Femara scientific update |
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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.
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.
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.
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.
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. 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, 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.
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 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.
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.
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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