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Letrozole

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

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Summary

Abstract

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.

Tolerability

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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References

  1. Miller WR, Mullen P, Sourdaine P, et al. Regulation of aroma-tase activity within the breast. J Steroid Biochem Mol Biol 1997 Apr; 61: 193–202

    PubMed  Google Scholar 

  2. Santen RJ. Estrogen synthesis inhibitors: from “off the rack” to haute couture [editorial; comment]. J Clin Endocrinol Metab 1993 Aug; 77: 316–8

    Article  PubMed  CAS  Google Scholar 

  3. Masamura S, Adlercreutz H, Harvey H, et al. Aromatase inhibitor development for treatment of breast cancer. Breast Cancer Res Treat 1995 Jan; 33: 19–26

    Article  PubMed  CAS  Google Scholar 

  4. Lønning PE, Dowsett M, Powles TJ. Postmenopausal estrogen synthesis and metabolism: alterations caused by aromatase inhibitors used for the treatment of breast cancer. J Steroid Biochem Mol Biol 1990; 35(3/4): 355–66

    Google Scholar 

  5. Dowsett M, Jones A, Johnston SRD, et al. In vivo measurement of aromatase inhibition by letrozole (CGS 20267) in postmenopausal patients with breast cancer. Clin Cancer Res 1995 Dec; 1: 1511–5

    PubMed  CAS  Google Scholar 

  6. Dowsett M, Mehta A, King N, et al. An endocrine and pharmacokinetic study of four oral doses of formestane in postmenopausal breast cancer patients. Eur J Cancer 1992; 28(2/3): 415–20

    Article  PubMed  CAS  Google Scholar 

  7. Lønning PE, Helle S-I, Johannessen DC, et al. Relation between sex hormones, sex hormone binding globulin, insulin-like growth factor-I and insulin-like growth factor binding protein-1 in post-menopausal breast cancer patients. Clin Endocrinol 1995; 42: 23–30

    Article  Google Scholar 

  8. Bhatnagar AS, Batzl C, Häusler A, et al. Pharmacology of non-steroidal aromatase inhibitors. In: Pasqualini JR, Katzenellenbogen BS, editors. Hormone-dependent cancer. New York: Marcel Dekker, Inc., 1996: 155–68

    Google Scholar 

  9. Kao Y-C, Cam LL, Laughton CA, et al. Binding characteristics of seven inhibitors of human aromatase: a site-directed mutagenesis study. Cancer Res 1996 Aug 1; 56: 3451–60

    PubMed  CAS  Google Scholar 

  10. Kudoh M, Susaki Y, Ideyama Y, et al. The potent and selective inhibition of estrogen production by non-steroidal aromatase inhibitor, YM511. J Steroid Biochem Mol Biol 1995 Sep; 54: 265–71

    Article  PubMed  CAS  Google Scholar 

  11. Lønning PE. Pharmacology of new aromatase inhibitors. Breast 1996; 5(3): 202–8

    Article  Google Scholar 

  12. Iveson TJ, Smith IE, Ahern J, et al. Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in healthy postmenopausal women. J Clin Endocrinol Metab 1993 Aug; 77: 324–31

    Article  PubMed  CAS  Google Scholar 

  13. Deniers LM. Effects of fadrozole (CGS 16949A) and letrozole (CGS 20267) on the inhibition of aromatase activity in breast cancer patients. Breast Cancer Res Treat 1994; 30(1): 95–102

    Article  Google Scholar 

  14. Lipton A, Deniers LM, Harvey HA, et al. Letrozole (CGS 20267): a phase I study of a new potent oral aromatase inhibitor of breast cancer. Cancer 1995 Apr 15; 75: 2132–8

    Article  PubMed  CAS  Google Scholar 

  15. Klein KO, Deniers LM, Santner SJ, et al. Use of ultrasensitive recombinant cell bioassay to measure estrogen levels in women with breast cancer receiving the aromatase inhibitor, letrozole. J Clin Endocrinol Metab 1995 Sep; 80: 2658–60

    Article  PubMed  CAS  Google Scholar 

  16. Lønning PE. Aromatase inhibition for breast cancer treatment. Acta Oncol 1996; 35(5) Suppl.: 38–43

    Article  PubMed  Google Scholar 

  17. Bajetta E, Zilembo N, Guillevin L, et al. Endocrine trial comparing 0.5 and 2.5 mg of letrozole in postmenopausal patients (pts) with advanced breast cancer (ABC) [abstract no. 879]. Proc Am Soc Clin Oncol 1998; 17: 229a

    Google Scholar 

  18. Iveson TJ, Smith IE, Ahern J, et al. Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in postmenopausal patients with advanced breast cancer. Cancer Res 1993 Jan 15; 53: 266–70

    PubMed  CAS  Google Scholar 

  19. Bisagni G, Cocconi G, Scaglione F, et al. Letrozole, a new oral non-steroidal aromatase inhibitor in treating postmenopausal patients with advanced breast cancer. Apilot study. Ann Oncol 1996 Jan; 7: 99–102

    Article  CAS  Google Scholar 

  20. Castiglione Gertsch-M. New aromatase inhibitors: more selectivity, less toxicity, unfortunately, the same activity. Eur J Can 1996; 32A(3): 393–5

    Article  Google Scholar 

  21. Masamura S, Santner SJ, Gimotty P, et al. Mechanism for maintenance of high breast tumor estradiol concentrations in the absence of ovarian function: role of very high affinity tissue uptake. Breast Cancer Res Treat 1997; 42: 215–26

    Article  PubMed  CAS  Google Scholar 

  22. Lipton A, Santner SJ, Santen RJ, et al. Aromatase activity in primary and metastatic human breast cancer. Cancer 1987; 59: 779–82

    Article  PubMed  CAS  Google Scholar 

  23. Miller WR, O’Neill J. The importance of local synthesis of estrogen within the breast. Steroids 1987; 50(4-6): 537–48

    Article  PubMed  CAS  Google Scholar 

  24. Dowsett M, Lee K, Macaulay VM, et al. The control and biological importance of intratumoural aromatase in breast cancer. J Steroid Biochem Mol Biol 1996 Jan; 56 (1-6 Spec Nos): 145–50

    Article  PubMed  CAS  Google Scholar 

  25. Miller WR, Telford J, Love C, et al. Qualitative effects of letrozole as primary medical therapy on in situ oestrogen synthesis and endogenous oestrogen levels within the breast [abstract]. Breast 1997 Aug; 6: 228

    Article  Google Scholar 

  26. Lee K, Macaulay VM, Nicholls JE, et al. An in vivo model of intratumoural aromatase using aromatase-transfected MCF7 human breast cancer cells. Int J Cancer 1995 Jul 28; 62: 297–302

    Article  PubMed  CAS  Google Scholar 

  27. Yue W, Wang J, Savinov A, et al. Effect of aromatase inhibitors on growth of mammary tumors in a nude mouse model. Cancer Res 1995 Jul 15; 55: 3073–7

    PubMed  CAS  Google Scholar 

  28. Brodie A, Lu Q, Liu Y, et al. Preclinical studies using the intratumoral aromatase model for postmenopausal breast cancer. Oncology 1998 Mar; 12 (3) Suppl. 5: 36–40

    Google Scholar 

  29. Lu Q, Liu Y, Long B, et al. Combined treatment with aromatase inhibitors and tamoxifen in a nude mice model [abstract no. 2616]. Proceedings of the 89th Annual Meeting of the American Association for Cancer Research 1998: Mar 28–Apr 1; New Orleans (LA); 39: 384-5

  30. Schieweck K, Bhatnagar AS, Batzl C, et al. Anti-tumor and endocrine effects of non-steroidal aromatase inhibitors on estrogen-dependent rat mammary tumors. J Steroid Biochem Mol Biol 1993 Mar; 44: 633–6

    Article  PubMed  CAS  Google Scholar 

  31. Heshmati HM, Khosla S, Robins SP, et al. Endogenous residual estrogen levels determine bone resorption even in late postmenopausal women [abstract no. 76]. J Bone Miner Res 1997; 12 Suppl. 1: 121

    Google Scholar 

  32. Sioufi A, Gauducheau N, Pineau V, et al. Absolute bioavailability of letrozole in healthy postmenopausal women. Biopharm Drug Dispos 1997 Dec; 18: 779–89

    Article  PubMed  CAS  Google Scholar 

  33. Sioufi A, Sandrenan N, Godbillon J, et al. Comparative bioavailability of letrozole under fed and fasting conditions in 12 healthy subjects after a 2.5 mg single oral administration. Biopharm Drug Dispos 1997 Aug; 18: 489–97

    Article  PubMed  CAS  Google Scholar 

  34. Novartis Pharmaceuticals Corporation. Femara™ (letrozole tablets) prescribing information. East Hanover, NJ, USA, 1997

  35. Wirz B, Valles B, Parkinson A, et al. CYP3A4 and CYP2A6 are involved in the biotransformation of letrozole (Rm Femara) [abstract]. 7th ISSX 1996 Oct 20; 10: 359

    Google Scholar 

  36. Morgan JM, Palmisano M, Spencer S, et al. Pharmacokinetic effect of cimetidine on a single 2.5 mg dose of letrozole in healthy subjects [abstract]. J Clin Pharmacol 1996 Sep; 36: 852

    Google Scholar 

  37. Dowsett M, Pfister CU, Johnston SRD, et al. Pharmacokinetic interaction between letrozole and tamoxifen in postmenopausal patients with advanced breast cancer [abstract]. Breast 1997 Aug; 6: 245

    Google Scholar 

  38. Zilembo N, Di Leo A, Bajetta E, et al. Two different letrozole doses in the treatment of postmenopausal advanced breast cancer [abstract no. 105]. Proc Am Soc Clin Oncol 1996 Mar 15: 110

    Google Scholar 

  39. Ingle JN, Johnson PA, Suman VJ, et al. A randomized phase II trial of two dosage levels of letrozole as third-line hormonal therapy for women with metastatic breast carcinoma. Cancer 1997 Jul 15; 80: 218–24

    Article  PubMed  CAS  Google Scholar 

  40. Tominaga T, Ohashi Y, Abe R, et al. Phase II trial of letrozole (a novel oral nonsteroidal aromatase inhibitor) in postmenopausal patients with advanced or recurrent breast cancer [abstract]. Eur J Cancer 1998 (31A) Suppl. 5: S81

    Google Scholar 

  41. Dombernowsky P, Smith I, Falkson G, et al. Letrozole, a new oral aromatase inhibitor for advanced breast cancer: doubleblind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 1998 Feb; 16: 453–61

    PubMed  CAS  Google Scholar 

  42. Gershanovich M, Chaudri HA, Campos D, et al. Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Ann Oncol 1998 (9): 639-45

  43. Smith IE. Pivotal trials of letrozole: a new aromatase inhibitor. Oncology 1998 Mar; 12 (5) Suppl. 5: 41–4

    Google Scholar 

  44. Gershanovich M, Chaudri HA, Hornberger U, et al. Comparison of letrozole 2.5mg (FemaraR) with megestrol acetate (MA) and with aminoglutethimide (AG) in patients with visceral disease [abstract no. 212]. Breast Cancer Res Treat 1998; 46: 53

    Google Scholar 

  45. Weinfurt KP, Wait SL, Boyko W, et al. Psychosocial quality of life in a phase III trial of letrozole [abstract no. 417]. Proc Am Soc Clin Oncol 1998; 17: 108a

    Google Scholar 

  46. Dixon JM, Love CDB, Tucker S, et al. Letrozole as primary medical therapy for locally advanced breast cancer [abstract]. Breast 1997 Aug; 6: 245–6

    Article  Google Scholar 

  47. Dixon JM, Love CDB, Tucker S, et al. Letrozole as primary medical therapy for locally advanced and large operable breast cancer [abstract no. 400]. Proc Am Soc Clin Oncol 1998; 17: 104a

    Google Scholar 

  48. Goldhirsch A, Gelber RD. Endocrine therapies of breast cancer. Semin Oncol 1996; 23(4): 494–505

    PubMed  CAS  Google Scholar 

  49. British National Formulary. No. 35: The Pharmaceutical Press, 1998, Mar

  50. Hayes TG, Peterson LE, Weinberg AD. Current guidelines for the diagnosis and treatment of breast cancer. Dis Manage Health Outcomes 1998 May; 3(5): 239–50

    Article  Google Scholar 

  51. Dowsett M. Future uses for aromatase inhibitors in breast cancer. J Steroid Biochem Mol Biol 1997; 61(3-6): 261–6

    Article  PubMed  CAS  Google Scholar 

  52. Howell A, Downey S, Anderson E. New endocrine therapies for breast cancer. Eur J Can 1996 Apr; 32A: 576–88

    Article  CAS  Google Scholar 

  53. Wiseman LR, Spencer CM. Vorozole. Drugs Aging 1997 Sep; 11: 245–50

    Article  PubMed  CAS  Google Scholar 

  54. Wiseman LR, Adkins JC. Anastrozole: a review of its use in the management of postmenopausal women with advanced breast cancer. Drugs Aging 1998 Oct; 13(4): 321–32

    Article  PubMed  CAS  Google Scholar 

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Harriet M. Lamb & Julie C. Adkins

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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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