埃及艳后与晚期乳腺癌患者真实结局
古埃及托勒密王朝末代女王克利奥帕特拉（CLEOPATRA）为了夺回失去的王位并避免国家被罗马吞并，曾经色诱凯撒大帝及其手下安东尼，人称埃及艳后。2007年，瑞士罗氏旗下美国基因泰克将帕妥珠单抗＋曲妥珠单抗＋多西他赛一线治疗HER2阳性晚期乳腺癌患者的国际多中心双盲安慰剂随机对照三期临床研究命名为CLEOPATRA。2012年，美国食品药品监督管理局（FDA）根据CLEOPATRA研究结果，批准帕妥珠单抗＋曲妥珠单抗＋多西他赛联合治疗尚未接受抗HER2治疗或化疗的HER2阳性晚期乳腺癌患者。不过，国际多中心双盲安慰剂随机对照三期临床研究与真实世界临床实践毕竟有所不同，目前对于帕妥珠单抗＋曲妥珠单抗＋多西他赛一线治疗HER2阳性晚期乳腺癌的真实疗效分析仍然较少。于是，瑞士罗氏亲自动手对此进行了分析。
CLEOPATRA (NCT00567190): A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Efficacy and Safety of Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-Positive Metastatic Breast Cancer
2021年1月13日，《美国医学会杂志》网络开放版在线发表瑞士罗氏和英国PHMR的研究报告，对真实世界帕妥珠单抗＋曲妥珠单抗＋多西他赛一线治疗晚期乳腺癌患者实际结局与CLEOPATRA研究结果进行了比较。
该队列回顾研究利用来自美国265家肿瘤医院的电子病历数据库，根据国际疾病分类第9版或第10版，对2011年1月1日～2020年10月31日接受帕妥珠单抗＋曲妥珠单抗＋多西他赛一线治疗的HER2阳性晚期乳腺癌患者数据进行检索，建立真实世界队列。如果患者开始治疗时未满18岁、开始治疗后就诊少于2次或确诊晚期乳腺癌至开始收集数据超过90天，那么其数据被剔除。对患者治疗前的人口统计学和临床特征进行描述统计，利用生存曲线对总生存进行分析。随后，将CLEOPATRA研究总生存曲线数字化，通过重建时间事件数据推算患者个体水平生存时间，通过对数秩检验与真实世界队列进行比较。通过敏感性分析剔除不符合CLEOPATRA研究关键入组标准的患者：美国东部肿瘤学协作组体力状态评分评分大于1或缺失、脑转移、查尔森合并症指数合并症史。通过PYTHON编程语言3.8版进行分析，经邦费罗尼校正的双侧P<0.05被认为具有统计学意义。
结果，符合上述分析条件的患者共计546例，其中女性541例（99.1%）、白人329例（60.3%），治疗开始时年龄中位59岁（四分位距：50～66）。真实世界队列某些患者特征与CLEOPATRA研究有所不同。
真实世界队列中位随访45.3个月（95%置信区间：40.6～48.0个月），中位总生存48.6个月（95%置信区间：41.4～53.9个月），接近CLEOPATRA研究生存曲线数字化重建中位总生存56.4个月（95%置信区间：51.0～71.9个月，对数秩检验P=0.05）。
通过敏感性分析剔除不符合CLEOPATRA研究关键入组标准的335例患者，其余211例患者中位总生存55.6个月（95%置信区间：46.7～82.4个月），与CLEOPATRA研究相似（对数秩检验P>0.99）。
因此，该真实世界队列研究结果表明，帕妥珠单抗＋曲妥珠单抗＋多西他赛一线治疗HER2阳性晚期乳腺癌患者的总生存与CLEOPATRA研究相似。这些结果与新加坡真实世界研究（中位随访20.6个月，中位总生存51.5个月，95%置信区间：35.8～60.0）和意大利真实世界研究（中位随访21个月，3年总生存率72.2%）相似。
不过，该研究采用的电子病历数据存在一定局限性，其中包括部分数据不完整，例如合并症、不良事件、转移灶、体力状态、死亡日期、早期术前或术后治疗方案。该研究还受到该队列中位随访时间相对较短的限制。虽然存在这些局限性，但是结果表明，真实世界人群已经实现了帕妥珠单抗＋曲妥珠单抗＋多西他赛联合治疗临床研究的获益。
相关链接
JAMA Netw Open. 2021 Jan 13;4(1):e2027764.
Association of Pertuzumab, Trastuzumab, and Docetaxel Combination Therapy With Overall Survival in Patients With Metastatic Breast Cancer.
Ramagopalan SV, Pisoni R, Rathore LS, Ray J, Sammon C.
F. Hoffmann-La Roche Ltd, Basel, Switzerland; PHMR Ltd, London, United Kingdom.
This cohort study compares the findings of combined pertuzumab, trastuzumab, and docetaxel therapy in women with metastatic breast cancer with those in the CLEOPATRA trial.
INTRODUCTION: In 2012, the combination of pertuzumab, trastuzumab, and docetaxel was approved by the US Food and Drug Administration for the treatment of patients with ERBB2 (formerly HER2)-positive metastatic breast cancer (MBC) who have not received prior anti-ERBB2 therapy or chemotherapy. The approval was based on data from the phase 3 pertuzumab, trastuzumab, and docetaxel for ERBB2-positive metastatic breast cancer (CLEOPATRA) trial. End-of-study results have confirmed the long-term benefit of this combination in the trial population; however, there has been limited analysis of its real-world effectiveness. To fill this evidence gap, we undertook a retrospective cohort study within the Flatiron Health electronic health record-derived database to assess the effectiveness of pertuzumab, trastuzumab, and docetaxel treatment of ERBB2-positive MBC in real-world US patients.
METHODS: The Flatiron Health database includes information from more than 265 cancer clinics across the United States. Research with the database was approved by the Copernicus Group Institutional Review Board, which waived informed consent because all data were deidentified. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies was followed. For this study, data from January 1, 2011, through October 31, 2020, were included for patients with an International Classification of Diseases, Ninth Revision (ICD-9) or International Classification of Diseases, Tenth Revision (ICD-10) diagnosis of breast cancer, documentation confirming MBC and a positive ERBB2 test result, who received pertuzumab, trastuzumab, and docetaxel combination therapy after their MBC diagnosis as first-line therapy for MBC. Patients were excluded if they were younger than 18 years at the time of treatment initiation, had fewer than 2 clinic encounters after treatment initiation, or had a gap of more than 90 days between the diagnosis of MBC and initiation of the collection of structured data. Baseline patient demographic and clinical characteristics were summarized using descriptive statistics, and the Kaplan-Meier method was used to evaluate overall survival (OS). The Kaplan-Meier curve for OS from the CLEOPATRA trial was digitized, and individual patient-level survival times were estimated using the Guyot algorithm to allow for comparison with the Flatiron Health cohort using log-rank tests. Sensitivity analyses were performed excluding patients who did not meet key inclusion criteria of the CLEOPATRA clinical trial: patients with Eastern Cooperative Oncology Group performance status greater than 1 (with or without missing values), brain metastases, and a history of comorbidities included in the Charlson comorbidity index. Analyses were performed using Python 3.8 series programming language (Python Software Foundation), with Bonferroni-corrected, 2-sided P<0.05 considered statistically significant.
RESULTS: In total, 546 patients with ERBB2-positive MBC received combined pertuzumab, trastuzumab, and docetaxel therapy. Of these, 541 (99.1%) were women, 329 (60.3%) were White, and their median age at treatment initiation was 59 (interquartile range, 50-66) years. The Flatiron Health cohort differed in some patient characteristics from that of the CLEOPATRA trial (Table). The median follow-up for the cohort was 45.3 months (95% CI, 40.6-48.0 months) and median OS was 48.6 months (95% CI, 41.4-53.9 months). Overall survival did not differ from that in the CLEOPATRA trial (Figure; digitized OS, 56.4 months; 95% CI, 51.0-71.9 months; log-rank test, P=0.05). In the sensitivity analysis excluding trial-ineligible patients (leaving 211 patients), survival did not differ from that in the CLEOPATRA trial (median OS, 55.6 months; 95% CI, 46.7-82.4 months); log-rank test P>0.99).
DISCUSSION: Overall survival in this real-world cohort of ERBB2-positive patients with MBC who were treated with pertuzumab, trastuzumab, and docetaxel combination therapy was similar to that demonstrated in the CLEOPATRA trial. The findings are comparable with recent real-world studies from Singapore (median, 51.5 [95% CI, 35.8-60.0] after median follow-up of 20.6 months) and Italy (3-year overall survival, 72.2% after median follow-up of 21 months). Limitations of electronic health records are well documented and include incomplete information on some variables, such as comorbidities, adverse events, metastases, performance status, date of death, and adjuvant/neoadjuvant treatments. Our analysis is also limited by the relatively short median follow-up of the cohort. Despite these limitations, the results suggest that the benefit of pertuzumab, trastuzumab, and docetaxel combination therapy demonstrated in clinical trials is being realized in real-world populations.
PMID: 33439261
DOI: 10.1001/jamanetworkopen.2020.27764