Mol Cancer Res.
2005 Apr;3(4):203-18.
Letrozole-, anastrozole-, and tamoxifen-responsive genes in MCF-7aro
cells: a microarray approach.
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.
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.
J Steroid Biochem Mol Biol. 2005 Feb;94(1-3):123-30. Epub 2005 Feb 5.
A letrozole-based dual aromatase-sulphatase inhibitor with in
vivo activity.
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.
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.
Clin Cancer Res. 2005 Jan 15;11(2 Pt 2):900s-5s.
Endocrine therapy trials of aromatase inhibitors for breast cancer
in the adjuvant and prevention settings.
Ingle JN.
Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, 55905,
USA. ingle.james@mayo.edu
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.
Pediatrics. 2005 Feb;115(2):e245-8. Epub 2005 Jan 14.
Letrozole significantly improves growth potential in a pubertal
boy with growth hormone deficiency.
Zhou P, Shah B, Prasad K, David R.
Division of Pediatric Endocrinology, New York University School of
Medicine, New York, New York 10016, USA.
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.
Semin Oncol. 2004 Dec;31(6 Suppl 12):9-14.
Aromatase inhibitors in early breast cancer therapy.
Smith IE.
Royal Marsden Hospital, Institute of Cancer Research, London, United
Kingdom.
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.
Semin Oncol. 2004 Dec;31(6 Suppl 12):23-30.
Optimizing bisphosphonate therapy in patients with breast cancer
on endocrine therapy.
Harvey HA.
Penn State Milton S. Hershey Medical Center, Hershey, PA 17033, USA.
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):31-4.
Aromatase inhibitors in the management of early breast cancer:
optimizing the clinical benefit.
Henderson IC.
University of California, San Francisco Comprehensive Cancer Center,
San Francisco, CA 94123, USA.
Several adjuvant trials evaluating aromatase inhibitors in postmenopausal
women with early breast cancer have shown significant improvement upon,
or extension of the efficacy benefits of, standard therapy with tamoxifen,
and treatments were generally well tolerated. Disease-free survival was
significantly improved by: anastrozole versus tamoxifen for 5 years of
adjuvant therapy, in the Arimidex, Tamoxifen Alone or in Combination trial;
switching to exemestane after 2 to 3 years of tamoxifen, compared with
remaining on tamoxifen for 5 years, in the Intergroup Exemestane Study;
and switching to letrozole (v placebo) for 5 years after 5 years of tamoxifen,
in the extended adjuvant trial, MA.17. Further analyses of these trials,
and data from ongoing trials, will address how to optimally use aromatase
inhibitors in the adjuvant breast cancer setting: whether these agents
should be used in place of, or sequenced with, tamoxifen; what is the
best order of sequencing, before or after tamoxifen, and when is the best
time to switch; what the long-term safety issues are associated with aromatase
inhibitor treatment; and how toxicities can be effectively managed.
Clin Oncol (R Coll Radiol). 2004 Oct;16(7):485-91.
Giving patients a choice improves quality of life: a multi-centre,
investigator-blind, randomised, crossover study comparing letrozole with
anastrozole.
Thomas R, Godward S, Makris A, Bloomfield D, Moody AM, Williams
M.
Bedford Hospital NHS Trust, UK. rt@cancernet.co.uk
AIMS: Although the third-generation aromatase inhibitors are generally
well tolerated, side-effects still occur in up to 40% of women. As more
women are taking these drugs for longer, the issue as to which version
is better tolerated is now a significant patient concern. This study aimed
to assess whether tolerance for either letrozole or anastrozole can differ
for each individual in terms of early quality of life (QoL), whether patients
welcome being given a preference and whether this correlated with formal
toxicity scoring. MATERIALS AND METHODS: A single-blind, crossover trial,
with 72 women with breast cancer who had experienced tamoxifen failure.
Randomised to either letrozole 2.5 mg or anastrozole 1 mg, for 4 weeks,
1 week off, then crossover for 4 weeks. RESULTS: Patients were confidently
able to choose which drug suited them best (letrozole 68%, anastrozole
32%; P < 0.01). Fewer patients, when taking letrozole, experienced
adverse events than when taking anastrozole (43% vs 65%; P = 0.0028).
QoL was better when patients were taking letrozole than when they took
anastrozole (P = 0.02). CONCLUSIONS: As toxicity and QoL strongly correlated
with patient preference for either drug, albeit with a tendency towards
letrozole, this suggests that patient preference is now a legitimate and
useful end point for future crossover studies. In routine practice, women
would warmly welcome extra involvement in the decision-making process
via a crossover manoeuvre if side-effects develop, whichever aromatase
inhibitor is prescribed initially.
Oncologist. 2004;9(5):497-506.
Efficacy of first-line letrozole versus tamoxifen as a function
of age in postmenopausal women with advanced breast cancer.
Mouridsen H, Chaudri-Ross HA.
Novartis Pharma AG, WKL-490.1.04, CH-4057 Basel, Switzerland.
PURPOSE: To compare the efficacy, in regard to time to progression (TTP)
and objective response rate (ORR), of letrozole (Femara; Novartis Pharma
AG; Basel Switzerland), an oral aromatase inhibitor, with that of tamoxifen
(Tamofen; Leiras OY; Turku, Finland) as first-line therapy in younger
(<70 years) and older (>/=70 years) postmenopausal women with advanced
breast cancer. MATERIALS AND METHODS: Nine hundred seven patients with
advanced breast cancer were randomly assigned to receive 2.5 mg letrozole
(n = 453) or 20 mg tamoxifen (n = 454) once daily in a double-blind, multicenter,
international trial. Among the prospectively planned analyses were analyses
of TTP and ORR by age (<70 and >/=70 years). The results of these
prospectively planned analyses are reported here. RESULTS: Letrozole was
as effective in older postmenopausal women (>/=70 years of age) as
it was in younger postmenopausal women (<70 years of age). The overall
ORR in the older subgroup was significantly higher in patients treated
with letrozole (38%) than in patients treated with tamoxifen (18%). In
the younger subgroup of postmenopausal patients, the ORRs were not significantly
different (letrozole, 26%; tamoxifen, 22%). TTP was significantly longer
for letrozole than for tamoxifen in both age groups (younger: letrozole
median TTP, 8.8 months; tamoxifen, 6.0 months; older: letrozole median
TTP, 12.2 months; tamoxifen, 5.8 months). Although age was independently
prognostic of TTP, there was no significant effect of age on ORR in the
presence of other factors. CONCLUSION: The data show that letrozole, 2.5
mg once daily, is as effective in older, postmenopausal women as it is
in younger postmenopausal women with advanced breast cancer. In addition,
letrozole was more effective than tamoxifen in both younger and older
patients.
Oncologist. 2004;9(5):489-96.
Superiority of letrozole to tamoxifen in the first-line treatment
of advanced breast cancer: evidence from metastatic subgroups and a test
of functional ability.
Mouridsen H, Sun Y, Gershanovich M, Perez-Carrion R, Becquart
D, Chaudri-Ross HA, Lang R.
Novartis Pharma AG, WKL-490.1.04, CH-4057 Basel, Switzerland.
PURPOSE: The letrozole study 025 is a large (n = 907), international,
double-blind, randomized, phase III trial in postmenopausal women with
advanced breast cancer. This subanalysis compares the efficacies of letrozole
and tamoxifen as first-line therapy in postmenopausual women with advanced
breast cancer according to site of metastatic lesions and Karnofsky Performance
Status (KPS). MATERIALS AND METHODS: Nine hundred seven patients with
advanced breast cancer were randomly assigned to once-daily oral letrozole
(2.5 mg; Femara; Novartis Pharma AG; Basel, Switzerland) or tamoxifen
(20 mg; Tamofen; Leiras OY; Turku, Finland). Time to progression (TTP)
was estimated using the Kaplan-Meier product-limit method. Treatments
were compared by Cox proportional hazards regression models. RESULTS:
Letrozole treatment significantly prolonged TTP in all subsets of patients:
those with nonvisceral metastases, those with visceral metastases without
liver involvement, and those with liver metastases. The reduction in risk
of progression ranged from 25%, for patients with nonvisceral metastases,
to 36%, for patients with liver metastases. The distributions of baseline
KPS scores for both treatment groups were similar (57% had KPS scores
>/=90). Time to worsening of 20 points or more in KPS score was significantly
longer with letrozole than with tamoxifen, but modest numbers of patients
experienced such deterioration (letrozole, 20%, tamoxifen, 22%, in patients
without visceral metastases; 23%-24% in patients with liver metastases;
and letrozole, 14%, tamoxifen, 30%, in patients with visceral metastases
without liver involvement). CONCLUSION: These data demonstrate the consistent
superiority of letrozole over tamoxifen and support the use of letrozole
as a new standard of endocrine therapy in postmenopausal women with advanced
breast cancer.
Clin Cancer Res. 2004 Sep 1;10(17):5717-23.
Effects of the steroidal aromatase inhibitor exemestane and the
nonsteroidal aromatase inhibitor letrozole on bone and lipid metabolism
in ovariectomized rats.
Goss PE, Qi S, Cheung AM, Hu H, Mendes M, Pritzker KP.
Breast Cancer Prevention Program, Princess Margaret Hospital, University
Health Network, University of Toronto, Ontario, Canada. pegoss@interlog.com
PURPOSE: Exemestane (EXE) and letrozole (LET) are third-generation aromatase
inhibitors currently prescribed for postmenopausal hormone-dependent breast
cancer. The impact on end organs of estrogen depletion in menopausal women
is of significant clinical importance. We studied the effects of EXE,
its principal metabolite, 17-hydroexemestane (17-H-EXE), and LET on bone
and lipid metabolism in ovariectomized (OVX) rats. EXPERIMENTAL DESIGN:
OVX rats were treated by weekly intramuscular injection for 16 weeks with
20, 50, and 100 mg/kg EXE, 20 mg/kg 17-H-EXE, and daily oral gavage of
1 mg/kg LET. At the end of the treatment period, bone mineral density
(BMD), the bone resorption marker serum pyridinoline, the bone formation
marker serum osteocalcin, bone mechanical properties, histomorphometry,
and serum lipid concentrations were determined. RESULTS: Lumbar vertebral
and femoral BMD, bending strength of the femur, compressive strength of
the fifth lumbar vertebra, and trabecular bone volume were significantly
higher in OVX animals given EXE and 17-H-EXE than in OVX controls. EXE
and 17-H-EXE significantly reduced an ovariectomy-induced increase in
serum pyridinoline and serum osteocalcin. EXE and 17-H-EXE given to OVX
rats caused significant reductions of serum cholesterol and low-density
lipoprotein cholesterol. In contrast, OVX rats treated with LET had BMD,
bone biomarkers, mechanical failure properties, and lipid levels similar
to those of OVX controls. CONCLUSIONS: EXE and 17-H-EXE significantly
prevent bone loss, enhance bone mechanical strength, and lower serum cholesterol
and low-density lipoprotein levels in OVX rats. These protective effects
on end-organ function are not seen with the nonsteroidal inhibitor LET.
Clin Cancer Res. 2004 Aug 15;10(16):5375-80.
Effects of the antiestrogen tamoxifen and the aromatase inhibitor
letrozole on serum hormones and bone characteristics in a preclinical
tumor model for breast cancer.
Nunez NP, Jelovac D, Macedo L, Berrigan D, Perkins SN, Hursting
SD, Barrett JC, Brodie A.
Division of Cancer Prevention, Cancer Prevention Fellowship Program, Division
of Cancer Control and Population Sciences, National Cancer Institute,
Bethesda, Maryland 20892-8325, USA. nunezn@mail.nih.gov
PURPOSE: The purpose of this study was to evaluate and compare the effects
of the antiestrogen tamoxifen and the aromatase inhibitor letrozole on
tumor growth, serum hormones, uterine weight, body composition, and bone
characteristics in mice. EXPERIMENTAL DESIGN: Human estrogen-dependent
breast cancer cells stably transfected with the aromatase gene (MCF-7CA
cells) were inoculated in Matrigel subcutaneously into ovariectomized
nude mice. This model represents postmenopausal breast cancer in many
respects, including the fact that estrogen is no longer produced by the
ovaries and is not under feedback regulation by gonadotropins. Mice that
received subcutaneously implanted MCF-7CA cancer cells were then treated
with tamoxifen or letrozole for 7 weeks. RESULTS: As reported previously,
tumor growth was markedly inhibited by both tamoxifen (100 microg/day)
and letrozole (10 microg/day). Tamoxifen treatment led to increased bone
mineral density (BMD) and hyperplastic uteri. Mice treated with letrozole
had significantly smaller uteri than the controls and tamoxifen-treated
mice. Letrozole did not affect BMD. There was no significant difference
in systemic leptin and insulin-like growth factor I levels as a result
of tamoxifen or letrozole treatment. CONCLUSIONS: Tamoxifen treatment
inhibited breast cancer cell growth and increased BMD but caused uterine
hypertrophy in this preclinical model of postmenopausal breast cancer.
Letrozole inhibited tumor growth without inducing uterine hypertrophy.
In addition, letrozole had no effect on BMD. These findings provide experimental
evidence that letrozole is an effective and safe (in terms of risk of
endometrial cancer risk and osteoporosis) alternative or complement to
tamoxifen treatment for breast cancer.
Int J Gynecol Cancer. 2004 Jul-Aug;14(4):650-8.
The activity of letrozole in patients with advanced or recurrent
endometrial cancer and correlation with biological markers--a study of
the National Cancer Institute of Canada Clinical Trials Group.
Ma BB, Oza A, Eisenhauer E, Stanimir G, Carey M, Chapman W, Latta
E, Sidhu K, Powers J, Walsh W, Fyles A.
Department of Medical Oncology, Princess Margaret Hospital, University
Health Network, Toronto, Ontario, Canada.
A multicenter phase II trial was conducted to define the activity of letrozole
in postmenopausal women with recurrent or advanced endometrial carcinoma,
who had no more than one prior line of progestins and never had chemotherapy
(except adjuvant). Archival paraffin-embedded tumor samples were retrieved
to determine the expression level of estrogen (ER) and progesterone receptor
(PgR), p53, HER-2, bcl-2 and PTEN protein, and phosphorylation status
of protein kinase B (PKB/Akt). Thirty-two eligible patients were treated
with letrozole at 2.5 mg daily continuously, of whom 10 (31%) had prior
progestins. Of the 28 patients evaluated for response, one complete and
two partial responses were noted; overall response was 9.4% (95% confidence
interval 2-25%). Eleven patients had stable disease for a median duration
of 6.7 months (range 3.7-19.3 months). Amongst 22 patients who had tumor
blocks available, the proportion showing positive expression of the following
markers includes: PgR (86%), ER (86%), PTEN (82%), phosphorylated PKB/Akt
(59%), bcl-2 (45%), p53 (32%), and HER-2 (0%). None of these markers correlated
with response to letrozole or disease progression. In conclusion, letrozole
is well tolerated but has little overall activity in this cohort of women
with endometrial cancer.
Drugs. 2004;64(11):1213-30.
Letrozole: a review of its use in postmenopausal women with breast
cancer.
Simpson D, Curran MP, Perry CM.
Adis International Limited, Auckland, New Zealand. demail@adis.co.nz
Letrozole (Femara), a nonsteroidal, third-generation aromatase inhibitor
administered orally once daily, has shown efficacy in the treatment of
postmenopausal women with early-stage or advanced, hormone-sensitive breast
cancer. In early-stage disease, extending adjuvant endocrine therapy with
letrozole (beyond the standard 5-year period of tamoxifen) improved disease-free
survival; compared with placebo there was a 43% relative reduction in
disease recurrences or new contralateral breast tumours at a median follow-up
of 2.4 years. The results of 4 months' neoadjuvant treatment with letrozole
or tamoxifen in postmenopausal women with untreated primary disease favour
letrozole. In advanced breast cancer, letrozole was superior to tamoxifen
as first-line treatment; time to disease progression was significantly
longer (9.4 vs 6.0 months, p < 0.0001) and objective response rate
was significantly greater with letrozole, but median overall survival
was similar between groups. For second-line therapy of advanced breast
cancer that had progressed on antiestrogen therapy, letrozole showed efficacy
equivalent to that of anastrozole and similar to or better than that of
megestrol acetate. Letrozole is generally well tolerated and has a similar
tolerability profile to tamoxifen; the most common treatment-related adverse
events were hot flushes, nausea and hair thinning. In patients with tumours
that had progressed on antiestrogen therapy, letrozole was tolerated as
least as well as, or better than, anastrozole or megestrol acetate. In
the trial of extended adjuvant therapy, adverse events reported more frequently
with letrozole than placebo were hot flushes, arthralgia, myalgia and
arthritis. The long-term effects of letrozole on bone mineral density
or lipid profile have not been determined and these parameters may require
monitoring. In several pharmacoeconomic modelling studies from various
public healthcare system perspectives, letrozole was considered a cost
effective choice for first-line (vs tamoxifen) or second-line (vs megestrol
acetate) treatment for advanced breast cancer in postmenopausal women.
In conclusion, letrozole 2.5 mg/day is effective in the treatment of postmenopausal
women with early-stage or advanced breast cancer. The efficacy, cost effectiveness
and favourable tolerability profile of letrozole are reflected in current
treatment guidelines recommending the drug as first-line therapy for advanced
breast cancer. Letrozole is superior to tamoxifen for first-line treatment
and is at least as effective as standard second-line treatments in disease
that has progressed on antiestrogen therapy. For early-stage disease,
letrozole is superior to tamoxifen in the neoadjuvant setting, and prolongs
disease-free survival when administered after the standard 5-year period
of adjuvant tamoxifen therapy.
Oncology. 2004;66(2):112-7.
Hormonal therapy with letrozole for relapsed epithelial ovarian
cancer. Long-term results of a phase II study.
Papadimitriou CA, Markaki S, Siapkaras J, Vlachos G, Efstathiou
E, Grimani I, Hamilos G, Zorzou M, Dimopoulos MA.
Department of Clinical Therapeutics, Alexandra Hospital, Athens University
School of Medicine, Athens, Greece. mdimop@med.uoa.gr
OBJECTIVE: We conducted a phase II trial to evaluate the activity of oral
letrozole in women with relapsed or recurrent epithelial ovarian cancer.
METHODS: Twenty-seven patients were treated with letrozole at a dose of
2.5 mg once a day. Patients with measurable or evaluable disease (n =
21) and those with only increasing CA 125 serum levels (n = 6) were eligible.
Paraffin-fixed histological sections from tumor specimens resected at
the initial laparotomy were assessed for the presence of estrogen, and
progesterone receptors. RESULTS: Among the 21 patients with measurable
or evaluable disease who were evaluated for response by WHO criteria,
we observed one complete and two partial responses for an objective response
rate of 15%. Using criteria for CA 125 response we obtained a marker response
in 4 of 27 patients (15%), and the marker remained stable in 5 additional
patients (18%). Letrozole treatment was generally well tolerated. No correlation
was observed between tumor marker response or stabilization and either
estrogen or progesterone receptor expression. CONCLUSION: The results
of our study suggest that the aromatase inhibitor letrozole is an agent
with some activity and limited toxicity for relapsed ovarian cancer. As
we could not find any association between response and hormonal receptor
expression, the underlying mechanisms of letrozole action have to be elucidated.
Copyright 2004 S. Karger AG, Basel
J Natl Cancer Inst. 2004 Mar 17;96(6):456-65.
Therapeutic strategies using the aromatase inhibitor letrozole
and tamoxifen in a breast cancer model.
Long BJ, Jelovac D, Handratta V, Thiantanawat A, MacPherson N,
Ragaz J, Goloubeva OG, Brodie AM.
Department of Pharmacology and Experimental Therapeutics, University of
Maryland School of Medicine, Health Sciences Facility, Baltimore, MD 21201,
USA.
BACKGROUND: The antiestrogen tamoxifen has potent activity against estrogen
receptor-positive breast cancer, but two nonsteroidal aromatase inhibitors,
letrozole and anastrozole, show considerable advantages over tamoxifen
with respect to patient survival and tolerability. To determine the optimal
way to use letrozole and tamoxifen, we studied their effects on a breast
tumor xenograft model, MCF-7Ca, that is responsive to both antiestrogens
and aromatase inhibitors. METHODS: Female ovariectomized BALB/c athymic
nude mice carrying xenograft tumors were treated daily subcutaneously
with one of the following first-line therapies for varying durations:
no drug (control), tamoxifen (100 microg/day) alone, letrozole (10 microg/day)
alone, both drugs at the same time, or alternating 4-week courses of each
drug (beginning with a course of tamoxifen or beginning with a course
of letrozole). Tumor volumes and weights were estimated using linear mixed-effects
models. The time to tumor doubling was calculated, and tumor weights in
the treatment groups were compared, with adjustments for multiple comparisons
being made with either Tukey's or Dunnett's procedure. Second-line therapies
(with tamoxifen, letrozole, or fulvestrant) were initiated when tumors
doubled in size under first-line therapies. All statistical tests were
two-sided. RESULTS: The times for doubling of tumor volume were as follows:
control, 3-4 weeks; tamoxifen alone, 16 weeks; tamoxifen alternating with
letrozole, 17-18 weeks; tamoxifen plus letrozole, 18 weeks; letrozole
alternating with tamoxifen, 22 weeks; letrozole alone, 34 weeks. First-line
treatment with letrozole was superior to treatment with tamoxifen alone
or with the two drugs combined (at week 16, both P<.001). Alternating
tamoxifen and letrozole and alternating letrozole and tamoxifen were also
not as effective as letrozole alone (at week 16, P =.002 and P<.001,
respectively). Tumors progressing on tamoxifen remained sensitive to second-line
therapy with letrozole compared with those remaining on tamoxifen at the
end of treatment (week 28, P<.001), whereas tumors progressing on letrozole
were unaffected by second-line treatment with the antiestrogens tamoxifen
or fulvestrant. CONCLUSIONS: First-line letrozole therapy extends time
for tumor progression in this model relative to the other treatment regimens
tested. However, further studies are needed to determine the most effective
second-line therapy for tumors that progress on letrozole.
