瑞宁得治疗绝经后妇女晚期乳腺癌临床研究

目的 研究瑞宁得（ａｎａｓｔｒｏｚｏｌｅ）治疗绝经后妇女晚期乳腺癌的临床疗效和不良反应。方法 采用多中心开放非随机自身对照方法,６１例绝经妇女晚期乳腺癌患者口服瑞宁得每日１次,每次１ｍｇ连服４－６周,疗前２周内及治疗４周后的３天内检测血中雌二醇（Ｅ２）水平,同时评价疗效和不良反应。结果 ６０例可评价疗效和不良反应,部分缓解（ＰＲ）１３例,好转（ＭＲ）２例,缓解率２１．７％,有效率２５．０％,绝经时     

Assessing the risk of bone fracture among postmenopausal women who are receiving adjuvant hormonal therapy for breast cancer

ABSTRACT

Objective: To understand better the true impact of wide­spread adoption of adjuvant aromatase inhibitor (AI) therapy on postmenopausal breast cancer patients’ risk of bone fracture.

Methods: Data from three different studies were used to estimate the relative risk of bone fracture for each of the following groups of women (i.e., versus a control group of healthy postmenopausal women): (a) healthy postmenopausal women receiving tamoxifen; (b) post­menopausal women who had received treatment for early breast cancer; (c) postmenopausal breast cancer patients on adjuvant tamoxifen therapy; (d) postmenopausal breast cancer patients on adjuvant anastrozole therapy. The results of these analyses were then used to estimate the likely incidence of clinical fracture among such popula­tions in ‘real-life’ clinical practice.

Results: Breast cancer survivors were calculated to be at increased risk of clinical bone fracture (i.e., RR 1.15 vs. control group over 5 years). Breast cancer patients initiated on adjuvant anastrozole were also calculated to be at increased risk of bone fracture (RR = 1.36 vs. control group over 5 years), while the calculated risk of fracture among tamoxifen-treated breast cancer patients was similar to that observed in the control population (RR = 0.91).

Conclusion: Breast cancer patients are at increased risk of clinical bone fracture (compared with the general postmenopausal population) and adjuvant anastrozole therapy slightly adds to this risk. Importantly, however, the absolute risk of bone fracture appears to remain low in each of the evaluated patient populations, suggesting that fear of fracture should not prevent the initiation of adjuvant aromatase inhibitor therapy.     

Reduced breast cancer incidence in women treated with subcutaneous testosterone,or testosterone with anastrozole: A prospective,observational study

Objectives

There is evidence that androgens are breast protective and that testosterone therapy treats many symptoms of hormone deficiency in both pre and postmenopausal patients. However, unlike estrogen and progestins, there is a paucity of data regarding the incidence of breast cancer in women treated with testosterone therapy. This study was designed to investigate the incidence of breast cancer in women treated with subcutaneous testosterone therapy in the absence of systemic estrogen therapy.

Study design

This is a 5-year interim analysis of a 10-year, prospective, observational, IRB approved study investigating the incidence of breast cancer in women presenting with symptoms of hormone deficiency treated with subcutaneous testosterone (T) implants or, T combined with the aromatase inhibitor anastrozole (A), i.e., T + A implants. Breast cancer incidence was compared with that of historical controls reported in the literature, age specific Surveillance Epidemiology and End Results (SEER) incidence rates, and a representative, similar age group of our patients used as a ‘control’ group. The effect of adherence to T therapy was also evaluated.

Results

Since March 2008, 1268 pre and post menopausal women have been enrolled in the study and eligible for analysis. As of March 2013, there have been 8 cases of invasive breast cancer diagnosed in 5642 person-years of follow up for an incidence of 142 cases per 100 000 person-years, substantially less than the age-specific SEER incidence rates (293/100 000), placebo arm of Women's Health Initiative Study (300/100 000), never users of hormone therapy from the Million Women Study (325/100 000) and our control group (390/100 000). Unlike adherence to estrogen therapy, adherence to T therapy further decreased the incidence of breast cancer (73/100 000).

Conclusion

T and/or T + A, delivered subcutaneously as a pellet implant, reduced the incidence of breast cancer in pre and postmenopausal women. Evidence supports that breast cancer is preventable by maintaining a T to estrogen ratio in favor of T and, in particular, by the use of continuous T or, when indicated, T + A. This hormone therapy should be further investigated for the prevention and treatment of breast cancer.     

Reduced breast cancer incidence in women treated with subcutaneous testosterone,or testosterone with anastrozole: A prospective,observational study

ObjectivesThere is evidence that androgens are breast protective and that testosterone therapy treats many symptoms of hormone deficiency in both pre and postmenopausal patients. However, unlike estrogen and progestins, there is a paucity of data regarding the incidence of breast cancer in women treated with testosterone therapy. This study was designed to investigate the incidence of breast cancer in women treated with subcutaneous testosterone therapy in the absence of systemic estrogen therapy.Study designThis is a 5-year interim analysis of a 10-year, prospective, observational, IRB approved study investigating the incidence of breast cancer in women presenting with symptoms of hormone deficiency treated with subcutaneous testosterone (T) implants or, T combined with the aromatase inhibitor anastrozole (A), i.e., T + A implants. Breast cancer incidence was compared with that of historical controls reported in the literature, age specific Surveillance Epidemiology and End Results (SEER) incidence rates, and a representative, similar age group of our patients used as a ‘control’ group. The effect of adherence to T therapy was also evaluated.ResultsSince March 2008, 1268 pre and post menopausal women have been enrolled in the study and eligible for analysis. As of March 2013, there have been 8 cases of invasive breast cancer diagnosed in 5642 person-years of follow up for an incidence of 142 cases per 100 000 person-years, substantially less than the age-specific SEER incidence rates (293/100 000), placebo arm of Women's Health Initiative Study (300/100 000), never users of hormone therapy from the Million Women Study (325/100 000) and our control group (390/100 000). Unlike adherence to estrogen therapy, adherence to T therapy further decreased the incidence of breast cancer (73/100 000).ConclusionT and/or T + A, delivered subcutaneously as a pellet implant, reduced the incidence of breast cancer in pre and postmenopausal women. Evidence supports that breast cancer is preventable by maintaining a T to estrogen ratio in favor of T and, in particular, by the use of continuous T or, when indicated, T + A. This hormone therapy should be further investigated for the prevention and treatment of breast cancer.     

唑来膦酸或帕米膦酸二钠联合阿那曲唑治疗绝经后乳腺癌骨转移的疗效观察

目的 比较唑来膦酸和帕米膦酸二钠分别联合阿那曲唑治疗绝经后乳腺癌骨转移的临床疗效及不良反应。方法 收集2010年1月至2014年6月我院肿瘤科收治的绝经后乳腺癌骨转移患者51例,以随机数字表法分为对照组（n=27）和治疗组（n=24）。治疗组口服阿那曲唑（1 mg/d）联合唑来膦酸4 mg静滴;对照组口服阿那曲唑（1 mg/d）联合帕米膦酸二钠60 mg静滴,28 d为1个周期。观察两组骨痛缓解情况、骨转移灶清退情况、无骨相关事件（skeletal related evend,SRE）生存时间、总生存时间及不良反应。结果 治疗14　d后对照组和治疗组疼痛控制总有效率分别为66.7%和87.5%,差异有统计学意义（P＜0.05）;治疗56 d后对照组疼痛控制总有效率为77.8%,治疗组为91.7%,差异无统计学意义（P＞0.05）。治疗组的骨转移灶清退情况显著优于对照组,差异有统计学意义（P＜0.05）。对照组与治疗组中位无SRE生存时间为17.4个月和22.4个月,中位总生存时间为25.8个月和35.1个月,差异均有统计学意义（P＜0.05）。不良反应主要为发热、肌肉及骨酸痛等,给予对症治疗后缓解。结论 唑来膦酸联合阿那曲唑治疗绝经后乳腺癌骨转移疗效较好,不良反应可耐受,安全性良好,值得临床推广应用。     

Cost-effectiveness analysis of anastrozole versus tamoxifen as primary adjuvant therapy for postmenopausal women with early breast cancer: a US healthcare system perspective. The 5-year completed treatment analysis of the ATAC (‘Arimidex’, Tamoxifen Alone or in Combination) trial

Background This study evaluated the cost-effectiveness of anastrozole versus generic tamoxifen for primary adjuvant treatment of postmenopausal women with hormone receptor-positive (HR+) early breast cancer (EBC), from a US healthcare perspective. Methods A probabilistic Markov model was developed using the 5-year completed treatment analysis of the ATAC (‘Arimidex’, Tamoxifen Alone or in Combination) trial (ISRCTN 18233230) to project outcomes for anastrozole and tamoxifen to 25 years. Resource utilization data were obtained primarily from published literature and a physician survey (including expert opinion from ATAC Steering Committee members). Drug costs were taken from published wholesale acquisition costs (anastrozole $6.56/day, generic tamoxifen $1.33/day). Other unit costs ($US 2003–4) were from standard sources. Utility estimates of relevant health states, used to compute quality-adjusted life-years (QALYs), were collected using the standard gamble technique in a cross-sectional sample of 44 patients. Costs and benefits were discounted 3% annually. Results In a cohort of 1000 postmenopausal women with HR+ EBC, the model showed anastrozole treatment (versus tamoxifen) would lead to 257 QALYs gained (0.26 QALYs gained per patient), at an additional cost of $5.21 million over 25 years ($5,212 per patient). The estimated incremental cost-effectiveness ratio (ICER) of anastrozole compared with tamoxifen was $20,246 per QALY gained ($23,541 per life-year gained). Cost-effectiveness acceptability curves indicated a >90% probability that the cost per QALY gained with anastrozole would be <$50,000. Results were robust in a sensitivity analysis. Conclusion Anastrozole is a cost-effective alternative to tamoxifen for the primary adjuvant treatment of postmenopausal women with HR+ EBC.     

Résistances à l’hormonothérapie dans le cancer du sein

Résumé: La castration et le tamoxifène ont été pendant des décennies les principaux traitements antihormonaux des patientes atteintes de cancer du sein en situation métastatique et adjuvante. Depuis la possibilité d’utiliser en clinique de nouveaux agents antihormonaux, la connaissance des mécanismes de résistance à ces traitements suscite de plus en plus d’intérêt. Dans cette revue bréve, nous nous attacherons à décrire les principaux mécanismes de résistance permettant d’expliquer les nouvelles stratégies thérapeutiques dans cette population de cancers du sein hormonodépendants.      

Plasma Levels of Tamoxifen, N-Desmethyl Tamoxifen and Anastrozole in a Patient with Metastatic Breast Cancer and Chronic Hemodialysis

Endocrine therapy for hormone-sensitive breast cancer is a well-established treatment option, both in adjuvant and palliative settings. For patients undergoing chronic hemodialysis, only scant pharmacokinetic data have been published for tamoxifen, and no data have been published for anastrozole. We therefore measured plasma levels of tamoxifen, its major metabolite, N-desmethyl tamoxifen, and anastrozole in a breast cancer patient undergoing chronic hemodialysis. Clinical tolerability was good. The blood levels for tamoxifen, N-desmethyl tamoxifen and anastrozole were within the expected therapeutic ranges. From this study, we can conclude that endocrine therapy for breast cancer with tamoxifen or anastrozole seems feasible and safe for patients undergoing chronic hemodialysis.     

Cost-Benefit Analysis of Endocrine Therapy in the Adjuvant Setting for Postmenopausal Patients with Hormone Receptor-Positive Breast Cancer, Based on Survival Data and Future Prices for Generic Drugs in the Context of the German Health Care System

Background

Cost-effectiveness analyses have focused on aromatase inhibitors (AIs), but the results are inconsistent and disease-free survival has often been extrapolated to overall survival. The present study calculates the cost-effectiveness of 5 years of letrozole versus tamoxifen versus anastrozole in the context of the German health care system, using survival data from the Breast International Group (BIG) 1–98 study and the Arimidex, Tamoxifen, Alone or in Combination (ATAC) study and generic prices.

Materials and Methods

A hybrid model was developed that incorporates recurrence rates, overall survival, treatment costs and treatment-associated adverse events and the resulting costs. The basic assumption was that generic anastrozole would lead to a price reduction to 75% of the original price. Further analyses were carried out with 50% and 25% of the original prices for anastrozole and letrozole.

Results

The cost-benefit model showed a gain of 0.3124 or 0.0659 quality-adjusted life years (QALYs) for letrozole or anastrozole. Incremental costs of € 29,375.15/QALY for letrozole (100% of original price) were calculated and € 94,648.03/QALY for anastrozole (75% of original price). Marked increases in cost-effectiveness are observed with further decreases in price (anastrozole: 50% price € 54,715.17/QALY, 25% price € 14,779.57/QALY; letrozole 75% price € 20,988.59/QALY, 50% price € 12,602.03/QALY, 25% price € 4,215.46/QALY).

Conclusion

The present model including the inverse probability of censoring weighted analysis (IPCW) for letrozole and generic prices for both AIs shows that letrozole is cost effective.     

Development and validation of an improved high-throughput method for the determination of anastrozole in human plasma by LC-MS/MS and atmospheric pressure chemical ionization

In the present study, an automated, 96-well format LC-MS/MS method for the determination of anastrozole in human plasma was developed and fully validated. Within method development procedure, atmospheric pressure chemical ionization (APCI) and electrospray ionization (ESI) were compared in terms of sensitivity and specificity, with the former proven to be more appropriate and thus being chosen for analyte ionization. In addition, the effect of declustering potential (DP) and collision energy (CE) in sensitivity was, as well, studied and compared between APCI and ESI source employment. Samples were treated with an acetonitrile (ACN) protein precipitation step followed by liquid-liquid extraction (LLE) with methyl t-butyl ether (MTBE) as the organic solvent, using omeprazole as the internal standard (IS). The statistical evaluation for the APCI protocol revealed excellent linearity, accuracy and precision values for the range of concentrations 0.100-100 ng/mL. The method proposed involves the lowest plasma volume so far reported (190 microL), as well as the shortest run time (1.6 min) and along with the employment of two robotic liquid handling systems enabled the rapid and reliable determination of anastrozole in a bioequivalence study (>1000 plasma samples) after per os administration of 1mg tablet within a 4-day period of time.