The activity of letrozole in patients with advanced or recurrent endometrial cancer and correlation with biological markers – a study of the National Cancer Institute of Canada Clinical Trials Group

A multicenter phase II trial was conducted to define the activity of letrozole in postmenopausal women with recurrent or advanced endometrial carcinoma, who had no more than one prior line of progestins and never had chemotherapy (except adjuvant). Archival paraffin-embedded tumor samples were retrieved to determine the expression level of estrogen (ER) and progesterone receptor (PgR), p53, HER-2, bcl-2 and PTEN protein, and phosphorylation status of protein kinase B (PKB/Akt). Thirty-two eligible patients were treated with letrozole at 2.5 mg daily continuously, of whom 10 (31%) had prior progestins. Of the 28 patients evaluated for response, one complete and two partial responses were noted; overall response was 9.4% (95% confidence interval 2-25%). Eleven patients had stable disease for a median duration of 6.7 months (range 3.7-19.3 months). Amongst 22 patients who had tumor blocks available, the proportion showing positive expression of the following markers includes: PgR (86%), ER (86%), PTEN (82%), phosphorylated PKB/Akt (59%), bcl-2 (45%), p53 (32%), and HER-2 (0%). None of these markers correlated with response to letrozole or disease progression. In conclusion, letrozole is well tolerated but has little overall activity in this cohort of women with endometrial cancer.     

Aromatase inhibition reduces gonadotrophin dose required for controlled ovarian stimulation in women with unexplained infertility

BACKGROUND: Adding clomiphene citrate (CC) to FSH for controlled ovarian stimulation (COS) decreases FSH dose required for optimum stimulation. However, because of its anti-estrogenic effects, CC may be associated with lower pregnancy rates offsetting the FSH-dose reduction benefit. Previously, we reported the success of aromatase inhibition in inducing ovulation without antiestrogenic effects. METHODS: A prospective pilot study that included women with unexplained infertility undergoing COS and intrauterine insemination. Thirty-six women received the aromatase inhibitor letrozole + FSH, 18 women received CC + FSH and 56 women received FSH only. Each woman received one treatment regimen in one treatment cycle. All patients were given recombinant or highly purified FSH (50-150 IU/day) starting on day 3 to 7 until day of hCG. RESULTS: The FSH dose needed was significantly lower in letrozole + FSH and CC + FSH groups compared with FSH-only without a difference in number of follicles >1.8 cm. Pregnancy rate was 19.1% in the letrozole + FSH group, 10.5% in the CC + FSH group and 18.7% in the FSH-only group. Both pregnancy rate and endometrial thickness were significantly lower in CC + FSH group compared with the other two groups. Estradiol (E2) levels were significantly lower in the letrozole + FSH group compared with the other two groups. CONCLUSIONS: Similar to CC, aromatase inhibition with letrozole reduces FSH dose required for COS without the undesirable antiestrogenic effects sometimes seen with CC.     

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。     

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.     

McCune-Albright综合征患儿超说明书用药并文献复习

探讨甲羟孕酮、来曲唑和唑来膦酸超说明书用药的合理性。方法：1例6岁8个月男性患儿，出生时发现左臀部咖啡样色斑，4岁颅面部畸形，5岁时出现第二性征发育，同时出现骨龄超前，诊断为"McCune-Albright综合征"。入院后，相继给予甲羟孕酮片（4 mg bid po）+来曲唑片（1.25 mg qd po）+唑来膦酸注射液（3 mg once iv gtt）+碳酸钙片（250 mg qd po）和维生素AD滴剂（胶囊型）（1粒qdpo）治疗。结果：经过23 d的对症治疗后，患者一般情况及症状稳定，要求出院。结论：临床药师参与患者的药物治疗过程，对唑来膦酸和甲羟孕酮、来曲唑的超说明书用药有了进一步的认识，提高了药物的治疗水平。临床药师通过参与临床实践，协助医师参与患者的用药监护，提高药物治疗的安全性。     

Do men with normal testosterone–oestradiol ratios benefit from letrozole for the treatment of male infertility?

Research question

Previous studies of aromatase inhibitors on male infertility have focused on men with low testosterone–oestradiol ratio of less than 10. Can aromatase inhibitors improve spermatogenesis in men with idiopathic male infertility with normal testosterone–oestradiol ratio?

Suppressed estrogen supply via extra-ovarian progesterone receptor membrane component 1 in menopause

In post-menopausal women, intra-mammary estrogen, which is converted from extra-ovarian estrone (E1), promotes the growth of breast cancer. Since the aromatase inhibitor letrozole does not suppress 17β-estradiol (E2) production from E1, high intra-mammary E1 concentrations impair letrozole''s therapeutic efficacy. Progesterone receptor membrane component 1 (Pgrmc1) is a non-classical progesterone receptor associated with breast cancer progression. In the present study, we introduced a Pgrmc1 heterozygous knockout (hetero KO) murine model exhibiting low Pgrmc1 expression, and observed estrogen levels and steroidogenic gene expression. Naïve Pgrmc1 hetero KO mice exhibited low estrogen (E2 and E1) levels and low progesterone receptor (PR) expression, compared to wild-type mice. In contrast, Pgrmc1 hetero KO mice that have been ovariectomized (OVX), including letrozole-treated OVX mice (OVX-letrozole), exhibited high estrogen levels and PR expression. Increased extra-ovarian estrogen production in Pgrmc1 hetero KO mice was observed with the induction of steroid sulfatase (STS). In MCF-7 cell, letrozole suppressed PR expression, but PGRMC1 knockdown increased PR and STS expression. Our presented results highlight the important role of Pgrmc1 in modulating estrogen production when ovary-derived estrogen is limited, thereby suggesting a potential therapeutic approach for letrozole resistance.     

来曲唑联合地屈孕酮治疗不孕症疗效及对血清孕酮的影响

目的:研究来曲唑片和地屈孕酮片联合治疗不孕症的疗效及其对患者血清孕酮的影响。方法:选取在某院确诊为不孕症并接受治疗的患者100例作为研究对象,按照治疗方法的不同,将其均分为单一组和联合组两个组别。单一组患者在常规治疗基础上通过来曲唑片进行的单一治疗,联合组患者在对照组基础上通过地屈孕酮片进行治疗,对比两组患者治疗的效果及相关指标的变化。结果:联合组患者治疗的总有效率为90%,显著高于单一组患者的72%(P<0.05);联合组患者的排卵率、SP、E2、LH水平均有显著改善,且优于单一组患者(P<0.05)。结论:对于不孕症患者来说,相比于使用来曲唑片进行单一治疗,来曲唑片和地屈孕酮片联合治疗不仅可以有效提高治疗效果及妊娠率,而且可以更有效改善患者的血清孕酮等水平,因此值得推广。     

Controlled ovarian hyperstimulation with sequential letrozole co-treatment in normo/high responders

Objective: To investigate the effect of co-administration of letrozole in an ovarian stimulation protocol using recombinant FSH and GnRH antagonists for ICSI in normo/high responders.

Methods: Computerized data of 320 antagonist ICSI/ET cycles with or without letrozole were retrospectively analyzed. In 105 cases, letrozole (5?mg/day) was started at the second day of the cycle continued for 5 days. At the second day of letrozole, gonadotropins were added. The remaining 215 cases were stimulated with recombinant FSH only. In all cases on day 6, GnRH antagonist was started. Ovarian stimulation protocols with or without letrozole were compared for cycle outcome parameters.

Results: In cycles with letrozole, significantly lower gonadotropin consumption and lower peak estradiol levels were found. In cycles with letrozole, mean number of metaphase II and fertilized oocytes retrieved were significantly higher compared to cycles without letrozole. The pregnancy and clinical pregnancy rates were similar.

Conclusion: Should the number of oocytes retrieved being higher in letrozole group might indicate that letrozole might contribute to successful ovarian stimulation with a lower dosage of gonadotropins. Despite the lower peak estradiol levels, pregnancy rates being similar to other group also support the idea that letrozole can contribute to normal potential of implantation.     

Lapatinib nano-delivery systems: a promising future for breast cancer treatment

Introduction: Breast cancer stands the second prominent cause of death among women. For its efficient treatment, Lapatinib (LAPA) was developed as a selective tyrosine kinase inhibitor of receptors, overexpressed by breast cancer cells. Various explored delivery strategies for LAPA indicated its controlled release with enhanced aqueous solubility, improved bioavailability, decreased plasma protein binding, reduced dose and toxicity to the other organs with maximized clinical efficacy, compared to its marketed tablet formulation.

Areas covered: This comprehensive review deals with the survey, performed through different electronic databases, regarding various challenges and their solutions attained by fabricating delivery systems like nanoparticles, micelle, nanocapsules, nanochannels, and liposomes. It also covers the synthesis of novel LAPA-conjugates for diagnostic purpose.

Expert opinion: Unfortunately, clinical use of LAPA is restricted because of its extensive albumin binding capacity, poor oral bioavailability, and poor aqueous solubility. LAPA is marketed as the oral tablet only. Therefore, it becomes imperative to formulate alternate efficient multiparticulate or nano-delivery systems for administration through non-oral routes, for active/passive targeting, and to scale-up by pharmaceutical scientists followed by their clinical trials by clinical experts. LAPA combinations with capecitabine and letrozole should also be tried for breast cancer treatment.