Approval summary: letrozole in the treatment of postmenopausal women with advanced breast cancer.

Letrozole (Femara; Novartis Pharmaceuticals Corp., East Hanover, NJ) is a nonsteroidal inhibitor of aromatase enzyme complex. It inhibits the peripheral conversion of circulating androgens to estrogens. In postmenopausal women, letrozole decreases plasma concentrations of estradiol, estrone, and estrone sulfate by 75-95% from baseline with maximal suppression achieved within 2-3 days of treatment initiation. Suppression is dose related, with doses of >or=0.5 mg giving estrone and estrone sulfate values that were often below assay detection limits. At clinically used dosage, letrozole does not impair adrenal synthesis of glucocorticoids or aldosterone. In 1998, letrozole was approved by the United States Food and Drug Administration (FDA) for the treatment of advanced breast cancer in postmenopausal women, with hormone receptor positive or unknown breast cancer, who had failed one prior antiestrogen treatment (i.e., for "second-line" treatment). Approval was based on two randomized trials comparing tumor RRs of patients receiving 0.5 mg of letrozole, 2.5 mg of letrozole, and either megestrol acetate (MA) or aminoglutethimide. In the megestrol trial, 2.5 mg/day letrozole was superior to 0.5 mg of letrozole and MA (RRs 24, 13, and 16%, respectively), whereas in the aminoglutethimide trial, there was no significant difference in 2.5 mg of letrozole and 0.5 mg of letrozole RRs (20 and 17%). There was a trend toward RR superiority of 2.5 mg of letrozole over aminoglutethimide (P = 0.06). Letrozole (2.5 mg) was the dose chosen for comparison with tamoxifen in the first-line setting. In July 2000, a marketing application for first-line letrozole treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer was submitted to the FDA. A single double-blind, double dummy, randomized, and multicenter trial compared 2.5 mg of letrozole to 20 mg of tamoxifen (456 patients/arm). Letrozole was superior to tamoxifen with regard to time to progression (TTP) and objective response rate (RR). The median TTP for letrozole treatment was 9.9 months [95% confidence interval (CI) 9.1-12.2] versus 6.2 months (95% CI 5.8-8.5) for tamoxifen, P = 0.0001, hazard ratio 0.713, (95% CI 0.61-0.84). RR was 32% for letrozole versus 21% for tamoxifen (odds ratio 1.74, 95% CI 1.29-2.34, P = 0.0003). Preliminary survival data (survival data are still blinded) indicate that letrozole is unlikely to be worse than tamoxifen. Both treatments were similarly tolerated. On the basis of these results, the United States FDA approved letrozole tablets, 2.5 mg/day, for first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer. The manufacturer made a commitment to provide updated information on survival.     

Letrozole (Femara), a new aromatase inhibitor for advanced breast cancer]

The study compares letrozole (Femara and aminoglutethimide (AG), a standard therapy for postmenopausal women with advanced breast cancer, previously treated with anti-estrogens. 555 women were randomly assigned letrozole 2.5 mg once daily (n = 185), letrozole 0.5 mg once daily (n = 192) or aminoglutethimide 250 mg twice daily with corticosteroid support (n = 178) in an open-label, multicenter trial. The primary end-point was objective response rate (ORR), with time events as secondary. ORR was analysed nine months after enrollment of the last patient, while survival was analysed 15 months after the last patients was enrolled. We report the results of these analyses plus an extended period of observation (covering a total duration of approximately 45 months) to determine the duration of response and clinical benefit. Overall objective response rates (complete + partial) of 19.5%, 16.7% and 12.4% were seen for letrozole 2.5 mg, 0.5 mg and AG respectively. Median duration of response and stable disease was longest for letrozole 2.5 mg (21 months) compared with letrozole 0.5 mg (18 months) and AG (14 months). Letrozole 2.5 mg was superior to AG in time to progression, time to treatment failure and overall survival. Treatment-related adverse events occurred in fewer patients on letrozole (33%) than on AG (46%). Letrozole 2.5 mg offers longer disease control than aminoglutethimide and letrozole 0.5 mg in the treatment of postmenopausal women with advanced breast cancer, previously treated with anti-estrogens.     

Letrozole is superior to anastrozole in suppressing breast cancer tissue and plasma estrogen levels

PURPOSE: To evaluate the influence of the third-generation aromatase inhibitor letrozole (Femara) on breast cancer tissue levels of estrone (E(1)), estradiol (E(2)), and estrone sulfate (E(1)S) in postmenopausal women undergoing primary treatment for locally advanced estrogen receptor/progesterone receptor-positive breast cancers. EXPERIMENTAL DESIGN: Breast cancer tissue samples were collected before and following 4 months of neoadjuvant therapy with letrozole (2.5 mg o.d.), and tissue estrogen levels measured using a highly sensitive RIA after high-pressure liquid chromatography purification. RESULTS: Letrozole suppressed pretreatment tumor levels of E(2), E(1), and E(1)S by 97.6%, 90.7%, and 90.1%, respectively. These data reveal that letrozole suppresses tissue estrogen levels significantly below what has previously been recorded with anastrozole (89.0%, 83.4%, and 72.9% suppression, respectively) using the same methods. To confirm the differential effect of letrozole and anastrozole on each plasma estrogen fraction, we re-analyzed plasma samples obtained from a previous intrapatient cross-over study comparing letrozole and anastrozole using an improved RIA (detection limits of 0.67, 1.14, and 0.55 pmol/L for E(2), E(1), and E(1)S, respectively). Letrozole consistently suppressed each plasma estrogen fraction below the levels recorded for anastrozole: E(2) (average suppression by 95.2% versus 92.8%; P = 0.018), E(1) (98.8% suppression versus 96.3%; P = 0.003), and E(1)S (98.9% suppression versus 95.3%; P = 0.003). CONCLUSION: Our data reveals that letrozole (2.5 mg o.d.) is more effective compared with anastrozole (1.0 mg o.d.) with respect to tissue as well as plasma estrogen suppression in patients with postmenopausal breast cancer.     

Efficacy of first-line letrozole versus tamoxifen as a function of age in postmenopausal women with advanced breast cancer

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.     

Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group.

PURPOSE: To compare the efficacy and tolerability of tamoxifen with that of letrozole, an oral aromatase inhibitor, with tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. PATIENTS AND METHODS: Nine hundred seven patients were randomly assigned letrozole 2.5 mg once daily (453 patients) or tamoxifen 20 mg once daily (454 patients). Patients had estrogen receptor- and/or progesterone receptor-positive tumors, or both receptors were unknown. Recurrence during adjuvant antiestrogen therapy or within the following 12 months or prior endocrine therapy for advanced disease precluded enrollment. One prior chemotherapy regimen for metastatic disease was allowed. The primary end point was time to progression (TTP). Secondary end points included overall objective response rate (ORR), its duration, rate and duration of clinical benefit, time to treatment failure (TTF), overall survival, and tolerability. RESULTS: TTP was significantly longer for letrozole than for tamoxifen (median, 41 v 26 weeks). Treatment with letrozole reduced the risk of progression by 30% (hazards ratio, 0.70; 95% confidence interval, 0.60 to 0.82, P =.0001). TTP was significantly longer for letrozole irrespective of dominant site of disease, receptor status, or prior adjuvant antiestrogen therapy. Similarly, TTF was significantly longer for letrozole (median, 40 v 25 weeks). ORR was higher for letrozole (30% v 20%; P =.0006), as was the rate of clinical benefit (49% v 38%; P =.001). Survival data are currently immature and not reported here. Both treatments were well tolerated. CONCLUSION: Letrozole was significantly superior to tamoxifen in TTP, TTF, ORR, and clinical benefit rate. Our results support its use as first-line endocrine therapy in postmenopausal women with advanced breast cancer.     

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

Background: The study compares letrozole and aminoglutethimide (AG), astandard therapy for postmenopausal women with advanced breast cancer,previously treated with anti-oestrogens.Patients and methods: 555 women were randomly assigned letrozole 2.5 mgonce daily (n = 185), letrozole 0.5 mg once daily (n = 192) oraminoglutethimide 250 mg twice daily with corticosteroid support (n = 178)in an open-label, multicentre trial. The primary endpoint was objectiveresponse rate (ORR), with time events as secondary. ORR was analysed ninemonths after enrolment of the last patient, while survival was analysed 15months after the last patient was enrolled. We report the results of theseanalyses plus an extended period of observation (covering a total durationof approximately 45 months) to determine the duration of response andclinical benefit.Results: Overall objective response rates (complete + partial) of19.5%, 16.7% and 12.4% were seen for letrozole 2.5 mg,0.5 mg and AG respectively. Median duration of response and stable diseasewas longest for letrozole 2.5 mg (21 months) compared with letrozole 0.5 mg(18 months) and AG (14 months). Letrozole 2.5 mg was superior to AG in timeto progression, time to treatment failure and overall survival.Treatment-related adverse events occurred in fewer patients on letrozole(33%) than on AG (46%). Transient nausea was the most frequentevent with letrozole (7% on 0.5 mg, 10% on 2.5 mg, 10%on AG), rash with AG (11%, 1% on 0.5 mg, 3% on 2.5 mgletrozole).Conclusions: Letrozole 2.5 mg offers longer disease control thanaminoglutethimide and letrozole 0.5 mg in the treatment of postmenopausalwomen with advanced breast cancer, previously treated with anti-oestrogens.     

来曲唑与氨鲁米特对照治疗绝经后晚期乳腺癌113例

目的对比来曲唑和氨鲁米特治疗妇女绝经后晚期乳腺癌患者的有效性和耐受性。方法采用开放、随机、多中心对照研究。患者随机分组接受口服来曲唑2.5mg.d~(-1)或氨鲁米特1g.d(-1)的对照治疗。结果来曲唑组(n=59)有效率23.73%(CR 2例,PR 12例,ITT 有效率21.88%),SD 20.31%(13例)。氨鲁米特组(n=54)有效率11.11%(CR 1例,PR 5例,ITT 有效率10.17%),SD 20.34%(12例),2组疗效无统计学差异(P>0.05)。来曲唑组和氨鲁米特组不良反应发生率分别为18.64%和42.11%,与治疗相关的不良反应发生率分别为13.56%和33.33%。比较2组总的和与治疗相关的不良反应发生率均以来曲唑组明显较低,P 值均为0.002。结论来曲唑对绝经后、ER/PR 阳性或不明的晚期乳腺癌患者有效率为23.73%,与氨鲁米特比较无统计学差异。但来曲唑不良反应较氨鲁米特明显低,可以代替氨鲁米特用于晚期绝经后受体阳性或不明乳癌患者的治疗。     

来曲唑及去势联合来曲唑综合治疗晚期乳腺癌46例分析

目的观察来曲唑组及去势联合来曲唑治疗组间治疗晚期乳腺癌的疗效及不良反应。方法来曲唑组36例绝经后晚期乳腺癌患者接受来曲唑2.5mg口服,每日1次;去势联合来曲唑治疗组10例绝经前晚期乳腺癌接受去势治疗和来曲唑治疗,部分患者加用局部放疗。结果来曲唑组及去势联合来曲唑组治疗晚期乳腺癌均有较好效果。但来曲唑组较去势联合来曲唑组在平均生存时间(37.1个月对26.1个月)以及两年生存率(94.0%对60.0%)均有优势。结论来曲唑治疗晚期乳腺癌效果较好,药物不良反应轻。绝经前女性通过去势联合来曲唑也可以取得满意效果。     

来曲唑与氨鲁米特对照治疗绝经后晚期乳腺癌113例

目的 对比来曲唑和氨鲁米特治疗妇女绝经后晚期乳腺癌患者的有效性和耐受性。 方法 采用开放、随机、多中心对照研究。患者随机分组接受口服来曲唑2．5mg．d-1或氨鲁米特1g．d-1的对照治疗。 结果 来曲唑组(n=59)有效率23．73％(CR 2例，PR 12例，ITT有效率21．88％)，SD 20．31％(13例)。氨鲁米特组(n=54)有效 率11．11％(CR 1例，PR 5例，ITT有效率10．17％)，SD 20．34％(12例)，2组疗效无统计学差异(P>0．05)。来曲唑组和氨鲁米特 组不良反应发生率分别为18．64％和42．11％，与治疗相关的不良反应发生率分别为13．56％和33．33％。比较2组总的和与治疗 相关的不良反应发生率均以来曲唑组明显较低，P值均为0．002。 结论 来曲唑对绝经后、ER／PR阳性或不明的晚期乳腺癌患者有效率为23．73％，与氨鲁米特比较无统计学差异。但来曲唑不良 反应较氨鲁米特明显低，可以代替氨鲁米特用于晚期绝经后受体阳性或不明乳癌患者的治疗。     

来曲唑在老年乳腺癌新辅助内分泌治疗中的疗效观察

目的探讨来曲唑在老年绝经后乳腺癌新辅助内分泌治疗中的近期疗效,耐受性及与临床病理因素的相关性。方法对58例绝经后激素受体阳性的乳腺癌患者进行来曲唑新辅助内分泌治疗,以他莫昔芬新辅助内分泌治疗为对照组。结果来曲唑组临床疗效显著优于他莫昔芬组（P〈0.05）。来曲唑组临床分期晚,ER及PR均阳性的有效率高,与HER-2表达无关。他莫昔芬组HER-2阳性的有效率低。2组治疗前后Ki-67水平均显著下降,有统计学意义（P〈0.05）。2组未出现明显不良反应。结论绝经后、激素受体阳性的乳腺癌选择来曲唑新辅助内分泌治疗安全,有效,尤其适合有合并症的老年体弱者。     

Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate.

PURPOSE: To compare two doses of letrozole (0.5 mg and 2.5 mg every day) and megestrol acetate (40 mg qid) as endocrine therapy in postmenopausal women with advanced breast cancer previously treated with antiestrogens. PATIENTS AND METHODS: This double-blind, randomized, multicenter, multinational study enrolled 602 patients, all of whom were included in the primary analysis in the protocol. Patients had advanced or metastatic breast cancer with evidence of disease progression while receiving continuous adjuvant antiestrogen therapy, had experienced relapse within 12 months of stopping adjuvant antiestrogen therapy given for at least 6 months, or had experienced disease progression while receiving antiestrogen therapy for advanced disease. Tumors were required to be estrogen receptor- and/or progesterone receptor-positive or of unknown status. Confirmed objective response rate was the primary efficacy variable. Karnofsky Performance Status and European Organization for Research and Treatment of Cancer quality-of-life assessments were collected for 1 year. RESULTS: There were no statistically significant differences among the three treatment groups for overall objective tumor response. Patients treated with letrozole 0.5 mg had improvements in disease progression (P =.044) and a decreased risk of treatment failure (P =.018), compared with patients treated with megestrol acetate. Letrozole 0.5 mg showed a trend (P =.053) for survival benefit when compared with megestrol acetate. Megestrol acetate was more likely to produce weight gain, dyspnea, and vaginal bleeding, and the letrozole groups were more likely to experience headache, hair thinning, and diarrhea. CONCLUSION: Given a favorable tolerability profile, once-daily dosing, and evidence of clinically relevant benefit, letrozole is equivalent to megestrol acetate and should be considered for use as an alternative treatment of advanced breast cancer in postmenopausal women after treatment failure with antiestrogens.     

CGS20267 (Letrozole), a new aromatase inhibitor: late phase II study for postmenopausal women with advanced or recurrent breast cancer (no. 1)--investigation of recommended clinical dose CGS20267 Study Group

To determine the recommended clinical dose of CGS20267 (Letrozole), we conducted a randomized comparative study as a late phase II study (first part) in postmenopausal women with advanced or recurrent breast cancer. Forty-one patients were randomly assigned to receive 0.5 mg or 1.0 mg once daily. There were no statistically significant differences in background between the two groups. Although there was no significant difference in the objective response rates between the two groups, the rate was higher at 1.0 mg (44.4%) than at 0.5 mg (38.1%). We also combined these data with the results of an early phase II study. The objective response rates (CR + PR) were 31.4% at 0.5 mg and 42.2% at 1.0 mg, and response rates consisting of CR, PR, and NC for longer than 6 months were significantly higher at a dose of 1.0 mg (68.9%) than 0.5 mg (41.2%). Side effects included drug-related adverse events in 36.8% at 0.5 mg and in 31.6% at 1.0 mg. All of the events were grade 2 or lower, indicating a favorable tolerability of CGS20267. These results demonstrated that CGS20267 1.0 mg once daily is more effective than 0.5 mg, and has comparable safety, in the treatment of postmenopausal women with advanced or recurrent breast cancer. We conclude the recommended clinical dose of CGS20267 should be 1.0 mg once daily.     

Letrozole, a new oral non-steroidal aromastase inhibitor in treating postmenopausal patients with advanced breast cancer. A pilot study

PURPOSE: To evaluate the endocrine effects as well as the pharmacokineticparameters, efficacy and safety of letrozole, a new fourth-generationnon-steroidal aromatase in hibitor. Patients and methods: Fourteen postrnenopausal women with progressivemetastatic breast cancer, previously treated with endocrinetherapy and/or chemotherapy for advanced disease, were treatedwith 0.5 mg daily doses of letrozole, orally. Endocrine andpharmacokinetic measurements were made before treatment andon days 14, 28, 56, and 84 of therapy. RESULTS: Letrozole induced a >86% decrease in plasma estrone and a=67% reduction in circulating estradiol from day 14 on. Therewas a statistically significant decrease in plasma cortisol,which appeared clinically irrelevant since all values remainedwithin the normal range. No significant changes in aldosteroneconcentration were noted. One patient achieved a complete response(CR) and 4 patients a partial response (PR), with an objectiveresponse rate of 36% (95% CI 13% to 6 5%). Median duration ofresponse was 24 months, ranging from 4 to 44 months. No toxiceffects attributable to letrozole were noted in any patient. CONCLUSION: Letrozole appears to be a very promising new antiaromatase drug.The characteristics of the patients more likely to respond,taking into account prior systemic treatment, should be definedby future studies. Further phase II and phase III studies comparingletrozole to other available second or even first-line endocrine-therapyagents, are war ranted. aromatase inhibitors, breast carconoma, endocrine therapy, letrozole     

Superiority of letrozole to tamoxifen in the first-line treatment of advanced breast cancer: evidence from metastatic subgroups and a test of functional ability

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.     

A randomized,placebo-controlled trial (NCIC CTG MAP1) examining the effects of letrozole on mammographic breast density and other end organs in postmenopausal women

Mammographically detected breast density has been correlated with breast cancer risk. Breast density appears to be influenced by hormonal factors including increasing age, postmenopausal status, number of pregnancies, lower body weight, hormone replacement therapy, and tamoxifen therapy. The aromatase inhibitor letrozole profoundly reduces breast and circulating estrogen levels in postmenopausal women. We hypothesize that letrozole may reduce breast density and report here on its effects on mammographic breast density, bone mineral density (BMD), bone biomarkers, plasma hormone, and serum lipid levels. MAP1 was a multicenter, randomized, double-blind, placebo-controlled, feasibility trial in which postmenopausal women with or without prior invasive breast cancer were randomized in a 2:1 ratio of letrozole (2.5 mg daily) or placebo for 12 months and followed for a total of 24 months. Eligible women had an estimated >25% breast density on baseline mammogram. The primary endpoint was change in percent breast density (PD) between the baseline and 12-month mammograms as estimated by a computer-assisted thresholding program. Baseline and 12-month mammographic density was also assessed in a blinded manner by visual inspection. Secondary endpoints included changes in serum hormones, plasma lipid levels, bone biomarkers, and BMD. Data are available for 67 women (44 on letrozole and 23 on placebo). No significant changes in PD were noted between the treatment arms at either 12 or 24 months. No distinguishable difference in density measurements by visual inspection were noted between baseline and 12-month mammograms. A significant decrease in percentage change in T-score of the femoral neck at 12 months was noted in the letrozole arm without other significant changes in BMD parameters. Lipid values did not differ between treatment groups except for a borderline significant decrease in total cholesterol at 3 months among women treated with letrozole. Letrozole therapy was associated with a significant reduction in mean serum estradiol, estrone, and estrone sulfate levels at 12 months, but not at 24 months. A significant increase in serum IGF-1 levels was also noted in the letrozole group compared to the placebo group at both 12 and 24 months. To conclude, compared with placebo, 12 months of letrozole therapy does not appear to have a significant effect on mammographic PD. Twelve months of letrozole was associated with a decrease of uncertain clinical significance in the T-score of the femoral neck at 12 months which was reversible at 24 months with recovery of estrogen levels. Letrozole therapy was found to increase IGF-1 levels at 12 and 24 months.     

Anti-tumor effects of letrozole

The use of drugs, which inhibit estrogen biosynthesis, is an attractive treatment for postmenopausal women with hormone-dependent breast cancer. Estrogen deprivation is most specifically achieved using inhibitors which block the last stage in the biosynthetic sequence, i.e., the conversion of androgens to estrogens by the aromatase enzyme. Recently, a new generation of aromatase inhibitors has been developed. Among these, letrozole (Femara) appears to be the most potent. When given orally in milligram amounts per day to postmenopausal women, the drug almost totally inhibits peripheral aromatase and causes a marked reduction in circulating estrogens to levels that are often undetectable in conventional assays. Similarly, neoadjuvant studies demonstrate that letrozole substantially inhibits aromatase activity in both malignant and nonmalignant breast tissues, and markedly suppresses endogenous estrogens within the breast cancers. These studies also illustrate anti-estrogenic and anti-proliferative effects of letrozole in estrogen receptor (ER)-rich tumors. Thus, tumor expression of progesterone receptors and the cell-cycle marker Ki67 is significantly and consistently reduced with treatment. Additionally, clear pathological responses as evidenced by decreased cellularity and increased fibrosis are seen in the majority of cases. These results translated into clinical benefit in a series of 24 breast cancers treated neoadjuvantly with letrozole (either 2.5 or 10 mg): tumor volume reductions > 25% were observed in 23 women, and > 50% reductions in 18 patients. Pathological and clinical effects are seen much more consistently than with tamoxifen. Thus, in a multicenter randomized trial of letrozole vs. tamoxifen (PE 024), clinical study outcomes were superior for letrozole in comparison with tamoxifen with regard to overall tumor response and an increase in the proportion of patients treated by breast conserving surgery. Letrozole has also been used in advanced breast cancer, both as second-line hormone treatment following tamoxifen failure, and more recently as first-line therapy. Trials of second-line treatment in which letrozole has been compared with either older aromatase inhibitors or progestins have shown equivalent or superior clinical activity and improved tolerability favoring letrozole. In first-line comparison with tamoxifen in metastatic disease, a phase III trial of over 900 postmenopausal women showed letrozole to be significantly better than tamoxifen in terms of overall tumor response rates, clinical benefit, and time to treatment failure. In summary, letrozole is an exceptionally potent and specific endocrine agent. In patients with ER-rich tumors, high rates of pathological and clinical response have been documented, and large phase III trials against established treatments such as tamoxifen and progestin suggest superior (or at least equivalent) clinical efficacy. Letrozole is a drug of immense potential and in the future is likely to occupy a central role in the management of postmenopausal women with hormone-dependent breast cancer.     

Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study.

PURPOSE: To compare the effects of the two novel, potent, nonsteroidal aromatase inhibitors anastrozole and letrozole on total-body aromatization and plasma estrogen levels. PATIENTS AND METHODS: Twelve postmenopausal women with estrogen receptor-positive, metastatic breast cancer were treated with anastrozole 1 mg orally (PO) and letrozole 2.5 mg PO once daily, each given for a time interval of 6 weeks in a randomized sequence. Total-body aromatization was determined before treatment and at the end of each treatment period using a dual-label isotopic technique involving isolation of the metabolites with high-performance liquid chromatography. Plasma levels of estrone (E(1)), estradiol (E(2)), and estrone sulfate (E(1)S) were determined in samples obtained before each injection using highly sensitive radioimmunoassays. RESULTS: Pretreatment aromatase levels ranged from 1.68% to 4.27%. On-treatment levels of aromatase were detectable in 11 of 12 patients during treatment with anastrozole (mean percentage inhibition in the whole group, 97.3%) but in none of the 12 patients during treatment with letrozole (> 99.1% suppression in all patients; Wilcoxon, P =.0022, comparing the two drug regimens). Treatment with anastrozole suppressed plasma levels of E(1), E(2), and E(1)S by a mean of 81.0%, 84.9%, and 93.5%, respectively, whereas treatment with letrozole caused a corresponding decrease of 84.3%, 87.8% and 98.0%, respectively. The suppression of E(1) and E(1)S was found to be significantly better during treatment with letrozole compared with anastrozole (P =.019 and.0037, respectively). CONCLUSION: This study revealed letrozole (2.5 mg once daily) to be a more potent suppressor of total-body aromatization and plasma estrogen levels compared with anastrozole (1 mg once daily) in postmenopausal women with metastatic breast cancer.     

Effect of letrozole on the lipid profile in postmenopausal women with breast cancer

Hormonal therapy plays a central role in the overall treatment of breast cancer. Aromatase inhibitors can inhibit the aromatase enzyme system resulting in a reduction of oestrogens. Letrozole is a non-steroidal aromatase inhibitor that effectively blocks aromatase activity without interfering with adrenal steroid biosynthesis. The drug can significantly reduce the levels of plasma oestrogens, which remain suppressed throughout the treatment. Data are scarce concerning the influence of these drugs on serum lipid levels. In the present study, we evaluated the effects of letrozole on the serum lipid profile in postmenopausal women with breast cancer. A total of 20 patients with breast cancer were treated with letrozole, 2.5 mg once daily. After an overnight fast, serum lipid parameters (total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides, apolipoproteins A1, B and E and lipoprotein (a)) were measured before treatment and at 8 and 16 weeks afterwards. A significant increase in total cholesterol (P=0.05), LDL cholesterol (P<0.01) and apolipoprotein B levels (P=0.05) in the serum, as well as in the atherogenic risk ratios total cholesterol/HDL cholesterol (P<0.005) and LDL cholesterol/HDL cholesterol (P<0.005) was noticed after letrozole treatment. We conclude that letrozole administration in postmenopausal women with breast cancer has an unfavourable effect on the serum lipid profile.     

First-line fadrozole HCI (CGS 16949A) versus tamoxifen in postmenopausal women with advanced breast cancer: Prospective randomised trial of the Swiss Group for Clinical Cancer Research SAKK 20/88

BACKGROUND:: In a phase III randomized trial, we compared the effectivenessand tolerability of fadrozole (CGS 16949A), a non-steroidalaromatase inhibitor, to tamoxifen as first-line endocrine therapyin postmenopausal women with advanced breast cancer. PATIENTS AND METHODS:: Two hundred twelve eligible patients were randomized to receivetamoxifen 20 mg daily, or fadrozole 1 mg twice daily orallyuntil disease progression or the advent of undue toxicity. Thetreatments were to be discontinued upon disease progression. RESULTS:: Prognostic factors were well balanced between the treatmentgroups, except for sites of metastatic disease. Fadrozole-treatedpatients had significantly more visceral, especially liver,involvement and less bone-dominant disease. Response rates forfadrozole and tamoxifen were similar, 20% and 27% (95% ConfidenceLimits (CL): 13%–29% and 21%–35%), respectively.Time to treatment failure was longer in patients randomizedto tamoxifen (8.5 months for tamoxifen vs. 6.1 months for fadrozole),but did not reach statistical significance after adjustmentfor prognostic factors (P=0.09). Fadrozole, for which a significantlylower percentage of clinically relevant toxic effects (WHO toxicitygrade     

A randomised study of CGS 16949A (fadrozole) versus tamoxifen in previously untreated postmenopausal patients with metastatic breast cancer

BACKGROUND:: Fadrozole, a potent, highly specific inhibitor of aromataseactivity, has only been used as second-line therapy in treatmentof post-menopausal women with advanced breast cancer. A prospectivelyrandomised study was therefore undertaken to compare relativeclinical efficacy of fadrozole as first-line treatment to thatof tarnoxifen. PATIENTS AND METHODS:: Eighty postmenopausal women who had not received prior treatmentfor advanced/metastatic breast cancer were randomised to receiveeither fadrozole, 1 mg twice daily, or tamoxifen, 20 mg daily. RESULTS:: Toxicity was not statistically different on the two treatmentarms. Only mild to moderate toxicity was documented: hot flashesin 37%, headaches in 6.5%, mild fatigue in 2.6%. There werealso no statistically significant differences in objective responserates, survival or time to treatment failure (TTF). Objectiveresponse rate on fadrozole was 50% (complete response (CR) 8.3%and partial response (PR) 42%). On tamoxifen objective responsewas 44.7% (CR 21% and PR 24%). Median TTF was 4.9 months onfadrozole and 5 months on tamoxifen. Median survival was 22.7months on fadrozole and 27.5 months on tamoxifen. CONCLUSION:: While response rates, survival and TTF were not statisticallysignificantly different, there were more complete responseson tamoxifen and duration of objective response (CR + PR) wassignificantly longer in the patients treated with tamoxifen. breast cancer, fadrozole, postmenopausal, tamoxifen