.A.H., S.K.) and Health Sciences Research (E.J.A.), College of Medicine, Mayo Clinic, Rochester, Minnesota 55905.
Study of bone resorption markers in post menopausal women [Effects of Suppression of Follicle Stimulating Hormone Secretion on Bone Resorption Markers in Postmenopausal Women.]
Context: It has recently been proposed that the increase in bone resorption after the menopause may not be due principally to estrogen deficiency but rather to the concomitant increase in circulating FSH levels. Objective: The objective of the study was to test whether suppression of FSH secretion in postmenopausal women reduces levels of bone resorption markers. Design: This was a prospective study. Setting: The study was conducted at a clinical research unit. Participants and Interventions: Postmenopausal women were treated with a GnRH agonist (leuprolide acetate, 7.5 mg im every 28 d; n = 21) or placebo injections (control; n = 20). Both groups received the aromatase inhibitor, letrozole, 2.5 mg/d, to eliminate variations in endogenous estrogen levels as a confounder. Main Outcome Measures: Serum FSH and bone resorption markers [serum C-terminal telopeptide of type I collagen (CTX) and tartrate-resistant acid phosphatase 5b (TRAP5b)] at d 105 (3.5 months) of treatment as compared with baseline. Results: Compared with baseline, serum FSH levels did not change significantly in controls (+6%) but were reduced (-86%, into the premenopausal range) in the GnRH group. Due to the aromatase inhibitor-induced reduction in estrogen production, serum CTX and TRAP5b levels increased significantly in controls (+20 and +10%, respectively). In the GnRH group, suppression of FSH secretion did not reduce serum CTX or TRAP5b levels; rather, both markers also increased in these women (+34 and +15%, respectively; P = 0.161 and 0.266 for comparison of percent changes between groups). Conclusions: This direct interventional study demonstrates that FSH does not regulate bone resorption in postmenopausal women
Curr Opin Obstet Gynecol. 2010 Aug;22(4):289-94.
Pritts EA.
Wisconsin Fertility Institute, Middleton, Wisconsin, USA.
Letrozole effective uses [Letrozole for ovulation induction and controlled ovarian hyperstimulation.]
PURPOSE OF REVIEW: Letrozole, an aromatase inhibitor, is the newest addition to our armamentarium in the treatment of infertility. It is utilized in much the same way as clomiphene citrate, but with some additional benefits. In this review, the latest studies will be summarized with emphasis on dose, duration of use, safety, number of mature follicles, and pregnancy outcomes. RECENT FINDINGS: Letrozole has fewer side effects, and a shorter half-life than clomiphene citrate, and no demonstrable effect upon the receptivity of the endometrium. It is efficacious in treating women with chronic anovulation, unexplained infertility and diminished ovarian reserve. Its safety is superior to clomiphene citrate. Utilizing bio-equivalent doses, letrozole pregnancy rates are equal or superior to clomiphene citrate. Several studies suggest situations where it is more efficacious than gonadotropin treatment. SUMMARY: With further study, this drug could replace clomiphene citrate as the primary medication for chronic anovulation and/or unexplained infertility. It could augment or even obviate the use of gonadotropins in the treatment of women who have been unsuccessful in achieving pregnancy with clomiphene citrate. It may also be an adjunct for women with diminished ovarian reserve. Further studies are needed to determine optimal dosing and long term safety for women treated with the drug.
J Physiol Biochem. 2009 Sep;65(3):267-75.
Yonden Z, Aydin M, Alcin E, Kelestemur MH, Kutlu S, Yilmaz B.
Department of Biochemistry, Mustafa Kemal University, Hatay, Turkey. zaferyonden@yahoo.com
Effects of letrozone [Effects of letrozole on bone biomarkers and femur fracture in female rats.]
We aimed to investigate the effects of the aromatase inhibitor letrozole on femur fracture and serum levels of alkaline phosphatase (ALP), calcium and phosphate in female rats. Intact 32 Sprague-Dawley female rats were divided into four groups (n=8): control, letrozole 0.2 , letrozole 1 (treatment of 0.2 and 1 mg/kg for six weeks) and recovery (letrozole-treated 1 mg/kg for six weeks then allowed to recover for two weeks). Besides, 24 ovariectomized rats were divided into three groups (n=8): ovariectomized+control, ovariectomized+letrozole and ovariectomized+letrozole+ estradiol (10 microg/rat). After experimental period, rats' femur bones were removed for biomechanical studies following decapitation. Serum ALP, calcium and phosphate were measured. Biomechanical values, ALP and phosphate significantly increased by letrozole in a dose-dependent manner (p<0.05) while calcium levels and net bone area decreased (p<0.05). Ultimate strength was positively correlated with ALP and phosphate and negatively correlated with calcium. The results indicate that letrozole may increase risk of bone fracture and affect bone biomarkers such as ALP, calcium and phosphate in both intact and ovariectomized rats.
Klin Onkol. 2009;22(6):268-72.
Kubatka P, Péc M.
Ustav lekárskej biológie, Jesseniova LF UK, Martin, Slovenská republika. kubatka@jfmed.uniba.sk
Decrease in the risk of breast cancer by aromatase inhibitors [Aromatase inhibitors in risk reduction of breast cancer: potential use in premenopausal women] [Article in Slovak]
Aromatase inhibitors are effective and well tolerated drugs in the endocrine therapy of estrogen-receptor positive breast cancer in postmenopausal women. Questions remain about the long-term side effects and safety profile of aromatase inhibitors. The results of ongoing studies may indicate the role of aromatase inhibitors in the prevention of breast cancer. The effectiveness and safety of aromatase inhibitor monotherapy in premenopausal breast cancer patients is unknown, so this is an area of future exploration. Our results in the chemoprevention of mammary carcinogenesis in female rats pointed to the potential favourable effects of aromatase inhibitors--anastrozole and letrozole in premenopausal women affected by breast cancer.
Am J Ther. 2009 Dec 19. [Epub ahead of print]
Montero AJ, Talebi TN, Zhu Y, Branch KD, Goldsberry GT, Baker MK, Gluck S.
1Department of Medicine, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL; 2Department of Medicine, Division of Hematology/Oncology; 3Department of Pathology; 4Department of Radiology; and 5Department of Surgery, Medical Universit
Analysis of gemcitabine and nab paclitaxel [Successful Use of Biweekly Gemcitabine Plus Nab-Paclitaxel in Two Male Patients With Stage IV Breast Cancer: Case Reports and Review of the Literature.]
Male breast cancer is a rare disease. As a consequence, male breast cancer is often recognized later, and most patients present at an advanced clinical stage. We report the cases of two men with stage IV hormone receptor positive breast cancer who had both received at different times both systemic endocrine therapy with an aromatase inhibitor and gemcitabine as well as nab-paclitaxel-based combination chemotherapy. Although the aromatase inhibitors such as anastrozole, exemestane, and letrozole are very active in postmenopausal women with hormone receptor positive breast cancer, their efficacy in male breast cancer has not been demonstrated in phase II or III trials. Moreover, Gemcitabine and nab-paclitaxel every 14 days, with or without bevacizumab, are an active combination in male metastatic breast cancer and should be considered as an option in patients with extensive visceral metastases or hormone refractory disease.
Ther Clin Risk Manag. 2008 Dec;4(6):1295-304.
Untch M, Jackisch C.
Interdisciplinary Breast Centre, Helios Klinikum Berlin-Buch, University Charité, Berlin, Germany;
Review of exemestane in breast cancer [Exemestane in early breast cancer: a review.]
The adjuvant treatment of women with endocrine-sensitive early breast cancer has been dominated for the last 40 years by tamoxifen. However, the side-effects associated with this therapy have prompted a search for safer and biochemically more selective endocrine agents and led to the development of the third-generation aromatase inhibitors (AIs) anastrozole, letrozole and exemestane. Promising results in advanced disease have paved the way for treating early breast cancer, and AIs are increasingly replacing tamoxifen in the adjuvant setting. Several large, randomized trials with AIs have been completed or are ongoing in women with early-stage breast cancer, documenting the significant impact that these drugs are making on the risk for recurrence of breast cancer. As a result, there is increasing and widespread use of AI therapy for the treatment of early-stage endocrine-responsive breast cancer. This review summarizes the data for exemestane in the adjuvant setting, showing that a switch to exemestane after 2 to 3 years of tamoxifen therapy is associated with a statistically significant survival benefit and is regarded as being sensitive by international and national experts.
Curr Opin Oncol. 2008 Sep;20(5):548-53.
Langdon SP, Smyth JF.
Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK.
Ovarian cancer for for hormone therapy [Hormone therapy for epithelial ovarian cancer.]
PURPOSE OF REVIEW: Hormonal therapy has been used erratically to treat epithelial ovarian cancer since the mid 1960s; however, there has been little progress until recently in our understanding of which patients might benefit from treatment. Some clarity in the field is now beginning to emerge from recent studies, which have started to define biomarkers within epithelial ovarian cancers that link with hormonal response and thereby indicate which cohort of patients might be amenable to hormonal treatment. RECENT FINDINGS: Oestrogen-deprivation therapy in the form of the aromatase inhibitor letrozole has demonstrated activity in three clinical studies. As only a minority of patients will benefit from hormonal approaches, recent efforts have focussed on the use of molecular markers to help identify which subgroup of patients might respond to treatment. Parallel laboratory studies using primary cancer material for which endocrine response is known and model-based findings have identified components of oestrogen signalling pathways that may help predict outcome. SUMMARY: Use of the antioestrogen letrozole in ovarian cancer has consistently demonstrated a significant level of activity and the larger clinical studies have linked response with oestrogen receptor alpha expression and other biomarkers.
Breast Cancer Res Treat. 2008 Dec;112 Suppl 1:35-43. Epub 2008 Dec 20.
Blackwell KL.
Department of Medicine, Division of Medical Oncology, Duke University Medical Center, P.O. Box 3893, Durham, NC 27710, USA. kimberly.blackwell@duke.edu
Similarity in aromatase inhibitors [Are all aromatase inhibitors alike?]
The anti-estrogen tamoxifen was the gold-standard adjuvant therapy for hormone-receptor-positive (HR+) early breast cancer for several decades, but has recently been displaced by the third-generation aromatase inhibitors (AIs). Three AIs are commercially available: letrozole, anastrozole and exemestane. All are more effective and at least as well tolerated as tamoxifen as adjuvant therapy for HR+ breast cancer in postmenopausal women. Despite the wealth of data comparing AIs with tamoxifen, it is unclear whether the three AIs are clinically equivalent, owing to the lack of head-to-head trials directly comparing them. Preclinical and small clinical studies suggest that letrozole is the most potent inhibitor of aromatase, reducing circulating estrogen levels to a greater degree than the other agents. However, whether this greater activity translates into superior clinical efficacy remains to be determined. In the absence of direct comparative data, cross-trial comparisons have been used to gain insights into any safety or efficacy differences. All three AIs have been compared directly with tamoxifen, and efficacy relative to tamoxifen has been compared across trials, although such analyses are complicated by differences in treatment schedules, patient populations and trial designs. Definitive conclusions cannot yet be drawn, but some important differences are coming to light, with upfront letrozole appearing particularly effective at preventing early distant metastasis, an event strongly associated with breast-cancer-related death. No safety differences between the AIs have yet been identified. This article explores the pharmacologic and clinical differences between the AIs, based on data from clinical and preclinical studies.
Clin Breast Cancer. 2007 Dec;8 Suppl 1:S22-34.
Brufsky AM.
Magee-Women's Hospital of the University of Pittsburgh Medical Center, 300 Halket Street, Pittsburgh, PA 15213, USA.
Administering bone loss in women in breast cancer [Managing bone loss in women with early-stage breast cancer receiving aromatase inhibitors.]
Third-generation aromatase inhibitors (AIs; anastrozole, letrozole, exemestane) have replaced tamoxifen as the adjuvant treatment of choice for postmenopausal women with hormone receptor-positive early-stage breast cancer. Because bone loss is a predictable adverse event of AI therapy, early recognition, prevention, and/or treatment of AI-induced bone loss is needed. One to 5 years of AI therapy causes a bone mineral density (BMD) loss of up to 7.2% in postmenopausal women; however, current clinical guidelines do not recommend initiating bisphosphonate therapy for the treatment of BMD loss until fragility fractures or frank osteoporosis occur. Results of recent trials evaluating the use of intravenous (I.V.) zoledronic acid as prevention and treatment of AI-induced bone loss in women with early-stage breast cancer receiving letrozole suggest a potential benefit to the concurrent use of zoledronic acid and letrozole. To our knowledge, clinical trials assessing oral or other I.V. bisphosphonates for these indications have not been published. Recently, concerns of bisphosphonate-induced renal safety and osteonecrosis of the jaw have emerged. Studies evaluating bisphosphonates in women with breast cancer have reported lower rates of renal dysfunction than those reported in patients with metastatic cancer receiving bisphosphonates, and no cases of jaw osteonecrosis. The use of bisphosphonates in this population requires further study to more clearly define the most appropriate timing and length of therapy as well as the long-term efficacy and safety of these drugs. Until these data become available, balancing the safety concerns with the potential benefits of I.V. bisphosphonates to minimize or prevent AI-induced bone loss in women with early-stage breast cancer is required.
J Natl Cancer Inst. 2007 Dec 19;99(24):1845-53. Epub 2007 Dec 11.
Jakesz R, Greil R, Gnant M, Schmid M, Kwasny W, Kubista E, Mlineritsch B, Tausch C, Stierer M, Hofbauer F, Renner K, Dadak C, Rücklinger E, Samonigg H; Austrian Breast and Colorectal Cancer Study Group.
Department of Surgery, Vienna Medical University, Vienna General Hospital, Waehringer Guertel 18-20, Vienna A-1090, Austria. raimund.jakesz@meduniwien.ac.at
Analysing anastrazole in post menopausal breast cancer patients [Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from the randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a.]
BACKGROUND: Clinical trial data have shown that among breast cancer patients who were disease free after 5 years of adjuvant treatment with tamoxifen, further extended treatment with the nonsteroidal aromatase inhibitor letrozole reduces breast cancer recurrence. We examined the efficacy and tolerability of extended adjuvant therapy with another aromatase inhibitor, anastrozole, for 3 years among women who had completed 5 years of adjuvant therapy. METHODS: Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 6a is an extension of ABCSG Trial 6, in which hormone receptor-positive postmenopausal patients received 5 years of adjuvant tamoxifen, with or without the aromatase inhibitor aminoglutethimide, for the first 2 years of therapy. For ABCSG Trial 6a, patients who were disease free at the end of Trial 6 were randomly assigned to receive either 3 years of anastrozole or no further treatment. Efficacy data were analyzed with the use of a Cox proportional hazards regression model with two-sided P values and Kaplan-Meier curves, and tolerability data were estimated using logistic regression analysis with odds ratios and 95% confidence intervals (CIs). RESULTS: ABCSG Trial 6a included 856 patients. At a median follow-up of 62.3 months, women who received anastrozole (n = 387) had a statistically significantly reduced risk of recurrence (locoregional recurrence, contralateral breast cancer, or distant metastasis) compared with women who received no further treatment (n = 469; hazard ratio = 0.62; 95% CI = 0.40 to 0.96, P = .031). Anastrozole was well tolerated, and no unexpected adverse events were reported. CONCLUSIONS: These data confirm the benefit of extending adjuvant tamoxifen therapy beyond 5 years with anastrozole compared with no further treatment. Further research is required to define the optimum length of extended adjuvant therapy and to investigate the possibility of tailoring this period to suit different disease types.
Clin Ter. 2007 Sep-Oct;158(5):441-52.
Viola G, Sergi D, Conti F, Lopez M.
Istituto Nazionale Tumori Regina Elena, Roma, Italia.
Treating local advanced breast cancer [Neoadjuvant endocrine therapy for locally advanced breast cancer][Article in Italian]
The use of neoadjuvant chemotherapy in the treatment of locally advanced breast cancer is now well established. However, endocrine therapy can be a valid alternative to primary chemotherapy in the treatment of hormone-sensitive tumors, particularly in post-menopausal women. Tamoxifen (TAM) was initially used in older or frail patients who were not candidates for chemotherapy. Response rate of 49% to 68% were observed. These encouraging results prompted subsequent randomized phase III studies demonstrating the superiority of surgery in comparison to TAM as primary treatment. The successful use of aromatase inhibitors (AI) in the metastatic and adjuvant setting has encouraged studies that compare these agents with tamoxifen in the neoadjuvant setting. In terms of response rates, anastrozole and exemestane did not differ from TAM, while letrozole was superior. Nevertheless, all the AI were found to be superior to TAM as far as breast conserving surgery is concerned. The Americal College of Surgeons Oncology Group (ACOSOG) has recently activated a neoadjuvant randomized trial comparing anastrozole, letrozole and exemestane in postmenopausal patients with estrogen receptor positive tumors. Hopefully, this study will clarify which of these agents is more effective as primary endocrine therapy. In the meantime, neoadjuvant hormonal treatment should be considered in elderly patients with inoperable tumors or tumors not amenable to conservative surgery, with highly expressed estrogen receptors and contraindication to chemotherapy.
J Clin Oncol. 2007 Apr 23;
Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Pater JL.
Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA; Mayo Clinic, Rochester, MN; John Wayne Cancer Institute, Santa Monica, CA; and other
Efficacy of Letrozole Extended Adjuvant Therapy According to Estrogen Receptor and Progesterone Receptor Status of the Primary Tumor: National Cancer Institute of Canada Clinical Trials Group MA.17.
Controversy exists regarding estrogen (ER) and progesterone (PgR) receptor expression on efficacy of adjuvant endocrine therapy. The present study results suggest greater benefit for letrozole in DFS, DDFS, and OS in patients with ER+/PgR+ tumors, implying greater activity of letrozole in tumors with a functional ER.
PURPOSE: Controversy exists regarding estrogen (ER) and progesterone (PgR) receptor expression on efficacy of adjuvant endocrine therapy. In the ATAC
(Arimidex, Tamoxifen, Alone or in Combination) trial, the benefit of anastrozole over tamoxifen was substantially greater in ER+/PgR- than ER+/PgR+ tumors.
In BIG 1-98 (Breast International Group), the benefits of letrozole over tamoxifen were the same in ER+ tumors irrespective of PgR. MA.17 randomized
postmenopausal women after 5 years of tamoxifen, to letrozole or placebo. We present outcomes according to tumor receptor status. PATIENTS AND METHODS:
Disease-free survival (DFS) and other outcomes were assessed in subgroups by ER and PgR status using Cox's proportional hazards model, adjusting for nodal
status and prior adjuvant chemotherapy. RESULTS: The DFS hazard ratio (HR) for letrozole versus placebo in ER+/PgR+ tumors (N = 3,809) was 0.49 (95% CI, 0.36
to 0.67) versus 1.21 (95% CI, 0.63 to 2.34) in ER+/PgR- tumors (n = 636). ER+/PgR+ letrozole patients experienced significant benefit in distant DFS (DDFS;
HR = 0.53; 95% CI, 0.35 to 0.80) and overall survival (OS; HR = 0.58; 95% CI, 0.37 to 0.90). A statistically significant difference in treatment effect
between ER+/PgR+ and ER+/PgR- subgroups for DFS was observed (P = .02), but not for DDFS (P = .06) or OS (P = .09). CONCLUSION: These results suggest greater
benefit for letrozole in DFS, DDFS, and OS in patients with ER+/PgR+ tumors, implying greater activity of letrozole in tumors with a functional ER. However,
because this is a subset analysis and receptors were not measured centrally, we caution against using these results for clinical decision making.
Curr Opin Obstet Gynecol. 2007 Jun;19(3):248-52.
Kafy S, Tulandi T.
Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec, Canada.
New advances in ovulation induction.
The present study is to review recent advances in ovulation induction. The recent findings suggest that Aromatase inhibitors can replace clomiphene citrate as ovulation-inducing substances. The present study revealed that Aromatase inhibitors are alternative drugs to clomiphene or gonadotropin for ovulation induction or superovulation.
PURPOSE OF REVIEW: To review recent advances in ovulation induction. RECENT FINDINGS: Aromatase inhibitors can replace clomiphene citrate as
ovulation-inducing substances. The most widely used aromatase inhibitor for this purpose is letrozole and the optimal dose is 5 mg daily for 5 days. Compared
to clomiphene citrate, it is associated with a thicker endometrium and a better pregnancy rate. It is as effective as gonadotropin but yet less expensive.
The overall rates of congenital malformation among newborns conceived after infertility treatment with letrozole or clomiphene citrate are similar. When
letrozole is combined with gonadotropin, it leads to lower gonadotropin requirements with pregnancy rates comparable to gonadotropin treatment alone. Another
promising aromatase inhibitor is anastrazole. Recent evidence suggests that luteinizing hormone activity in human menopausal gonadotropin modifies follicular
development so that fewer intermediate-sized follicles develop. Compared to the use of follicular stimulating hormone only, human menopausal gonadotropin is
associated with less ovarian hyperstimulation. SUMMARY: Aromatase inhibitors are alternative drugs to clomiphene or gonadotropin for ovulation induction or
superovulation.
J Clin Endocrinol Metab. 2007 Apr 3;
Feuillan P, Calis K, Hill S, Shawker T, Robey PG, Collins MT.
National Human Genome Research Institute (PF), Clinical Center (KC, SH, TS), National Institute of Dental and Craniofacial Research) (PGR, MTC), National Institutes of Health, Bethesda, MD, 20892.
Letrozole treatment of precocious puberty in girls with the McCune-Albright syndrome; a pilot study.
The objective of the present study was to assess the effectiveness of the potent, 3(rd) generation aromatase inhibitor letrozole in decreasing pubertal progression in girls with MAS, and to assess the response of indices of bone turnover associated with the patients' polyostotic fibrous dysplasia. And become successful.
Context: Girls with McCune-Albright syndrome (MAS) and related disorders have gonadotropin-independent precocious puberty due to estrogen secretion from
ovarian cysts. Their puberty does not respond to GnRH agonist therapy, and short-acting aromatase inhibitors have had limited effectiveness. Objective: Our
objective was to assess the effectiveness of the potent, 3(rd) generation aromatase inhibitor letrozole in decreasing pubertal progression in girls with MAS,
and to assess the response of indices of bone turnover associated with the patients' polyostotic fibrous dysplasia. Design: Subjects were evaluated at
baseline, and every 6 mo for 12-36 mo while on treatment with letrozole 1.5 - 2.0 mg /M(2)/d. Setting: An open-label therapeutic trial at a single clinical
center. Patients: Nine girls age 3 - 8 yr with MAS and/or gonadotropin-independent puberty. Main outcome measures: Rates of linear growth, bone age (BA)
advance (BA/CA), mean ovarian volume (MOV), E, episodes of vaginal bleeding, and levels of the indices of bone metabolism: serum osteocalcin (OC) and
alkaline phosphatase (AP), urinary hydroxyproline (OHP), pyridinoline (PYR), deoxypyridinoline (dPYR) and N telopeptides (NTP). Results: Girls had decreased
rates of growth (P
Cancer Treat Rev. 2006 Nov;32(7):548-56.
Venturini M, Del Mastro L.
Divisione di Oncologia, Ospedale Sacrocuore - Don Calabria, Via Sempreboni, 5, Negrar Verona,
Safety of adjuvant aromatase inhibitor therapy.
Aromatase Inhibitors (AIs) confer an increased risk of bone loss and osteoporosis and fractures, while the effects on lipid profiles and cardiovascular health seem to indicate only that AIs lack the cardioprotective and lipid-lowering effects of tamoxifen. The present study reveals significant clinical benefits of AIs compared with tamoxifen have been achieved without worsening quality of life.
The long-term effects of aromatase inhibitors (AIs) on lipids and bone and cardiovascular and
gynecological health are of particular interest to clinicians. The safety data of anastrozole,
letrozole, and exemestane are limited to trials with follow-up periods of 5 years or less, and
much of the data arise from comparisons with tamoxifen, a drug that has both estrogen agonist
and antagonist effects. With the lack of extensive long-term data, indirect comparisons
between the safety profiles of the AIs provide some insights. Although results from these
indirect comparisons should be interpreted cautiously, they may assist physicians in the
decision-making process. Thus far, AIs confer an increased risk of bone loss and osteoporosis
and fractures, while the effects on lipid profiles and cardiovascular health seem to indicate
only that AIs lack the cardioprotective and lipid-lowering effects of tamoxifen. Some data
also are available from comparisons with placebo, a more appropriate comparator to investigate
the tolerability and safety of a specific drug. In the MA.17 trial, patients receiving
letrozole experienced similar rates of cardiovascular ischemic events and hypercholesterolemia
compared with those on placebo. The significant clinical benefits of AIs compared with
tamoxifen have been achieved without worsening quality of life.
Semin Oncol. 2004 Dec;31(6 Suppl 12):23-30.
Harvey HA.
Penn State Milton S. Hershey Medical Center, Hershey, PA 17033, USA.
Optimizing bisphosphonate therapy in patients with breast cancer on endocrine therapy.
Deterioration of bone health is a major concern during progression and treatment of patients with breast cancer, especially in postmenopausal women. The present study reveals the possibility of such treatment-reversing aromatase inhibitor-associated bone loss during adjuvant therapy of breast cancer is being evaluated in a trial of letrozole, with zoledronic acid added initially or after the onset of bone loss or fracture.
Deterioration of bone health is a major concern during progression and treatment of patients with breast cancer, especially in postmenopausal women. Disease- and treatment-associated skeletal-related events include fractures, spinal compression, bone pain, and hypercalcemia of malignancy. Bisphosphonates, which inhibit osteoclastic bone resorption, are important new agents in the management of skeletal-related events, and their impact on breast cancer-related bone metastases and on bone loss during long-term estrogen deprivation therapies such as aromatase inhibitors is reviewed. Intravenous pamidronate has become the standard bisphosphonate to reduce or delay skeletal complications of advanced breast cancer bone metastases, but the more potent agent, zoledronic acid, appears to be at least as effective. Another agent, ibandronate, is also active but has not been investigated in comparison with the other intravenous bisphosphonates. Zoledronic acid is the most convenient to administer, requiring only a short infusion. The effects of bisphosphonates on bone health in women with early breast cancer are also being investigated. A single yearly infusion of zoledronic acid has been shown to significantly increase bone mineral density in osteoporotic postmenopausal women and to reduce biochemical markers of bone turnover. The possibility of such treatment-reversing aromatase inhibitor-associated bone loss during adjuvant therapy of breast cancer is being evaluated in a trial of letrozole, with zoledronic acid added initially or after the onset of bone loss or fracture.
Semin Oncol. 2004 Dec;31(6 Suppl 12):9-14.
Smith IE.
Royal Marsden Hospital, Institute of Cancer Research, London, United Kingdom.
Aromatase inhibitors in early breast cancer therapy.
Third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, are active and well tolerated in postmenopausal patients with hormone-sensitive advanced or metastatic breast cancer. In this study all three aromatase inhibitors as adjuvant therapy were well tolerated, long-term effects on bone health and lipids are being monitored.
Third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, are active and well tolerated in postmenopausal patients with hormone-sensitive advanced or metastatic breast cancer, as either first- or second-line therapy. These agents are being investigated as neoadjuvant therapy of locally advanced breast cancer and as adjuvant therapy of early breast cancer. In a large neoadjuvant study, letrozole resulted in significantly more responses than tamoxifen, with significantly more patients becoming eligible for breast-conserving surgery. Greater letrozole responses were associated with high and low levels of estrogen receptor expression and with coexpression of ErbB-1 and/or ErbB-2. Neoadjuvant anastrozole, in two studies, was also significantly superior to tamoxifen in rendering patients eligible for breast-conserving surgery. In the adjuvant setting, the Arimidex, Tamoxifen Alone or in Combination trial compared 5 years of anastrozole versus tamoxifen versus the combination. At 47 months' median follow-up, disease-free survival was significantly improved with anastrozole compared with the other arms. In the Intergroup Exemestane Study, switching to exemestane after 2 to 3 years of tamoxifen significantly improved disease-free survival compared with remaining on tamoxifen for 5 years. The MA.17 trial evaluated switching to letrozole versus placebo following 5 years of adjuvant tamoxifen, and letrozole was significantly superior to placebo in disease-free survival. While all three aromatase inhibitors as adjuvant therapy were well tolerated, long-term effects on bone health and lipids are being monitored. Ongoing trials will better define the optimum use of aromatase inhibitors as adjuvant therapy.
Pediatrics. 2005 Feb;115(2):e245-8. Epub 2005 Jan 14.
Zhou P, Shah B, Prasad K, David R.
Division of Pediatric Endocrinology, New York University School of Medicine, New York, New York 10016, USA.
Letrozole significantly improves growth potential in a pubertal boy with growth hormone deficiency.
The present report documents treatment of such a patient with a combination of growth hormone and letrozole, a third-generation aromatase inhibitor.
Clinical experience with using an aromatase inhibitor to suppress estrogen production during puberty for improvement of growth potential in adolescents with short stature is limited. This report documents treatment of such a patient with a combination of growth hormone and letrozole, a third-generation aromatase inhibitor. Our case demonstrates a favorable outcome on a short-term basis.
Clin Cancer Res. 2005 Jan 15;11(2 Pt 2):900s-5s.
Ingle JN.
Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, 55905, USA. ingle.
Endocrine therapy trials of aromatase inhibitors for breast cancer in the adjuvant and prevention settings.
The three major studies to date with Arimidex, tamoxifen alone, or in combination (ATAC), and letrozole after 5 years of tamoxifen (MA.17) evaluated three different populations of women from the standpoints of duration of prior tamoxifen and thus time since the treatment of the primary breast cancer and tamoxifen has been evaluated in multiple trials involving >28,000 women and, despite clear evidence of benefit, the level of acceptance of this agent by women seems to be low.
The recent past has witnessed the appearance of substantial data relating to endocrine therapy of breast cancer. In the adjuvant therapy setting in early breast cancer, several large, well-conducted, randomized, double-blind clinical trials have provided evidence for the value of the third-generation aromatase inhibitors (AI) anastrozole, exemestane, and letrozole. The three major studies to date [i.e., Arimidex, tamoxifen alone, or in combination (ATAC), International Exemestane Study (IES), and letrozole after 5 years of tamoxifen (MA.17)] evaluated three different populations of women from the standpoints of duration of prior tamoxifen and thus time since the treatment of the primary breast cancer. A consistent pattern of improvement in disease-free survival was seen whether the control arm was tamoxifen (ATAC and IES) or placebo following tamoxifen (MA.17). From a toxicity standpoint, the major findings with the AIs were a decreased incidence of thromboembolic events and endometrial cancers but an increase in musculoskeletal complaints and potential for decreasing bone density. The last issue should be clarified with ongoing studies addressing the impact of the three AIs on bone density and fractures. In summary, based on ATAC, IES, and MA.17, respectively, the following conclusions can be drawn relating to postmenopausal women with hormone receptor positive early breast cancer: anastrozole is a reasonable choice for initial endocrine adjuvant therapy, exemestane should be considered for women who have received 2 to 3 years of tamoxifen, and letrozole should be considered for those who have completed about 5 years of tamoxifen.In the prevention setting, tamoxifen has been evaluated in multiple trials involving >28,000 women and, despite clear evidence of benefit, the level of acceptance of this agent by women seems to be low. Two recently developed prevention trials, IBIS 2 and MAP.3, involve the study of aromatase inhibitors against a placebo control rather than tamoxifen. Whereas the recent adjuvant trials have established the value of the third-generation aromatase inhibitors in early-stage breast cancer, the marked reductions in contralateral breast cancers seen in these trials suggest they will be of value in the prevention setting in women at increased risk of developing the disease.
J Steroid Biochem Mol Biol. 2005 Feb;94(1-3):123-30. Epub 2005 Feb 5.
Wood PM, Woo LW, Humphreys A, Chander SK, Purohit A, Reed MJ, Potter BV.
Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd, University of Bath, Claverton Down, Bath, England BA2 7AY, UK.
A letrozole-based dual aromatase-sulphatase inhibitor with in vivo activity.
It is now recognised that steroid sulphatase (STS) inhibitors represent a new form of endocrine therapy. After the following study the concept of a letrozole-based DASI has been validated and could be further developed and modified for therapeutic exploitation.
The role of aromatase inhibitors in the treatment of hormone-dependent breast cancer is well established. However, it is now recognised that steroid sulphatase (STS) inhibitors represent a new form of endocrine therapy. To explore the potential advantage of dual inhibition by a single agent, we recently developed a series of dual aromatase-sulphatase inhibitors (DASIs) based on the aromatase inhibitor YM511. We report here a new structural class of DASI obtained by obtained introducing the pharmacophore for STS inhibition, i.e. a phenol sulphamate ester into another established aromatase inhibitor letrozole. Hence, the bis-sulphamate 9 was synthesised which exhibited IC(50) values of 3044nM for aromatase and >10muM for STS in JEG-3 cells. However, at a single oral dose of 10mg/kg, 9 inhibited aromatase and rat liver STS by 60% and 88%, respectively, 24h after administration. A proposed metabolite of 9, carbinol 10, was synthesised. Despite also showing weak STS inhibition in JEG-3 cells, 10 inhibited rat liver STS activity to the same extent as 9 at a single oral dose of 10mg/kg. Thus, the concept of a letrozole-based DASI has been validated and could be further developed and modified for therapeutic exploitation.
Mol Cancer Res. 2005 Apr;3(4):203-18.
Itoh T, Karlsberg K, Kijima I, Yuan YC, Smith D, Ye J, Chen S.
Department of Surgical Research, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA.
Letrozole-, anastrozole-, and tamoxifen-responsive genes in MCF-7aro cells: a microarray approach.
The present study was to investigate the effects of antiestrogens and aromatase inhibitors on gene expression in breast cancer cells, and treated estrogen receptor-positive MCF-7 cells stably transfected with the aromatase gene with testosterone, 17 beta-estradiol, two aromatase inhibitors, and an antiestrogen. The study will ultimately be useful in customizing patient treatment strategies for hormone-dependent breast cancer.
Antiestrogens and aromatase inhibitors are important drugs in the treatment of estrogen-dependent breast cancer. To investigate the effects of these drugs on gene expression in breast cancer cells, we treated estrogen receptor-positive MCF-7 cells stably transfected with the aromatase gene (known as MCF-7aro cells) with testosterone, 17 beta-estradiol, two aromatase inhibitors (letrozole and anastrozole), and an antiestrogen (tamoxifen). We found that testosterone or 17 beta-estradiol induced the proliferation of MCF-7aro cells at a rate six times faster than the untreated cells. In addition, the testosterone-induced proliferation of MCF-7aro cells was effectively suppressed by letrozole, anastrozole, or tamoxifen. Microarray analyses on Affymetrix Human Genome U133A GeneChips (Affymetrix, Santa Clara, CA) were carried out using total RNA isolated from the control and treated cells. At the false discovery rate of 0.05 and a minimum fold-change criteria of 1.5, 104 genes were identified that were up-regulated and 109 genes were identified that were down-regulated by both androgen and estrogen. More than 50% of these hormone-regulated genes were counter-regulated by all three inhibitors and >90% were counter-regulated by at least one of the inhibitors. Comparing the effect of each inhibitor on gene expression, we observed that letrozole and anastrozole are more similar in terms of the genes they affect compared with treatment with tamoxifen. To validate the gene expression profiles identified from microarray analyses, the expression patterns of 13 representative genes were examined by Northern analysis. Finally, the genes identified as statistically significant were classified based on their expression patterns and biological function/pathways. The results of this study provide us with a better understanding of the actions of both aromatase inhibitors and antiestrogens at the molecular level. We believe that the results of this study serve as the first step in identifying unique expression patterns following drug treatment, and that this will ultimately be useful in customizing patient treatment strategies for hormone-dependent breast cancer.
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Drug category:Anti-cancer drugs
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