The effect of anastrozole on the pharmacokinetics of tamoxifen in post-menopausal women with early breast cancer

Thirty-four post-menopausal women with early breast cancer who had received 20 mg tamoxifen once daily as adjuvant therapy for at least 10 weeks participated in a randomized, double-blind, parallel-group, multicentre trial. The primary aim of the trial was to determine the effect of anastrozole upon tamoxifen pharmacokinetics, with secondary aims of assessing the tolerability of the two drugs in combination and whether or not tamoxifen had any effect upon the oestradiol suppression seen with anastrozole. Patients were randomized to receive either 1 mg anastrozole (16 patients) or matching placebo (18 patients) once daily on a double-blind basis for 28 days. No significant difference (P = 0.919) was observed in serum tamoxifen concentrations between the anastrozole and placebo groups during the trial. The serum concentration of oestradiol was significantly suppressed (P < 0.0001) in patients co-administered anastrozole compared with placebo in the presence of tamoxifen, confirming that anastrozole remained an effective suppressant of oestradiol in the presence of tamoxifen. The combination of tamoxifen and anastrozole was well tolerated, with very little difference in side-effects reported between anastrozole and placebo. In conclusion, the results of this study confirm that anastrozole does not affect the pharmacokinetics of tamoxifen when the two drugs are given in combination to post-menopausal women with early breast cancer. In addition, the oestradiol suppressant effects of anastrozole appear unaffected by tamoxifen. © 1999 Cancer Research Campaign     

Review of the ATAC study: tamoxifen versus anastrozole in early-stage breast cancer

A 5-year regimen of tamoxifen hormone therapy has historically been the recommendation for hormone receptor-positive, postmenopausal women with early-stage breast cancer. With the advent of aromatase inhibitors, there has been extensive work carried out to investigate the role of these agents in the adjuvant setting. Studies have been designed to answer whether these agents should be used upfront (instead of tamoxifen) or in conjunction (either in a switch or extended program). The Arimidex^®, Tamoxifen Alone or in Combination (ATAC) trial is a landmark trial that demonstrated the superiority of upfront anastrozole over tamoxifen. This article reviews the trial and discusses both the optimum timing of initiation of aromatase inhibitors and the future approach of more individualized therapy, with the detection of predictive markers.     

Idoxifene versus tamoxifen: a randomized comparison in postmenopausal patients with metastatic breast cancer.

BACKGROUND: More efficacious and safer hormonal agents are needed for breast cancer treatment and prevention. Idoxifene is a novel selective estrogen receptor modulator (SERM) that, in preclinical models, has greater antiestrogenic but lower estrogenic activity than tamoxifen. PATIENTS AND METHODS: Three hundred and twenty-one postmenopausal patients with hormone receptor-positive or -unknown metastatic breast cancer were randomized to receive either tamoxifen or idoxifene as initial endocrine therapy for advanced disease. Data were analyzed based on intention to treat and all the responses were subject to independent review. RESULTS: At the time of a second planned interim analysis, the trial was stopped for economic considerations, not for reasons related to safety or efficacy. Complete data for the 219 patients included in the second interim analysis are fully available and reported here. Median age was 59.1 years for idoxifene patients and 59.9 years for tamoxifen patients. Complete response (CR) plus partial response (PR) rates were as follows: tamoxifen, 9%; idoxifene, 13% (P = 0.39). Clinical benefit rate [CR + PR + stable disease (SD) >or=6 months] was 34.3% for idoxifene and 38.7% for tamoxifen (P = 0.31). Median time to progression and duration of response were 140 days and 151.5 days, respectively, for tamoxifen compared with 166 days and 218 days for idoxifene. None of these endpoints was significantly different for the two drugs, nor was survival. Adverse events (lethal, serious but not lethal and important but not life threatening) were similar in the two arms. CONCLUSIONS: Idoxifene was both active and well tolerated in postmenopausal women with metastatic breast cancer. Idoxifene had similar efficacy and toxicity to tamoxifen in this randomized comparison.     

A trial-based cost-effectiveness analysis of letrozole followed by tamoxifen versus tamoxifen followed by letrozole for postmenopausal advanced breast cancer.

BACKGROUND: Third-generation aromatase inhibitors are being considered as an alternative to tamoxifen as first-line therapy for advanced breast cancer. These newer therapies are more expensive, and will gain greater acceptance if they can demonstrate cost-effectiveness. METHODS: Life table analyses are used to compare the costs and benefits [life years gained and quality-adjusted life years (QALYs) gained] of treating postmenopausal women with advanced breast cancer with first-line letrozole (with the option of second-line tamoxifen) compared with first-line tamoxifen (with the option of second-line letrozole). Patient-level data from a large clinical trial describes the effectiveness of the therapy options, clinicians estimate resource usage and utility values are obtained from the literature. RESULTS: The mean cost of providing first- and second-line hormonal therapy is pound 4765 if letrozole is the first-line therapy and pound 3418 if tamoxifen is provided first (a difference of pound 1347). However, patients receiving letrozole as first-line therapy gain an additional 0.228 life years, or 0.158 QALYs. The cost-effectiveness analysis found that first-line hormonal therapy with letrozole gains additional life years at a cost of pound 5917, whilst the cost per additional QALY gained is pound 8514. CONCLUSION: The strategy of letrozole as first-line hormonal therapy not only provides an opportunity for extending and improving patient's quality of life, but also is highly cost-effective compared with other generally accepted medical treatments.     

Adjuvant tamoxifen for pre- and postmenopausal women with estrogen receptor positive,node positive breast cancer: A randomized study

Summary 370 patients with operable, axillary node positive breast cancer, were randomized to receive tamoxifen (TAM) 20 mg/day for 2 years or no adjuvant hormone therapy. All patients had estrogen receptor (ER) positive (ER > 10 pmol/g) primary tumours. 350 patients, 93 younger than 50 years of age and 257 patients 50 years or older, were evaluable for the study. After a median follow up of 76 months, significantly (p = 0.0001) fewer loco-regional, but not distant (systemic), relapses have been recorded in the TAM group. Overall survival was also improved, but even though the study was designed to give maximum benefit from TAM statistically significant effect of TAM seemed to be limited to patients 50 years of age and older.     

Tamoxifen and fluoxymesterone versus tamoxifen and danazol in metastatic breast cancer — A randomized study

Summary A prospective randomized trial of tamoxifen and fluoxymesterone versus tamoxifen and danazol in metastatic breast cancer was conducted from December 1980 to September 1985. Patients were eligible regardless of site of disease, estrogen receptor status, or age. Sixty-two of sixty-three randomized patients were evaluable for response. Overall response for tamoxifen and fluoxymesterone was 11% with 61% stabilization of disease, versus 12% response rate for tamoxifen and danazol with 59% stabilization. Toxicities with tamoxifen and fluoxymesterone were greater with an increase in masculinization. We conclude that the response rates to the combinations of tamoxifen and fluoxymesterone or tamoxifen and danazol reported are equivalent in this study but that the increased toxicity with tamoxifen and fluoxymesterone would make tamoxifen and danazol the treatment of choice if a combination were to be used.     

A randomized phase II presurgical trial of weekly low-dose tamoxifen versus raloxifene versus placebo in premenopausal women with estrogen receptor-positive breast cancer

Introduction

We previously demonstrated that 1 or 5 mg per day of tamoxifen (T) given for four weeks before surgery reduces Ki-67 in breast cancer (BC) patients to the same extent as the standard 20 mg/d. Given the long half-life of T, a weekly dose (10 mg per week (w)) may be worth testing. Also, raloxifene (R) has shown Ki-67 reduction in postmenopausal patients in a preoperative setting, but data in premenopausal women are limited. We conducted a randomized trial testing T 10 mg/w vs. R 60 mg/d vs. placebo in a presurgical model.

Methods

Out of 204 screened subjects, 57 were not eligible, 22 refused to participate and 125 were included in the study. The participants were all premenopausal women with estrogen receptor-positive BC. They were randomly assigned to either T 10mg/w or R 60 mg/d or placebo for six weeks before surgery. The primary endpoint was tissue change of Ki-67. Secondary endpoints were modulation of estrogen and progesterone receptors and several other circulating biomarkers.

Results

Ki-67 was not significantly modulated by either treatment. In contrast, both selective estrogen receptor modulators (SERMs) significantly modulated circulating IGF-I/IGFBP-3 ratio, cholesterol, fibrinogen and antithrombin III. Estradiol was increased with both SERMs. Within the tamoxifen arm, CYP2D6 polymorphism analysis showed a higher concentration of N-desTamoxifen, one of the tamoxifen metabolites, in subjects with reduced CYP2D6 activity. Moreover, a reduction of Ki-67 and a marked increase of sex hormone-binding globulin (SHBG) were observed in the active phenotype.

Conclusions

A weekly dose of tamoxifen and a standard dose of raloxifene did not inhibit tumor cell proliferation, measured as Ki-67 expression, in premenopausal BC patients. However, in the tamoxifen arm women with an extensive phenotype for CYP2D6 reached a significant Ki-67 modulation.     

Effect of tamoxifen on serum cholesterol in Japanese women with breast cancer

Background To investigate whether tamoxifen therapy has a favorable effect on plasma lipids, serum cholesterol levels were measured in 228 Japanese women with breast cancer (116 premenopausal women and 112 postmenopausal women). Methods These women were treated with tamoxifen or tamoxifen+chemotherapy (tamoxifen-treated group) or were given no therapy or chemotherapy alone (control group). Results There was no difference between cholesterol levels before treatment and after a 2-year follow-up period in these groups, except for the postmenopausal tamoxifen-treated group. In this particular group, the mean levels of serum cholesterol after 1 and 2 years of follow-up (197 and 188 mg/dL, respectively) were 8% and 12% lower than those before treatment (215 mg/dL,P<0.0001). In addition, the mean level of serum cholesterol after a 2-year follow-up period was significantly higher in the postmenopausal tamoxifen-treated group than in the postmenopausal control group (218 and 188 mg/dL, respectively,P=0.0066). Conclusions In multiple regression models that included age, body mass index, and chemohormonal therapy, only tamoxifen treatment appeared to predict the change between cholesterol levels before treatment and after 2-year follow-up in postmenopausal women. These results suggest that tamoxifen has the potential benefit of reducing the serum cholesterol level, which may be closely related to cardiovascular risk, in Japanese postmenopausal women.     

Randomized clinical trial of tamoxifen plus sequential CMF chemotherapy versus tamoxifen alone in postmenopausal women with advanced breast cancer

Summary Eighty-eight postmenopausal women with metastatic breast cancer, in whom estrogen receptors (ER) were positive or unknown, were treated on a controlled trial to determine the effectiveness of tamoxifen and to assess the therapeutic advantage of sequentially adding low-dose cyclophosphamide-methotrexate-5-fluorouracil (CMF) chemotherapy in tamoxifen responders. Patients with known ER negative status were not studied. After the initial 12-week treatment with tamoxifen alone, 60% of ER positive patients achieved complete or partial response as did 35% in whom ER were unknown. Response status further improved in 18% randomized to continue tamoxifen alone vs 31% in whom CMF was added to tamoxifen. There were no statistically significant differences in time to the development of progressive disease or survival between the ER positive and ER unknown patients or between the tamoxifen and tamoxifen plus CMF groups. We conclude that inability to determine ER status should not prejudice against the use of tamoxifen in postmenopausal patients with advanced breast cancer. No benefit has been demonstrated from the addition of CMF chemotherapy in tamoxifen responders. Address for reprints: J.H. Glick, M.D., Hospital of the University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104.     

The value of high adherence to tamoxifen in women with breast cancer: a community-based cohort study

Background:

Low adherence to adjuvant tamoxifen is associated with worse health outcomes but little is known about the cost-effectiveness of high adherence.

Methods:

We conducted an economic evaluation using data for all women with incident breast cancer between 1993 and 2000 who were subsequently prescribed tamoxifen in the Tayside region of Scotland. Patient-level, lifetime Markov models evaluated the impact of high vs low adherence to tamoxifen using linked prescribing, cancer registry, clinical cancer audit, hospital discharge and death records. Direct medical costs were estimated for each patient and quality-of-life weights were assigned. Recurrence information was collected by case note review and adherence calculated from prescribing records with low adherence classed below 80%.

Results:

A total of 354 (28%) patients had a recorded recurrence and 504 (39%) died. Four hundred and seventy-five (38%) patients had low adherence over the treatment period, which was associated with reduced time to recurrence of 52% (P<0.001). Time to other cause mortality was also reduced by 23% (P=0.055) but this was not statistically significant. For an average patient over her lifetime, low adherence was associated with a loss of 1.43 (95% CI: 1.15–1.71) discounted life years or 1.12 (95% CI: 0.91–1.34) discounted quality-adjusted life years (QALYs) and increased discounted medical costs of £5970 (95% CI: £4644–£7372). Assuming a willingness to pay threshold of £25 000 per QALY, the expected value of changing a patient from low to high adherence is £33 897 (95% CI: £28 322–£39 652).

Conclusion:

Patients with low adherence have shorter time to recurrence, increased medical costs and worse quality of life. Interventions that encourage patients to continue taking their treatment on a daily basis for the recommended 5-year period may be highly cost-effective.     

The association of nonalcoholic steatohepatitis and tamoxifen in patients with breast cancer

BACKGROUND:

Nonalcoholic steatohepatitis (NASH) is a form of liver damage that can progress to cirrhosis. NASH is associated with obesity and diabetes. The condition also may be associated with some medications, including tamoxifen. Early case reports and small series have documented NASH in patients who received tamoxifen.

METHODS:

The records of patients registered in the St. Vincent Hospital Cancer Registry of Green Bay Wisconsin from January 1, 1992 to December 31, 2000 were reviewed.

RESULTS:

In total, 1105 patients with breast cancer were evaluated for NASH, and 24 cases of NASH were documented (2.2%). Seven patients had NASH before their diagnosis of breast cancer, and 17 patients developed NASH after their diagnosis of breast cancer. In multivariate analysis, the factors associated with NASH were tamoxifen use (odds ratio [OR], 8.2; 95% confidence interval [CI], 1.06‐63.72), body mass index (BMI) (OR, 1.13; 95% CI, 1.06‐1.20), and age (OR, 95% CI, 0.91‐0.99). NASH improved after tamoxifen was stopped. After discontinuation of tamoxifen, transaminase levels returned to normal in 14 of 16 patients.

CONCLUSIONS:

NASH was present in 24 of 1105 patients with breast cancer (2.2%). Seven patients had NASH before they were diagnosed with breast cancer, and 17 patients developed NASH after their diagnosis. NASH was associated with the use of tamoxifen and improved when tamoxifen was stopped. Cancer 2009. © 2009 American Cancer Society.     

Patterns of failure in a randomized trial of adjuvant chemotherapy in postmenopausal patients with early breast cancer treated with tamoxifen.

BACKGROUND: We studied the effect of adjuvant anthracycline-based chemotherapy in postmenopausal patients with resected early breast cancer treated with adjuvant tamoxifen. PATIENTS AND METHODS: The trial included 835 patients with either axillary lymph node involvement, or tumors with histological grade II or III. They were randomized after local surgery to receive either tamoxifen (TAM group) or tamoxifen plus chemotherapy (TAM-CT group) consisting of six courses of 5-fluorouracil, doxorubicin and cyclophosphamide (FAC), or 5-fluorouracil, epidoxorubicin and cyclophosphamide (FEC). Radiotherapy was given after completion of adjuvant chemotherapy in the TAM-CT group and after surgery in the TAM group. RESULTS: The 5-year disease-free survival (DFS) rates were 73% in the TAM group and 79% in the TAM-CT group (log-rank test, P = 0.06). The 5-year overall survival rates were 82% and 87%, respectively (P = 0.06). The 5-year distant metastasis rates were 22% and 16% (P = 0.02), and the 5-year local recurrence rates were 6% and 4%, respectively (P = 0.23). There were no significant differences for contralateral breast cancer or other new primary malignancies. Chemotherapy tended to be more effective for patients who had tumors without estrogen receptors (trend test, P = 0.05). CONCLUSIONS: Anthracycline-based chemotherapy administered to postmenopausal patients receiving adjuvant tamoxifen gave a borderline significant benefit on overall and DFS, mainly by a reduction in distant metastases. Delaying radiotherapy after six courses of chemotherapy did not affect local control after up to 10 years of follow-up.     

乳腺癌患者应用三苯氧胺导致的妇科并发症及其监测

三苯氧胺具有抗雌激素和雌激素的双重特性,长期持续使用可导致子宫内膜发生多种病理改变。临床应予以重视,并加以监测。本文就妇科并发症的发生和临床监测方面做一综述,以早发现、并减少并发症的发生。     

Association between endometrial cancer and tamoxifen treatment of breast cancer

A retrospective cohortstudy in 4109 breast cancer patients was undertaken to determine how tamoxifen affected the risk of endometrial cancer. Data on 1701 tamoxifentreated women were analysed. Two thousand four hundred and eight nontamoxifen users served as control group. The occurrence of new primary uterine cancers was assessed by computerized linkage to the Austrian Cancer Registry. Twentyfive women who subsequently developed endometrial cancer were identified. Eight uterine cancers occurred in the tamoxifen group, whereas 17 uterine cancers were found in the control group. The estimate of the relative risk (RR) showed an increased risk to develop endometrial cancer for the tamoxifen group RR 1.136 (95% CI 0.71; 1.80). Analysis of relevant confounding variables did not show any differences in the two groups.In conclusion, this retrospective study demonstrated a nonsignificant increased risk of endometrial cancer in women receiving tamoxifen as treatment for breast cancer. However, the magnitude of RR and the absolute number of endometrial cancer cases in this long term observation demonstrate clearly that the clinical benefit of tamoxifen therapy greatly outweighs the risk.     

Combined endocrine treatment of elderly postmenopausal patients with metastatic breast cancer; A randomized trial of tamoxifen vs. tamoxifen + aminoglutethimide and hydrocortisone and tamoxifen + fluoxymesterone in women above 65 years of age

The efficacy of combined endocrine therapy with tamoxifen (TAM), aminoglutethimide (AG), and hydrocortisone (H) or tamoxifen and fluoxymesterone (FLU) was evaluated against treatment with tamoxifen alone in 311 patients above 65 years of age with a first recurrence of a metastatic breast cancer. A total of 279 patients were eligible. The response rates were assessed for 258 fully evaluable patients and were the following for the TAM (N=94), the TAM+AG+H (N=83), and the TAM+FLU (N=81) groups, respectively, PR: 14, 18, and 21%, and CR: 20, 11, and 23%. The overall response rates are not statistically different (p=0.30). The 95% CL of difference in response rates for TAM vs. TAM+AG+H are –9–19% and for TAM vs. TAM+FLU –4–25%. Time to treatment failure was comparable with median values of 9.2, 7.7, and 9.2 months in the TAM, TAM+AG+H, and TAM+FLU group, respectively (p=0.17). The corresponding figures for survival are median times of 22.0, 24.1, and 21.1 months with a p-value of 0.62. Toxicity was more pronounced in both the combined treatment groups, and could in most instances be attributed to treatment with either AG+H or FLU. Currently, new specific aromatase inhibitors with lesser toxicity than AG are being evaluated in combination with TAM for treatment of primary and metastatic breast cancer. In conclusion, the simultaneous use of TAM and AG+H or FLU does not seem to improve the therapeutic efficacy in elderly postmenopausal patients with metastatic disease. So far, combined endocrine therapy in this group of patients should only be used in the context of clinical trials.     

The incidence of hepatocellular carcinoma in US white women with breast cancer after the introduction of tamoxifen in 1977

Summary It has been hypothesized that hepatocellular carcinoma might be a long-term adverse effect of tamoxifen therapy. Data from nine population-based cancer registries in the United States were used to investigate time trends in the incidence of hepatocellular carcinoma in white women previously diagnosed with invasive breast cancer during 1974–1987 and followed until 1989. Of particular interest were the rates after 1977, the year tamoxifen was licensed by the FDA. Compared to rates in all white women, no increased risk of hepatocellular carcinoma was found in women most likely to have received tamoxifen - those 50 years of age or more at diagnosis of breast cancer and diagnosed after 1977. These results suggest that tamoxifen does not cause a large increase in the incidence of hepatocellular carcinoma within the first decade after use. However, smaller and/or later increases in the risk for hepatocellular carcinoma are possible and warrant continued monitoring of women treated with tamoxifen.     

A phase III comparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer

Efficacy and safety of toremifene 60 and 240mg daily (TOR60 and TOR240) are compared to40 mg tamoxifen daily (TAM40) in postmenopausal womenwith advanced estrogen receptor (ER) positive or ERunknown breast cancer. The study is randomized andopen label in three parallel groups. Primary efficacyvariables are response rate and time to progression.WHO and ECOG criteria were used for measurableand nonmeasurable disease assessment, respectively. Safety was reportedaccording to WHO criteria. Altogether 463 patients wererandomized (157 to TOR60, 157 to TOR240, and149 to TAM40). By data cut-off, after 20.5months median follow-up time, over 70% of thepatients had experienced disease progression. Response rates are20.4%, 28.7%, and 20.8% in TOR60, TOR240, andTAM40, respectively. TOR60 and TAM40 show statistically equivalentefficacy and the difference between TOR240 and TAM40is not significant (P=0.112). Median timesto progression are 4.9 (TOR60), 6.1 (TOR240), and5.0 (TAM40) months and the corresponding hazard ratios(TAM:TOR) 1.015 and 1.124. Again, TOR60 and TAM40are statistically equivalent and the difference between TOR240and TAM40 is not significant (P=0.374).All treatments were well tolerated. As a conclusion,TOR60 and TAM40 show equivalent clinical efficacy andtolerability. The higher dose of toremifene slightly butnot statistically significantly improves response rate and timeto progression. In postmenopausal women, toremifene 60 mgdaily is an effective and safe treatment ofadvanced ER-positive or ER-unknown breast cancer.     

Association of tamoxifen use and increased diabetes among Asian women diagnosed with breast cancer

Background:

We conducted a population-based cohort study to assess whether tamoxifen treatment is associated with an increased incidence of diabetes.

Methods:

Data obtained from the Taiwanese National Health Insurance Research Database were used for a population-based cohort study. The study cohort included 22 257 breast cancer patients diagnosed between 1 January 2000 and 31 December 2004. Among them, 15 210 cases received tamoxifen treatment and 7047 did not. Four subjects without breast cancer were frequency-matched by age and index year as the control group. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariate Cox proportional hazards regression analysis.

Results:

Breast cancer patients exhibited a 14% higher rate of developing diabetes (adjusted HR=1.14, 95% CI=1.08–1.20) compared with non-breast cancer controls, but the significant difference was limited to tamoxifen users. In addition, tamoxifen users exhibited a significantly increased risk of diabetes compared with non-tamoxifen users among women diagnosed with breast cancer (adjusted HR=1.31, 95% CI=1.19–1.45). Stratification by age groups indicated that both younger and older women diagnosed with breast cancer exhibited a significantly higher risk of diabetes than the normal control subjects did, and tamoxifen users consistently exhibited a significantly higher diabetes risk than non-tamoxifen users or normal control subjects did, regardless of age. Both recent and remote uses of tamoxifen were associated with an increased likelihood of diabetes.

Conclusions:

The results of this population-based cohort study suggested that tamoxifen use in breast cancer patients might increase subsequent diabetes risk. The underlying mechanism remains unclear and further larger studies are mandatory to validate our findings.