Tamoxifen Letrozole

Of 8028 postmenopausal women with receptor-positive early breast cancer who were randomly assigned doubleblind to letrozole, tamoxifen, or a sequence of these agents for 5 years, 7963 were included in an analysis of cardiovascular events over a median follow-up time of 30 months (8). There was a similar overall incidence of cardiac adverse events (letrozole 4.8% tamoxifen4.7%), but more grade 3-5 events with letrozole (2.4% versus 1.4%), an excess that was only partly attributable to prior hypercholesterolemia. There were more thromboembolic events with tamoxifen (3.9% versus 1.7% overall and 2.3% versus 0.9% for grade 3-5 events). There were no significant differences between tamoxifen and letrozole in the incidence of hypertension or cerebrovascular events. 

LETROZOLE TAMOXIFEN L plasma concentrations of letrozole (by approximately 40%) and 1 efficacy of letrozole Attributed to induction of enzymes metabolizing letrozole by tamoxifen Avoid concurrent use outside clinical trials... 

Itoh T, Karlsberg K, Kijima I, Yuan YC, Smith D, Ye J, et al. Letrozole-, anas-trozole-, and tamoxifen-responsive genes in MCF-7aro cells a microarray approach. Mol Cancer Res 2005 3 203-18. 

Options for adjuvant hormonal therapy in postmenopausal women include aromatase inhibitors (e.g. anastrozole, letrozole, or exemestane) either in place of or after tamoxifen. Adverse effects with aromatase inhibitors include hot flashes, myalgia/arthralgia, vaginal dryness/atrophy, mild headaches, and diarrhea. 

Aromatase inhibitors (including anastrozole, letrozole, aminoglutethimide, exemestane, formestane, testolactone), selective estrogen receptor modulators—SERMs (including raloxifene, tamoxifen, toremifene), clomiphene, cyclofenil, fulvestrant Diuretics, amiloride, bumetanide, canrenone, chlorthalidone, etacrynic acid, furosemide, indapamide, metolazone, spironolactone, thiazides, triamterene... 

Despite the significant benefit that tamoxifen has bestowed on breast cancer patients, the third-generation aromatase inhibitors are rapidly replacing tamoxifen as the first-Une treatment for breast cancers. In this chapter, focus will be given to three representative small-molecule aromatase inhibitors for breast cancer exemestane (1, Aromasin ), anastrozole (2, Arimidex ), and letrozole (3, Femara ). 

Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ et al. A randomized trial of letrozole in postmenopausal women after 5 years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003 349 1793-802. 

Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A et al. Phase III study of letro-zole versus tamoxifen as first-line therapy of advanced breast cancer in post-menopausal women Analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 2003 21 2101-9. 

Anastrozole, a selective nonsteroidal inhibitor of aromatase (the enzyme required for estrogen synthesis. Figures 40-2 and 40-5), is effective in some women whose breast tumors have become resistant to tamoxifen (see Chapter 54). Letrozole is similar. Exemestane, a steroid molecule, is an irreversible inhibitor of aromatase. Like anastrozole and letrozole, it is approved for use in women with advanced breast cancer (see Chapter 54). 

The risk of venous thromboembolism in women taking anastrozole is lower than that in women taking tamoxifen (1.6% versus 2.4%) (9), but still higher than in the untreated population. Cases of pulmonary embolism have been reported in an 80-year-old woman taking anastrozole (10) and a 72-year-old woman taking letrozole (11). 

However, in 12 patients who took letrozole 2.5 mg/day for 6 weeks with and without tamoxifen 20 mg/day plasma concentrations of letrozole were reduced by 38% during combination therapy (39). Tamoxifen did not significantly alter the effect of letrozole in suppressing estradiol, estrone, and estrone sulfate. The authors suggested that sequential therapy might be preferable with these two drugs. 

Dowsett M, Pfister C, Johnston SR, Miles DW, Houston SJ, Verbeek JA, Gundacker H, Sioufi A, Smith IE. Impact of tamoxifen on the pharmacokinetics and endocrine effects of the aromatase inhibitor letrozole in postmenopausal women with breast cancer. Clin Cancer Res 1999 5(9) 2338-43. 

This study has again confirmed that endometrial problems can be induced by tamoxifen early in the course of treatment and that these problems do not arise with aromatase inhibitors, which may actually reduce the endometrial changes induced by tamoxifen. The idea that the new oral aromatase inhibitors might well replace tamoxifen in breast cancer was tentatively advanced in SEDA-26 (p. 445) and has now been supported by some of the material cited above, as well as by a panel consensus (25). Citing efficacy and safety data on anastrozole, exemestane, and letrozole, the authors concluded that third-generation aromatase inhibitors may be considered first-line therapy of hormone-receptor-positive advanced breast cancer in postmenopausal women and may also be used for preoperative therapy of breast cancer. 

Fricker J. Letrozole better than tamoxifen in postmenopausal women. Lancet Oncol 2005 6 247. 

Beer B et al (2010) Development and validation of a liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of tamoxifen, anastrozole, and letrozole in human plasma and its application to a clinical study. Anal Bioanal Chem 398 1791-1800... 

The other approach to adjuvant hormonal therapy advances looks at the sequential use of newer agents after the optimal 5 years of tamoxifen or only 2 to 3 years of tamoxifen. Five additional years of letrozole, in a highly publicized study reported in the New England... 

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