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西達本胺（妥西司他,、妥諾司他）是中國自主研發(fā)的國際首個亞型選擇性組蛋白去乙?；福℉DAC）口服抑制劑，2014年獲得批準(zhǔn)上市,，用于治療復(fù)發(fā)及難治性的外周T細(xì)胞淋巴瘤,。表觀遺傳異常是腫瘤患者產(chǎn)生繼發(fā)耐藥的重要生物學(xué)基礎(chǔ)，乳腺癌耐藥機制前期研究表明,，西達本胺作為選擇性表觀遺傳調(diào)控劑,，可以改善耐藥,，并且增加第三代甾體類芳香酶不可逆滅活劑依西美坦的敏感性，對于激素受體陽性晚期乳腺癌表現(xiàn)出令人鼓舞的抗腫瘤初步活性,。 2019年4月26日，英國《柳葉刀》腫瘤學(xué)分冊在線發(fā)表中國人民解放軍總醫(yī)院第五醫(yī)學(xué)中心江澤飛,、吉林大學(xué)第一醫(yī)院李薇,、復(fù)旦大學(xué)附屬腫瘤醫(yī)院胡夕春、黑龍江省腫瘤醫(yī)院張清媛,、遼寧省腫瘤醫(yī)院孫濤,、河南省腫瘤醫(yī)院崔樹德、中山大學(xué)附屬腫瘤醫(yī)院王樹森,、湖南省腫瘤醫(yī)院歐陽取長,、江蘇省人民醫(yī)院殷詠梅、河北省腫瘤醫(yī)院耿翠芝,、天津醫(yī)科大學(xué)腫瘤醫(yī)院佟仲生,、吉林省腫瘤醫(yī)院程穎、安徽省立醫(yī)院潘躍銀,、濟南市中心醫(yī)院孫玉萍,、南昌市第三醫(yī)院王紅、北京大學(xué)腫瘤醫(yī)院歐陽濤,、安徽醫(yī)科大學(xué)第一附屬醫(yī)院顧康生,、江蘇省腫瘤醫(yī)院馮繼鋒、浙江省腫瘤醫(yī)院王曉稼,、北京大學(xué)深圳醫(yī)院王樹濱,、復(fù)旦大學(xué)附屬中山醫(yī)院劉天舒、滄州市中心醫(yī)院高敬華,、美國芝加哥西北大學(xué)范伯格醫(yī)學(xué)院馬西莫·克里斯托凡尼,、深圳微芯生物科技寧志強和魯先平等學(xué)者的研究報告，比較了依西美坦±西達本胺治療激素受體陽性晚期乳腺癌絕經(jīng)后患者的有效性和安全性,。 ACE: A Phase III Trial of Chidamide in Combination With Exemestane in Patients With Hormone Receptor-Positive Advanced Breast Cancer (NCT02482753) 該全國多中心隨機雙盲安慰劑對照三期研究于2015年7月20日～2017年6月26日從中國22家癌癥?？浦行?/span>入組激素受體陽性HER2陰性乳腺癌至少一輪內(nèi)分泌治療（晚期或轉(zhuǎn)移或輔助治療）后疾病復(fù)發(fā)或進展、至少有一個可測量病變,、各個器官功能正常,、東部腫瘤學(xué)協(xié)作組（ECOG）體力狀態(tài)評分0～1、血液學(xué)和生化指標(biāo)正常的絕經(jīng)后女性（年齡≥60歲或年齡<60歲如其血清卵泡刺激素和雌二醇濃度處于絕經(jīng)后范圍）患者365例,。通過交互式網(wǎng)絡(luò)反饋系統(tǒng)動態(tài)隨機方案,，將患者按2∶1隨機分組，每周兩次口服西達本胺30毫克（244例）或安慰劑（121例）,。兩組所有患者每天口服依西美坦25毫克,。根據(jù)內(nèi)臟轉(zhuǎn)移與否對隨機化進行分層,。患者、研究者,、研究當(dāng)?shù)毓ぷ髡?、資助者對治療分組均盲。主要終點為研究者評定的無進展生存,。對全部分析人群進行療效分析,，包括接受至少一次研究治療的所有患者，并且對接受至少一次研究治療和完成至少一份病例安全性報告表格的所有患者進行安全性分析,。該研究已經(jīng)達到對主要終點進行最終分析所需的事件數(shù)量,。該試驗已經(jīng)結(jié)束入組患者，目前正在進行總生存隨訪,。 結(jié)果,，經(jīng)過中位隨訪13.9個月（四分位：9.8～17.5），西達本胺組,、安慰劑組的中位無進展生存分別為7.4,、3.8個月（95%置信區(qū)間：5.5～9.2、3.7～5.5）,，進展或死亡風(fēng)險顯著減少25%（風(fēng)險比：0.75,，95%置信區(qū)間：0.58～0.98，P=0.033）,。 西達本胺組,、安慰劑組最常見的3～4級不良事件發(fā)生率：
因此,，該研究結(jié)果表明，對于既往內(nèi)分泌治療失敗的激素受體陽性HER2陰性晚期乳腺癌患者,，西達本胺＋依西美坦與安慰劑＋依西美坦相比,，無進展生存顯著延長，進展或死亡風(fēng)險顯著減少,，3～4級血液學(xué)不良事件較多,。西達本胺＋依西美坦可以作為此類患者的治療新選擇。 對此,，哈佛大學(xué)醫(yī)學(xué)院,、麻省總醫(yī)院癌癥中心發(fā)表同期評論：從遺傳學(xué)到表觀遺傳學(xué)，靶向激素受體陽性乳腺癌的組蛋白去乙?；?。 利益聲明：馬西莫·克里斯托凡尼教授為輝瑞,、諾華等公司顧問，寧志強博士為深圳微芯生物科技副總經(jīng)理,，魯先平博士為深圳微芯生物科技董事長兼總經(jīng)理,，所有其他作者均未聲明任何利益沖突。 相關(guān)閱讀 Lancet Oncol. 2019 Apr 26. [Epub ahead of print] Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Zefei Jiang, Wei Li, Xichun Hu, Qingyuan Zhang, Tao Sun, Shude Cui, Shusen Wang, Quchang Ouyang, Yongmei Yin, Cuizhi Geng, Zhongsheng Tong, Ying Cheng, Yueyin Pan, Yuping Sun, Hong Wang, Tao Ouyang, Kangsheng Gu, Jifeng Feng, Xiaojia Wang, Shubin Wang, Tianshu Liu, Jinghua Gao, Massimo Cristofanilli, Zhiqiang Ning, Xianping Lu. The Fifth Medical Centre of Chinese PLA General Hospital, Beijing, China; The First Hospital of Jilin University, Changchun, China; Fudan University Shanghai Cancer Centre, Shanghai, China; Harbin Medical University Cancer Hospital, Harbin, China; Liaoning Cancer Hospital & Institute, Shenyang, China; Henan Cancer Hospital, Zhengzhou, China; Sun Yat-Sen University Cancer Centre, Guangzhou, China; Hunan Cancer Hospital, Changsha, China; Jiangsu Province Hospital, Nanjing, China; Tumour Hospital of Hebei Province, Shijiazhuang, China; Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Jilin Cancer Hospital, Changchun, China; Anhui Provincial Hospital, Hefei, China; Jinan Central Hospital, Jinan, China; The Third Hospital of Nanchang, Nanchang, China; Beijing Cancer Hospital, Beijing, China; The First Affiliated Hospital of Anui Medical University, Hefei, China; Jiangsu Cancer Hospital, Nanjing, China; Zhejiang Cancer Hospital, Hangzhou, China; Beijing University Shenzhen Hospital, Shenzhen, China; Fudan University Zhongshan Hospital, Shanghai, China; Cangzhou Central Hospital, Cangzhou, China; Feinberg School of Medicine, Chicago, IL, USA; Chipscreen Biosciences, Shenzhen, China. BACKGROUND: Tucidinostat (formerly known as chidamide) is an oral subtype-selective histone deacetylase inhibitor. In an exploratory study, the combination of tucidinostat with exemestane showed preliminary signs of encouraging anti-tumour activity in patients with advanced hormone receptor-positive breast cancer. To build on these findings, we aimed to assess the efficacy and safety of this combination in a randomised trial in a larger population of postmenopausal patients with advanced, hormone receptor-positive breast cancer. METHODS: We did the randomised, double-blind, placebo-controlled, phase 3 ACE trial at 22 specialist cancer centres in China. Eligible patients were postmenopausal women (aged ≥60 years or aged <60 years if their serum follicle-stimulating hormone and oestradiol concentrations were within postmenopausal ranges) with hormone receptor-positive, HER2-negative breast cancer, whose disease had relapsed or progressed after at least one endocrine therapy (either in advanced or metastatic or adjuvant setting), and who had at least one measurable lesion, adequate organ function, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate haematological and biochemical parameters. Endocrine therapy did not have to be the most recent therapy before randomisation, but recurrence or progression after the most recent therapy was a prerequisite. Patients were randomly assigned (2:1) by a dynamic randomisation scheme via an interactive web-response system to receive 30 mg oral tucidinostat or placebo twice weekly. All patients in both groups also received 25 mg oral exemestane daily. Randomisation was stratified according to the presence of visceral metastases (yes vs no). Patients, investigators, study site staff, and the sponsor were masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival. Efficacy analyses were done in the full analysis set population, comprising all patients who received at least one dose of any study treatment, and safety analyses were done in all patients who received at least one dose of any study treatment and for whom at least one safety case report form was available. This study is registered with ClinicalTrials.gov, number NCT02482753. The study has reached the required number of events for final analysis of the primary endpoint. The trial is no longer enrolling patients, but follow-up for investigation of overall survival is ongoing. FINDINGS: Between July 20, 2015, and June 26, 2017, 365 patients were enrolled and randomly assigned, 244 to the tucidinostat group and 121 to the placebo group. The median duration of follow-up was 13.9 months (IQR 9.8-17.5). Investigator-assessed median progression-free survival was 7.4 months (95% CI 5.5-9.2) in the tucidinostat group and 3.8 months (3.7-5.5) in the placebo group (HR 0.75 [95% CI 0.58-0.98]; p=0.033). The most common grade 3 or 4 adverse events in either group were neutropenia (124 [51%] of 244 patients in the tucidinostat group vs three [2%] of 121 patients in the placebo group), thrombocytopenia (67 [27%] vs three [2%]), and leucopenia (46 [19%] vs three [2%]). Serious adverse events of any cause occurred in 51 (21%) of 244 patients in the tucidinostat group and seven (6%) of 121 patients in the placebo group. No treatment-related deaths were reported. INTERPRETATION: Tucidinostat plus exemestane improved progression-free survival compared with placebo plus exemestane in patients with advanced, hormone receptor-positive, HER2-negative breast cancer that progressed after previous endocrine therapy. Grade 3-4 haematological adverse events were more common in the tucidinostat plus exemestane group than in the placebo plus exemestane group. Tucidinostat plus exemestane could represent a new treatment option for these patients. FUNDING: Chipscreen Biosciences DOI: 10.1016/S1470-2045(19)30164-0 Lancet Oncol. 2019 Apr 26. [Epub ahead of print] Genetics to epigenetics: targeting histone deacetylases in hormone receptor-positive metastatic breast cancer. Seth A Wander, Laura M Spring, Aditya Bardia. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. DOI: 10.1016/S1470-2045(19)30279-7
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