十一年随访：赫赛汀辅助治疗两年无益
既往临床研究显示曲妥珠单抗（抗HER2受体的重组单克隆抗体）显著改善HER2阳性早期乳腺癌患者的总生存和无病生存，但是需要长期随访数据。
2017年2月16日，英国《柳叶刀》在线发表英国（爱丁堡大学、苏格兰前沿科学、皇家马斯登医院、伦敦大学癌症研究院）、比利时（布鲁塞尔自由大学）、美国（哈佛大学医学院、哈佛大学陈曾熙公共卫生学院、达纳法伯癌症研究所、前沿科学技术研究基金会、纽约纪念斯隆凯特林癌症中心、南达科他州阿韦拉癌症中心）、意大利（欧洲肿瘤研究所、圣拉斐尔医院）、巴西（圣保罗大学）、德国（柏林赫利俄斯医院、奥芬巴赫萨纳医院）、瑞士（冯·霍夫曼-罗氏）、澳大利亚（迪肯大学）的赫拉（赫赛汀辅助）研究报告，比较了曲妥珠单抗（商品名：赫赛汀）辅助治疗1年或2年的中位11年随访结果。根据文献检索，这是目前为止，HER2阳性早期乳腺癌抗HER2辅助疗法随访时间最长的研究。
该国际多中心非盲Ⅲ期随机研究（BIG1-01）于2011年12月7日～2005年6月20日从39个国家入组5102例完成所有主要治疗（包括符合指征的手术、化疗、放疗）后的HER2阳性早期乳腺癌女性，随机分配（1∶1∶1）接受曲妥珠单抗1年（静脉注射，首次8mg/kg，随后6mg/kg每3周1次）或2年（以相同给药方案）或观察。主要终点为意向治疗人群的无病生存（定义：未发生乳腺癌复发、对侧乳腺癌、非乳腺第二恶性病变、死亡），根据比例风险回归模型估计风险比，并进行生存曲线分析，根据366天界标分析比较2年和1年的曲妥珠单抗用药。该研究已在美国政府临床研究网站（ClinicalTrials.gov）注册，编号：NCT00045032。
结果发现，在赫拉研究随机入组的5102例女性中，由于3例患者无法证明曾经提供过书面知情同意书而被剔除，对其余意向治疗人群5099例患者（观察组、曲妥珠单抗1年组和2年组分别为1697、1702和1700例）中位随访11年（四分位距：10.09～11.53）后，随机分配至曲妥珠单抗1年组的无病生存事件、死亡风险分别显著降低24%、26%（风险比：0.76、0.74，95%置信区间：0.68～0.86、0.64～0.86）。
遗憾的是，曲妥珠单抗辅助治疗2年与1年相比，无病生存结局仍未改善（风险比：1.02，95%置信区间：0.89～1.17）。
根据生存曲线估算，观察组、曲妥珠单抗1年组和2年组的10年无病生存率分别为63%、69%和69%。分配至观察组的884例（52%）患者选择性交叉接受曲妥珠单抗。
观察组、曲妥珠单抗1年组和2年组的3或4级不良事件发生率分别为9%、18%、22%（152、295、364例），主要心脏终点事件（定义：心内科医生确认的纽约心脏学会NYHA分级III或IV级毒性，并且有临床意义的左心室射血分数LVEF相对起点降低≥10个百分点，并且LVEF绝对值＜50%，或者心源性死亡）发生率分别为0.1%、1%、1%（2、18、17例），次要心脏终点事件（定义：无症状或有轻度症状的NYHA分级I或II级毒性，并且有临床意义的LVEF相对起点降低≥10个百分点，并且LVEF绝对值＜50%，经过重复评定）发生率为
0.9%、4.4%、7.3%（15、74、122例）。所有研究组的心脏毒性主要发生于治疗期间，曲妥珠单抗治疗完成后的心脏终点事件发生较少。
此外，无证据表明疾病特征（例如淋巴结或激素受体水平）对上述结果有显著影响，亦无证据表明治疗完成后存在远期副作用。
因此，HER2阳性早期乳腺癌患者化疗后，与观察组相比，曲妥珠单抗辅助治疗1年显著改善长期无病生存，曲妥珠单抗辅助治疗2年无更多获益。
对此，华盛顿大学医学院、弗雷德哈钦森癌症研究中心的内科专家发表同期评论：曲妥珠单抗用于早期HER2阳性乳腺癌的最佳疗程。
关于赫拉
赫拉（Hera）是古希腊神话中的天后、奥林帕斯山众神之中地位及权力最高的女神、奥林帕斯十二主神之一、宙斯的姐姐和第三位合法妻子（墨提斯、忒弥斯、赫拉），而且还是宙斯的这三位合法妻子中唯一的一位正妻（包括不合法的妻子，继勒托后，赫拉排在第七位），被认为是婚姻和妇女的保护神，掌管婚姻和生育，她的名字在古希腊语中意为贵妇人、女主人、女统治者、高贵的女性。赫拉是自然力量的女性化身，因为宙斯向赫拉求婚时允诺与赫拉分享自己的权力和尊荣，所以赫拉可以享有丈夫的权力，每当赫拉出行时都伴有雷霆闪电，而且也能聚散乌云、呼风唤雨。她固定的标志是权杖和王冠，她往往以战服的装束出现，头戴镶有花叶的象征王权的冠冕和象征已婚妇女的面纱，威风凛凛。
2002年，赫赛汀辅助（HERceptin Adjuvant）研究被命名为赫拉（HERA）。
Lancet. 2017 Feb 16. [Epub ahead of print]
11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial.
David Cameron, Martine J Piccart-Gebhart, Richard D Gelber, Marion Procter, Aron Goldhirsch, Evandro de Azambuja, Gilberto Castro Jr, Michael Untch, Ian Smith, Luca Gianni, Jose Baselga, Nedal Al-Sakaff, Sabine Lauer, Eleanor McFadden, Brian Leyland-Jones, Richard Bell, Mitch Dowsett, Christian Jackisch; for the Herceptin Adjuvant (HERA) Trial Study Team.
University of Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, UK; Université Libre de Bruxelles, Brussels, Belgium; Dana-Farber Cancer Institute, Harvard Medical School, Harvard TH Chan School of Public Health and Frontier Science and Technology Research Foundation, Boston, MA, USA; Frontier Science Scotland Ltd, Kincraig, Kingussie, UK; European Institute of Oncology, Milan, Italy; Instituto do Cancer do Estado de Sao Paulo, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil; Helios Klinikum Berlin Buch, Multidisciplinary Breast Cancer Center, Berlin, Germany; Royal Marsden Hospital, and The Institute of Cancer Research, London, UK; San Raffaele Hospital, Scientific Institute, Milan, Italy; Memorial Sloan-Kettering Cancer Center, New York, NY, USA; F Hoffmann-La Roche, Basel, Switzerland; Avera Cancer Institute Center for Precision Oncology, Sioux Falls, SD, USA; Deakin University, Waurn Ponds, VIC, Australia; Sana Klinikum Offenbach, Offenbach, Germany.
BACKGROUND: Clinical trials have shown that trastuzumab, a recombinant monoclonal antibody against HER2 receptor, significantly improves overall survival and disease-free survival in women with HER2-positive early breast cancer, but long-term follow-up data are needed. We report the results of comparing observation with two durations of trastuzumab treatment at a median follow-up of 11 years, for patients enrolled in the HERA (HERceptin Adjuvant) trial.
METHODS: HERA (BIG 1-01) is an international, multicentre, open-label, phase 3 randomised trial of 5102 women with HER2-positive early breast cancer, who were enrolled from hospitals in 39 countries between Dec 7, 2001, and June 20, 2005. After completion of all primary therapy (including, surgery, chemotherapy, and radiotherapy as indicated), patients were randomly assigned (1:1:1) to receive trastuzumab for 1 year (once at 8 mg/kg of bodyweight intravenously, then 6 mg/kg once every 3 weeks) or for 2 years (with the same dose schedule), or to the observation group. Primary endpoint is disease-free survival, and analyses are in the intention-to-treat population. Hazard ratios (HRs) were estimated from Cox models, and survival curves were estimated by the Kaplan-Meier method. Comparison of 2 years versus 1 year of trastuzumab is based on 366-day landmark analyses. This study is registered with ClinicalTrials.gov (NCT00045032).
FINDINGS: Of the 5102 women randomly assigned in the HERA trial, three patients had no evidence of having provided written informed consent to participate. We followed up the intention-to-treat population of 5099 patients (1697 in observation, 1702 in 1-year trastuzumab, and 1700 in 2-years trastuzumab groups). After a median follow-up of 11 years (IQR 10.09-11.53), random assignment to 1 year of trastuzumab significantly reduced the risk of a disease-free survival event (HR 0.76, 95% CI 0.68-0.86) and death (0.74, 0.64-0.86) compared with observation. 2 years of adjuvant trastuzumab did not improve disease free-survival outcomes compared with 1 year of this drug (HR 1.02, 95% CI 0.89-1.17). Estimates of 10-year disease-free survival were 63% for observation, 69% for 1 year of trastuzumab, and 69% for 2 years of trastuzumab. 884 (52%) patients assigned to the observation group selectively crossed over to receive trastuzumab. Cardiac toxicity remained low in all groups and occurred mostly during the treatment phase. The incidence of secondary cardiac endpoints was 122 (7.3%) in the 2-years trastuzumab group, 74 (4.4%) in the 1-year trastuzumab group, and 15 (0.9%) in the observation group.
INTERPRETATION: 1 year of adjuvant trastuzumab after chemotherapy for patients with HER2-positive early breast cancer significantly improves long-term disease-free survival, compared with observation. 2 years of trastuzumab had no additional benefit.
EVIDENCE BEFORE THIS STUDY: We searched PubMed for randomised clinical trials published in English between Jan 1, 2000, and March 1, 2013, assessing long-term outcomes (>5 years' follow-up) from randomised trials of systemic therapy in patients with early breast cancer confirmed as HER2-positive, using the search terms "adjuvant", "breast", "randomised", and "HER2". We found no data in the published literature providing 10 years or more of follow-up from the use of adjuvant trastuzumab within a randomised trial.
ADDED VALUE OF THIS STUDY: To our knowledge, this 11-year follow-up of the HERA trial provides the longest survival data of any trial that assessed the addition of anti-HER2 therapy to standard treatment for HER2-positive early breast cancer. We provide long-term patient outcome data to support the use of 1 year of adjuvant trastuzumab in this patient population, with evidence that those patients randomly assigned to receive trastuzumab (in both the 1-year and 2-years groups) sustained relative reductions in recurrence and breast cancer deaths, with the reassurance that the rate of serious toxicity does not increase over time. We also showed no evidence of a benefit of 2 years of trastuzumab compared with 1 year, and could not identify a subgroup of patients studied in the HERA trial who would not have derived long-term benefits.
IMPLICATIONS OF ALL THE AVAILABLE EVIDENCE: Patients with HER2-positive early breast cancer who meet the criteria for the HERA trial (or the other studies reported elsewhere), including the cardiac disease criteria, we believe should be offered 1 year of adjuvant trastuzumab as part of standard of care. Patients can be reassured that there are benefits in terms of better disease-free and overall survival that are sustained to at least 10 years after diagnosis, with no evidence of significant differential benefit by disease characteristics, such as nodal status or tumour hormone receptor status. Additionally, there is no evidence of late emergent side-effects, including no evidence of more cardiac endpoints emerging up to 10 years after treatment.
FUNDING: F Hoffmann-La Roche (Roche).
DOI: 10.1016/S0140-6736(16)32616-2
Lancet. 2017 Feb 16. [Epub ahead of print]
Optimal duration of trastuzumab for early HER2-positive breast cancer.
Jennifer M Specht, Nancy E Davidson.
Department of Medicine, University of Washington School of Medicine, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Four pivotal randomised trials have shown that the addition of trastuzumab, a monoclonal antibody targeting the HER2 receptor, to adjuvant chemotherapy results in significant improvements in disease-free survival and overall survival for patients with early stage HER2-positive breast cancer. The HERA trial differed from the North American NSABP B-31 and NCCTG 9831 trials because it mandated completion of all adjuvant chemotherapy before administration of trastuzumab, and randomly assigned patients to none, or 1 or 2 years of trastuzumab.
DOI: 10.1016/S0140-6736(17)30322-7