Comparison of two-year and five-year tamoxifen use in Japanese post-menopausal women

AIM: Large multicenter, randomized trials have revealed the advantages of using tamoxifen for 5 years vs 2 years in breast cancer patients. The aim of this report is to confirm the optimal duration of tamoxifen administration in a study of Japanese breast cancer patients. METHODS: Japanese post-menopausal estrogen receptor-positive breast cancer patients treated with mastectomy were randomly assigned to either a 5-year or 2-year course of tamoxifen. The primary endpoint was disease-free survival, with secondary endpoints of overall survival and a reduction in the development of metachronous contra-lateral breast cancer. RESULTS: A total of 256 breast cancer patients were randomized to a 5-year or 2-year tamoxifen administration group. After a median follow-up time of 81 months, there were no significant differences seen in terms of disease-free or overall survival (p=0.65 and 0.56, respectively). Furthermore, the impact of the 5-year use of tamoxifen on the development of contra-lateral breast cancer did not reach statistical significance (p=0.0511). However, 5-year tamoxifen use was closely associated with gynaecological complications (p=0.0081). CONCLUSION: We could not show a beneficial effect of using tamoxifen for 5 years over 2 years in Japanese estrogen receptor-positive patients. This is likely due to the small number of patients enrolled in our study; however, racial disparity may influence this result. A reevaluation is necessary to study the advantages of the 5-year use of tamoxifen in the Japanese racial subgroup.     

TCMP方案治疗对常规化疗耐药的复发转移性乳腺癌

目的:为评估由三苯氧胺、环磷酰胺、氨甲喋呤和顺铂组成的TCMP方案对常规化疗耐药后复发转移性乳腺癌的疗效.方法:25例对常规化疗耐药的复发转移性乳腺癌患者接受TCMP方案化疗.给药方法是三苯氧胺,10mg,口服,每天2次;环磷酸胺,0.8～1.0,静推,第1天;氨甲喋呤,40mg,肌注,第1、8天;顺铂40mm,静滴,第1～4天.23例患者有客观评价指标,均接受TCMP方案化疗最小2周期.结果:23例可评价患者中,总客观有效率为52.17%(95%可信区间31～73%),其中2例CR,10例PR.经Ridit检验治疗效果与雌激素受体状态无关.结论:以上提示TCMP方案对常规治疗耐药后复发转移性乳腺癌有较好疗效,三苯氧胺与以顺铂为主化疗方案在乳腺癌的治疗中有协同作用.     

雌激素和血管内皮细胞生长因子促进血管瘤增殖的体外实验研究

目的：研究雌二醇(E2)和血管内皮细胞生长因子(VEGF)在促进血管瘤血管内皮细胞(HVEC)增殖中的作用和相互关系，以及4羟基他莫昔芬(4OH—TAM)对该促进作用的影响。方法：取2例雌激素受体阳性的皮肤增生期草莓状血管瘤标本，采用组织块培养法培养HVEC。HVEC原代及传代培养在M199培养液中进行，传至第三代时改用无雌激素培养液IMEM进行干预实验，实验分5组：组1(无干预，为对照组)、组2(加E2)、组3(加VEGF)、组4(加E2和VEGF)、组5(加E，、VEGF和4OH—TAM)。分别在0、3、6、9d进行细胞计数(CC)和流式细胞仪DNA增殖指数(PI)检测。结果例1在第9d时，组2示HVEC轻微增殖，CC和PI分别为组1的1．38倍和1．61倍；组3示CC及PI明显增加，分别为组2的2．10倍和1．61倍；组4示OC及PI的增加更加显著，分别是组3的1．62倍和1．40倍；组5的OC和PI与组1相仿。例2的实验结果与例1相似。结论：体外实验显示雌激素能够轻微促进HVEC增殖；VEGF可明显促进HVEC增殖；而雌激素和VEGF同时存在时，对HVEC的促增殖作用更加显著，二者存在协同作用；他莫昔芬能抑制这种协同促增殖作用。     

他莫昔芬和莪术油联合治疗大鼠子宫内膜异位症的实验研究

目的观察选择性雌激素受体调节剂他莫昔芬（TAM）与中药促细胞凋亡剂（莪术提取物）联合用药对大鼠子宫内膜异位症的治疗效果。方法建立雌性大鼠子宫内膜异位症模型，随机分为对照组，TAM、阿拉瑞林（GnRHa）和TAM＋莪术油治疗组，治疗4周后观察异位内膜生长情况，切取在位与异位子宫内膜，行HE染色观察组织形态学变化，SP免疫组化法检测异位内膜血管内皮生长因子（VEGF）的表达。结果各治疗组治疗后异位内膜体积较治疗前及对照组减小（P〈0．05）；治疗后各治疗组异位内膜的VEGF表达评分较对照组少，其差异有统计学意义（P〈0．05）；治疗后TAM组与阿拉瑞林（GnRHa）组、TAM组与TAM＋莪术油组异位内膜VEGF表达评分差异有统计学意义（P〈0．05）。结论TAM结合莪术油可使大鼠异位内膜病灶缩小，病灶VEGF表达降低。     

绝经期乳腺癌妇女服用他莫昔芬后Ki-67及Bcl-2在子宫内膜中的表达

目的:评估绝经期乳腺癌妇女服用他莫昔芬(tamoxifen,TAM)后Ki-67及Bcl-2在子宫内膜中的表达。方法:46例绝经后因乳腺癌服用TAM超过6个月妇女的子宫内膜为研究组,行宫腔镜检查及内膜活检。18例因子宫脱垂行子宫切除的绝经后妇女的萎缩型子宫内膜为对照组。用免疫组化法测定Ki-67及Bcl-2在子宫内膜中的表达。结果:与对照组比较,Ki-67在TAM相关内膜腺上皮细胞呈显著高表达(15.41±4.83vs9.05±5.52,P=0.009);Bcl-2在TAM相关内膜腺上皮细胞呈较高表达,但与对照组比较无统计学差异(0.50±0.17vs0.43±0.11,P=0.077)。结论:绝经后乳腺癌妇女服用TAM能引起子宫内膜细胞增殖,但并不代偿性促进细胞凋亡,诱导细胞增殖是TAM对绝经后子宫内膜作用机理的一部分。     

Diagnostic accuracy of sonohysterography in the evaluation of uterine cavities in tamoxifen administered asymptomatic postmenopausal breast cancer patients with endometrial thickness ≥5 mm

To evaluate diagnostic efficacy of transvaginal saline infusion sonohysterography (TV-SHG) in the evaluation of uterine cavities in tamoxifen (TAM) administered asymptomatic postmenopausal breast cancer patients with increased endometrial thickness, sixty asymptomatic postmenopausal breast cancer women receiving adjuvant TAM treatment for at least 6 months and with endometrial thickness’ ≥5 mm measured in transvaginal ultrasonography (TVS) were enrolled. Each patient underwent TV-SHG, followed by outpatient hysteroscopy (HYS) with endometrial biopsy. TV-SHG application was accepted as unsuccessful in four cases (6.7%). When office HYS combined biopsy was considered as gold standard, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of TV-SHG were estimated as 90%, 100%, 100%, and 95%, respectively. Our findings showed that TV-SHG was a valuable diagnostic tool in the evaluation of uterine cavities of TAM administered asymptomatic postmenopausal patients having an increased endometrial thickness.     

David Kupfer,Ph.D. A Mentor and a Scientist

I worked with the late Dr. David Kupfer for nearly nine years at the Worcester Foundation/University of Massachusetts Medical School, Worcester, MA. I was involved in the metabolism of methoxychlor and tamoxifen, the areas of research close to David's heart. We demonstrated the metabolic pathways of these compounds in rats and humans, and the covalent binding to microsomal proteins that could result in long-term toxic manifestations. I learned a lot from David, who was a mentor and friend/colleague. His death has left a void in my heart and he will be sorely missed.     

The Role of Flavin-Containing Monooxygenase (FMO) in the Metabolism of Tamoxifen and Other Tertiary Amines

Tamoxifen is utilized in breast cancer therapy and in chemoprevention. Tamoxifen may enhance risk for other neoplasias, especially endometrial cancer. The risk:benefit depends on the rate of metabolic activation versus detoxication. Cytochrome P450-dependent α-hydroxylation, followed by sulfonation, represents a metabolic activation pathway, producing products capable of covalent DNA adduction. In contrast, tamoxifen N-oxygenation represents a detoxication pathway, with the caveat that N-oxides can be reduced back to the parent amines. The N-oxygenation pathway will be the focus for this review. Dr. David Kupfer pioneered studies on cytochrome P450 and flavin-containing monooxygenase (FMO) tamoxifen metabolism. We collaborated with Dr. Kupfer's laboratory and recently determined that the low level of tamoxifen N-oxide production in human liver microsomes may be explained by the kinetics of FMO1 versus FMO3.     

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.     

David Kupfer: A Career Retrospective

David Kupfer's research career spanned 50 years and he authored or co-authored over 160 papers and book chapters. Although best known for his work centering on cytochrome P450 metabolism of prostaglandins, steroids, and proestrogenic compounds, David's research also contributed key advances in the areas of P450 induction and catalytic mechanism, breast cancer therapy, and analytical methodology. His research is reviewed here.