芳香酶抑制剂依西美坦(Exemestane)的合成

目的 :合成依西美坦并改进合成工艺。方法 :以雄甾烯二酮为原料 ,经 Mannich反应、溴化、脱溴等数步反应制得依西美坦。结果 :所得产物经元素分析、紫外光谱、红外光谱、核磁共振谱及质谱等确证了结构。结论

Exploratory clinical study of chidamide,an oral subtype-selective histone deacetylase inhibitor,in combination with exemestane in hormone receptor-positive advanced breast cancer

Objective: The recurrence or progression under endocrine therapy in hormone receptor-positive(HR+)advanced breast cancer(ABC) remained a critical clinical challenge.Chidamide is an oral subtype-selective histone deacetylase(HDAC) inhibitor with multiple functions in tumor growth inhibition and microenvironment modulation via epigenetic reprogramming.The purpose of this study was to evaluate the safety,pharmacokinetics(PK),and preliminary efficacy of chidamide in combination with exemestane in HR+ ABC patients.Methods: Eligible patients were postmenopausal women with HR+ ABC recurrent or progressed to at least one endocrine therapy.Blood samples were obtained in the run-in period and the first day of combination treatment for PK analysis.In combination treatment,patients were given exemestane 25mg daily and chidamide 30mg twice a week(BIW) until progression of disease or intolerable toxicities.A treatment cycle was defined as 4 weeks.Safety,PK parameters,and preliminary efficacy were evaluated.Results: A total of 20 patients were enrolled between July and December,2015.The median number of treatments cycle was 5.2(20.8 weeks) with 2 patients still on treatment at the data cut-off date of October,2017.The treatment-related adverse events(AE) ≥ grade 3 in more than 2 patients were neutropenia(35%),thrombocytopenia(30%),and leucopenia(20%).The plasma exposure of exemestane was consistent in the presence or absence of chidamide.A slight increase in chidamide exposure was noted in the presence of exemestane,probably due to the inter-and intra-patient variations.The best response in 16 evaluable patients was assessed by Response Evaluation Criteria in Solid Tumors(RECIST),including 4 patients with partial response,10 patients with stable disease.The median progression-free survival(PFS) was 7.6 months.Conclusions: The combination of chidamide with exemestane was generally well tolerated with promising preliminary efficacy in HR+ ABC patients.The overall results from this study encourage further pivotal trial in this patient population.

Adjuvant tamoxifen switched to exemestane treatment in postmenopausal women with estrogen receptor-positive early breast cancer:A pragmatic,multicenter,and prospective clinical trial in China

Objective:This post-approval safety study assessed the efficacy and safety of exemestane after 2-3 years of tamoxifen treatment among postmenopausal women with estrogen receptor-positive(ER+)early breast cancer in China.Methods:Enrolled patients had received 2-3 years of tamoxifen and were then switched to exemestane for completion of 5 consecutive years of adjuvant endocrine therapy.The primary endpoint was the time from enrollment to the first occurrence of locoregional/distant recurrence of the primary breast cancer,appearance of a second primary or contralateral breast cancer,or death due to any cause.Other endpoints included the proportion of patients experiencing each event,incidence rate per annum,relationships between human epidermal growth factor receptor 2 status and time to event,and relationship between disease history variables and time to event.Results:Overall,558 patients were included in the full analysis set:397(71.1%)completed the study,20experienced an event,and 141 discontinued[47 owing to an adverse event(AE);37 no longer willing to participate].Median duration of treatment was 29.5(range,0.1-57.7)months.Median time to event was not reached.Eventfree survival probability at 36 months was 91.4%(95%CI,87.7%-95.1%).The event incidence over the total exposure time of exemestane therapy was 3.5 events/100 person-years(20/565).Multivariate analysis showed an association between tumor,lymph node,and metastasis stage at initial diagnosis and time to event[hazard ratio:1.532(95%CI,1.129-2.080);P=0.006].Most AEs were grade 1 or 2 in severity,with arthralgia(7.7%)being the most common treatment-related AE.Conclusions:This study supports the efficacy and safety of exemestane in postmenopausal Chinese women with ER+breast cancer previously treated with adjuvant tamoxifen for 2-3 years.No new safety signals were identified in the Chinese population.

Diagnosis and guidance of treatment of breast cancer cutaneous metastases by multiple needle biopsy: A case report

BACKGROUND Breast cancer patients have a high skin metastasis rate.However,reports on treatment of cutaneous metastases of breast cancer are scarce.CASE SUMMARY We report the treatment process for one breast cancer case with bone,lung,and skin metastases.The patient was a 43-year-old woman with advanced breast cancer and skin metastasis.She underwent pathological diagnosis by needle biopsy to guide the treatment.When the disease progressed,a new pathological diagnosis was determined by needle biopsy to guide the treatment.The patient received chemotherapy,endocrine therapy,and photodynamic dynamic therapy,followed by sonodynamic therapy.CONCLUSION Repeated puncture should be performed for advanced breast cancer with skin metastasis,in order to obtain the pathology and directly determine diagnosis when the disease progresses.The treatment should focus on controlling the systemic metastasis,rather than the local disease.

依西美坦与阿那曲唑用于绝经后激素受体阳性乳腺癌患者辅助治疗的对比研究

Paul E．Goss等在2013年31卷11期（Journal of Clinical Oncology））发表题为《Exemestane versus anastrozole in postmenopausal women with eady breast cancer：NCICCTGMA．27-a randomized controlled phase Ⅲ trial》的论著，