A Review of its Use in Postmenopausal Women with Advanced Breast Cancer



Letrozole is an oral reversible nonsteroidal aromatase inhibitor. Clinical tracer studies show that it inhibits peripheral aromatase by over 98% and suppresses blood and urinary estrogen levels by over 95% after 2 weeks of treatment in postmenopausal women. Letrozole also significantly inhibits intratumoral aromatase in vivo. The action of letrozole appears to be selective for aromatase;long term administration did not affect basal levels of 17α-hydroxyprogesterone or aldosterone, although slight decreases in cortisol levels were observed in 2 studies, these did not appear to be clinically significant.

In 2 phase IIb/III trials, letrozole 2.5 mg/day achieved objective response rates of 19.5 and 23.6% which were sustained for a median duration of 24 and 33 months, respectively. The median duration of response compared favourably with both comparator agents, aminoglutethimide and megestrol (15 and 18 months, respectively), as did objective response rates (12.4 and 16.4%). Letrozole 2.5 mg/day was associated with an increase in median survival time of 8 and 3 months compared with aminoglutethimide and megestrol, respectively. According to analyses of overall function, letrozole 2.5 mg/day was significantly superior to both comparators with respect to duration of response and aminoglutethimide with respect to survival.

Letrozole has a good short term tolerability profile. The adverse events reported most commonly in association with letrozole 2.5 mg/day in the 2 phase IIb/III trials were headache (1.1 and 7%), nausea (6 and 10.3%), fatigue (3.2 and 5%), hot flushes (4.9 and 5%) and peripheral oedema (6%). Events were usually mild to moderate in severity; adverse events necessitated discontinuation of treatment in 3% of letrozole 2.5 mg/day recipients.

Conclusions: Letrozole, in common with vorozole and anastrozole, offers greater selectivity and potency of aromatase inhibition than the prototype aromatase inhibitor, aminoglutethimide, and can be administered once daily. Available clinical data suggest that letrozole achieves a significantly longer duration of response than megestrol and aminoglutethimide and longer overall survival than aminoglutethimide. However, direct comparisons are required to distinguish between the newer aromatase inhibitors. For this reason, letrozole should be recommended as a second-line treatment in postmenopausal women with advanced breast cancer whose disease has progressed on or failed to respond to antiestrogen therapy.

Pharmacodynamic Properties

In vitro, letrozole has greater inhibitory activity than aminoglutethimide (170-fold), anastrozole (19-fold), formestane (6-fold) and vorozole (2-fold) against human aromatase. The concentration of letrozole required to inhibit human placental aromatase activity by 50% (IC50) ranges from 0.39 to 11 nmol/L.

Letrozole rapidly and effectively inhibits aromatase activity in postmenopausal volunteers and patients with breast cancer. On average, >98% inhibition of aromatisation was achieved with letrozole 0.5 or 2.5 mg/day versus baseline in postmenopausal women with breast cancer. Consistent with this, >95% suppression of blood estradiol, estrone and estrone sulfate levels and urinary estrogens was achieved after 2 weeks’ treatment with letrozole 0.1 to 5 mg/day in the same patient group. In addition, letrozole inhibits intratumoral aromatase according to in vitro and in vivo data.

Letrozole is highly specific for the aromatase enzyme. The in vitro concentrations of letrozole required to inhibit progesterone, corticosterone and aldosterone production were over 10 000-fold greater than those required to inhibit estrogen production. Clinical endocrinological studies generally lend support to the selectivity of action of letrozole; decreases (6 and 27%) in mean cortisol levels reported in 2 of 4 studies after 1 to 3 month’s treatment were either not statistically significant or remained within the normal range.

Letrozole consistently demonstrated antitumour activity in a model of postmenopausal hormone-dependent breast cancer in mice and in dimethyl-benz[a]anthracene (DMBA)-induced mammary carcinoma in rats. In the mouse model, letrozole 5 to 250 μg/day achieved a 68 to 92% reduction in tumour size; its effect was significantly better than that observed in control animals and in those treated with anastrozole (92 vs 65% reduction) or tamoxifen (76 vs 36%).

Preliminary clinical data indicate that long term treatment with letrozole 2.5 mg/day is accompanied by increased bone resorption. Unlike tamoxifen, letrozole does not have an agonist effect on the uterus in mice.

Pharmacokinetic Properties

Letrozole is absorbed rapidly after oral administration. Maximum drug plasma concentrations of ⁈115 nmol/L were achieved 1 hour after administration of letrozole 2.5mg in healthy postmenopausal women. It has excellent systemic bioavailability (99.9%) and a large volume of distribution (1.87 L/kg). The rate, but not the extent, of absorption of letrozole is decreased when it is administered with food. Steady-state plasma concentrations are attained after 2 to 6 weeks.

The major route of elimination of letrozole is via metabolism to a pharmacologically inactive carbinol metabolite. Letrozole is metabolised by both cytochrome P450 CYP2A6 and CYP3A4. The total body clearance of letrozole is slow (2.21 L/h) and it has a long elimination half-life (42 hours). Letrozole and its metabolites are excreted mainly via the kidneys.

Therapeutic Use

Letrozole has been investigated in 3 phase II and 2 phase IIb/III trials involving postmenopausal women with locally or locoregionally advanced or metastatic breast cancer. Letrozole was administered orally as a once daily regimen (0.5, 1 or 2.5 mg/day) until disease progression.

In phase II studies, objective (complete plus partial) response rates were 20 to 28% with letrozole 0.5 mg/day, 39% with 1 mg/day and 10 and 22% with the 2.5 mg/day dosage.

In phase IIb/III trials, 19.5 and 23.6% of patients achieved an objective response with letrozole 2.5 mg/day compared with 12.4% of patients receiving aminoglutethimide 500 mg/day and 16.4% of patients receiving megestrol 160 mg/day (p = 0.04). The 0.5 mg/day dosage of letrozole was associated with poorer response rates in both studies (16.7 and 12.8%). Letrozole 2.5 mg/day consistently achieved better response rates than megestrol and aminoglutethimide in patients who had relapsed or who were refractory to antiestrogen therapy and in those with visceral disease. Median times to progression or treatment failure were generally similar in all treatment groups (approximately 3 to 5.6 months); however, analysis of curves of time to progression indicated that letrozole 2.5 mg/day was significantly superior to aminoglutethimide (p = 0.008) but not megestrol.

Letrozole 2.5 mg/day was associated with an increase in median survival time of 8 months versus aminoglutethimide (p = 0.002 according to analysis of overall survival) and 3 months versus megestrol (p = 0.15 according to analysis of overall survival). Letrozole 2.5 mg/day was significantly superior to the 0.5 mg/day dosage with respect to overall survival in both studies.

Letrozole is also being investigated as an adjuvant agent and as preoperative (neoadjuvant) therapy in patients with early or advanced disease. A preliminary study showed that 92% of 24 postmenopausal women with advanced estrogen receptor-positive breast cancer achieved an objective response after a 3-month preoperative course of letrozole 2.5 or 10 mg/day. Tumour volume reductions were such that all 15 patients, who would have required mastectomy before treatment, were considered suitable for breast-conserving surgery at treatment end.


The most common adverse events judged to be related to letrozole 2.5 mg/day in phase IIb/III trials were headache (1.1 and 7%), nausea (10.3 and 6%), fatigue (3.2 and 5%), hot flushes (4.9 and 5%), peripheral oedema (6%), rash (2.7%), somnolence (3.2%), vomiting (3.8%) and hypercholesterolaemia (3.8%). The majority of events seemed to be mild to moderate in severity. Adverse events necessitated discontinuation of treatment in 3% of letrozole 2.5 mg/day recipients.

Letrozole 2.5 mg/day was associated with a lower overall incidence of cardiovascular events (10 vs 20%, p = 0.02), serious cardiovascular events (usually thromboembolic events; 0 vs 9%), weight gain of ≥10% from baseline (6 vs 11.5%) and increased γ-glutamyl transferase levels (4 vs 12%) compared with megestrol. Compared with aminoglutethimide, letrozole 2.5 mg/day was associated with a lower incidence of rash (2.7 vs 11.2%), somnolence (3.2 vs 7.3%) and abdominal pain (0.5 vs 4.5%; no statistical analysis data provided).

No clinically significant effects on blood pressure, pulse, ECG or haematological or biochemical parameters were reported in association with letrozole. Disease flare has not been reported with letrozole.

Dosage and Administration

Letrozole is indicated for the treatment of postmenopausal women with advanced breast cancer after failure of antiestrogen therapy. The recommended oral dosage is 2.5 mg/day continued until tumour progression. No dosage adjustment is required in the elderly, those with renal impairment (creatinine clearance ≥10 ml/min or 0.6 L/h) or those with mild to moderate hepatic impairment. In patients with severe hepatic impairment, caution is recommended with the use of letrozole in the US but its use is contraindicated in this patient group in the UK.

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Correspondence to Harriet M. Lamb.

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Lamb, H.M., Adkins, J.C. Letrozole. Drugs 56, 1125–1140 (1998). https://doi.org/10.2165/00003495-199856060-00020

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  • Tamoxifen
  • Adis International Limited
  • Aromatase Inhibitor
  • Advanced Breast Cancer
  • Letrozole