他莫昔芬→依西美坦的早期乳腺癌患者十年随访最终分析
2017年5月3日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表英国伦敦大学癌症研究院、英国癌症研究中心、伦敦帝国学院、辛格尔顿医院、韦斯顿帕克医院、萨塞克斯大学、圣詹姆斯医院、西班牙圣塞巴斯蒂安医院、瑞士国际乳腺癌研究组织、澳大利亚悉尼大学、波兰格但斯克医科大学、美国肿瘤研究网络、挪威卑尔根大学、德国雷根斯堡大学、荷兰莱顿大学、丹麦奥胡斯大学、意大利国家肿瘤研究所、热那亚大学、圣马蒂诺医院、瑞典萨赫尔格雷斯卡大学、比利时鲁汶大学的组间依西美坦研究队列最终疗效分析报告。
该国际（37个国家）多中心（366个中心）大样本（4724例）随机对照研究（国际标准随机对照研究编号：ISRCTN11883920）于1998～2003年入组他莫昔芬内分泌辅助疗法2～3年后仍未发病的早期单侧浸润性乳腺癌绝经后患者，随机分配继续使用他莫昔芬（2372例）或改用依西美坦（2352例），以完成5年辅助内分泌疗法。2007年《柳叶刀》发表的中期分析已经证明改用依西美坦有利于改善临床疗效。
由于现在已有大量非乳腺癌所致死亡报告，无乳腺癌生存成为大家关心的主要生存终点。该最终分析对象为其中雌激素受体阳性或未知的患者4599例（依西美坦组2294例，他莫昔芬组2305例）。
结果发现，中位随访10年后（数据截至2013年9月4日），在雌激素受体阳性或雌激素受体状态未知的人群中，观察到无乳腺癌生存事件（原有乳腺癌的局部或远处复发、新的同侧或对侧原发性乳腺癌、不伴疾病复发的死亡）1111例，其中依西美坦组508例（22.1%）、他莫昔芬组603例（26.2%），两组之间10年数据绝对差为4.0%（95%置信区间：1.2%～6.7%）、风险比为0.81（95%置信区间：0.72～0.92，P＜0.001），即依西美坦组的风险减少19%。
通过多变量分析，校正淋巴结状态、既往使用激素替代治疗方案、既往化疗方案等影响因素后，两组之间仍有显著差异（风险比为0.80，95%置信区间：0.71～0.90，P＜0.001），即依西美坦组的风险减少20%。
依西美坦组与他莫昔芬组相比，总生存略改善：
在雌激素受体阳性或雌激素受体状态未知的人群中，两组之间10年绝对差2.1%（95%置信区间：-0.5%～4.6%）、风险比为0.89（95%置信区间：0.78～1.01，P=0.08）。
在全体意向治疗人群中，两组绝对差为1.6%（95%置信区间：-0.9%～4.1%）、风险比为0.91（95%置信区间：0.80～1.03，P=0.15）。
两组治疗后报告骨折事件的患者比例无统计学差异。
因此，组间依西美坦研究以及同期研究已经表明，他莫昔芬使用2～3年后改用芳香酶抑制剂的策略，可以带来减少疾病复发和乳腺癌死亡率的长期获益。
该研究得到了依西美坦研发者辉瑞（阿诺新）的资助。
J Clin Oncol. 2017 May 3. [Epub ahead of print]
Long-Term Follow-Up of the Intergroup Exemestane Study.
Morden JP, Alvarez I, Bertelli G, Coates AS, Coleman R, Fallowfield L, Jassem J, Jones S, Kilburn L, Lonning PE, Ortmann O, Snowdon C, van de Velde C, Andersen J, Del Mastro L, Dodwell D, Holmberg S, Nicholas H, Paridaens R, Bliss JM, Coombes RC.
The Institute of Cancer Research; Cancer Research UK; Imperial College London, London; Singleton Hospital, Swansea; Weston Park Hospital, Sheffield; University of Sussex, Brighton; St James Hospital, Leeds, United Kingdom; Hospital Donostia, San Sebastian, Spain; International Breast Cancer Study Group, Bern, Switzerland; University of Sydney, Sydney, Australia; Medical University of Gdansk, Gdansk, Poland; US Oncology Research, The Woodlands, TX; University of Bergen and Haukeland University Hospital, Bergen, Norway; University Medical Center Regensburg, Regensburg, Germany; Leiden University Medical Centre, Leiden, the Netherlands; Aarhus University Hospital, Aarhus, Denmark; IRCCS Azienda Ospedaliera Universitaria San Martino IST, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; Sahlgrenska Universitetssjukhuset, Goteborg, Sweden; Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium.
PURPOSE: The Intergroup Exemestane Study, an investigator-led study of 4,724 postmenopausal patients with early breast cancer (clinical trial information: ISRCTN11883920), has previously demonstrated that a switch from adjuvant endocrine therapy after 2 to 3 years of tamoxifen to exemestane was associated with clinically relevant improvements in efficacy. Here, we report the final efficacy analyses of this cohort.
PATIENTS AND METHODS: Patients who remained disease free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to exemestane to complete a total of 5 years of adjuvant endocrine therapy. Given the large number of non-breast cancer-related deaths now reported, breast cancer-free survival (BCFS), with censorship of intercurrent deaths, was the primary survival end point of interest. Analyses focus on patients with estrogen receptor-positive or unknown tumors (n = 4,599).
RESULTS: At the time of the data snapshot, median follow-up was 120 months. In the population that was estrogen receptor positive or had unknown estrogen receptor status, 1,111 BCFS events were observed with 508 (22.1%) of 2,294 patients in the exemestane group and 603 (26.2%) of 2,305 patients in the tamoxifen group. The data corresponded to an absolute difference (between exemestane and tamoxifen) at 10 years of 4.0% (95% CI, 1.2% to 6.7%), and the hazard ratio (HR) of 0.81 (95% CI, 0.72 to 0.92) favored exemestane. This difference remained in multivariable analysis that was adjusted for nodal status, prior use of hormone replacement therapy, and prior chemotherapy (HR, 0.80; 95% CI, 0.71 to 0.90; P < .001). A modest improvement in overall survival was seen with exemestane; the absolute difference (between exemestane and tamoxifen) at 10 years in the population that was estrogen receptor positive or had unknown estrogen receptor status was 2.1% (95% CI, -0.5% to 4.6%), and the HR was 0.89 (95% CI, 0.78 to 1.01; P = .08). For the intention-to-treat population, the absolute difference was 1.6% (95% CI, -0.9% to 4.1%); the HR was 0.91 (95% CI, 0.80 to 1.03, P = .15). No statistically significant difference was observed in the proportion of patients who reported a fracture event in the post-treatment period.
CONCLUSION: The Intergroup Exemestane Study and contemporaneous studies have established that a strategy of switching to an aromatase inhibitor after 2 to 3 years of tamoxifen can lead to sustained benefits in terms of reduction of disease recurrence and breast cancer mortality.
PMID: 28467729
DOI: 10.1200/JCO.2016.70.5640