编者按：对于HER2阳性早期乳腺癌患者，术后曲妥珠单抗＋化疗为标准的辅助治疗方案，虽然曲妥珠单抗治疗的标准持续时间为12个月，但是化疗结束之后继续使用曲妥珠单抗的利弊尚不明确。根据PHARE、HORG和HERA研究结果，已经证实使用曲妥珠单抗6个月、24个月均不优于12个月。那么，短期（9周）同时使用曲妥珠单抗＋紫杉类，与化疗＋1年曲妥珠单抗相比，早期HER2阳性乳腺癌患者的生存结局是否相似？
2018年5月31日，《美国医学会杂志》肿瘤学分册在线发表芬兰赫尔辛基大学医院、图尔库大学中心医院、东芬兰大学库奥皮奥医院、派亚特海梅中心医院、瓦萨中心医院、北卡累利阿中心医院、奥卢大学医院、坦佩雷大学医院、英国西苏格兰比特森癌症中心、比利时鲁汶大学医院、瑞典厄勒布鲁大学医院、韦斯特罗斯中心医院、隆德大学斯科讷医院、埃斯基尔斯蒂纳医院、乌普萨拉大学医院、冰岛大学医院、新西兰奥克兰市立医院的随机对照研究（SOLD）报告，对2174例HER2阳性早期乳腺癌女性接受曲妥珠单抗＋紫杉类前期化疗之后曲妥珠单抗辅助治疗继续维持9周或1年的有效性和安全性进行了评估。结果发现，两种治疗方案的5年无远处复发生存率和总生存率都较高，但是9周与1年曲妥珠单抗方案相比，无病生存较短、心脏不良反应较少、心脏功能维持较好。因此，化疗之后继续使用曲妥珠单抗可以提高有效性，但是可能引起较多心脏不良反应。
SOLD: Synergism Or Long Duration
该非盲随机临床研究于2008年1月3日～2014年12月16日从7个国家入组HER2阳性乳腺癌女性患者累计2176例，按1∶1随机分入曲妥珠单抗9周组（1087例）或1年组（1089例）。两组化疗方案相同，包括多西他赛（多西紫杉醇）80或100mg/m²每3周1次×3次共9周，随后氟尿嘧啶＋表柔比星＋环磷酰胺每3周1次×3次共9周。主要结局衡量指标为无复发生存，定义为随机分组至浸润癌复发（远处复发、局部复发、对侧乳腺癌或任何第二浸润癌）诊断或死亡（如果患者死于复发之前）的生存。次要结局衡量指标包括无远处复发生存、总生存、无心脏疾病生存、安全性。通过多因素比例风险回归模型和非劣效法，对两组的无复发生存进行比较。预设样本量为2168例患者，风险比的单侧检验相对非劣效临界值为1.3。
该研究由新西兰药品管理局、赛诺菲、诺华、芬兰科学院、芬兰癌症学会、赫尔辛基大学医院研究基金、芬兰西格丽德·朱塞利斯基金会、简和阿托斯·厄尔科基金会提供资助。部分作者得到罗氏资助。该研究的美国政府临床研究注册编号：NCT00593697。
结果发现，入组时已有远处转移2例被剔除后，其余2174例的中位年龄56岁（四分位距48～64岁），中位随访5.2年（四分位距3.8～6.7）。
曲妥珠单抗9周组与1年组相比：
无复发生存率：88.0%比90.5%（风险比：1.39，双侧90%置信区间：1.12～1.72；多因素比例风险回归模型校正后风险比：1.42，双侧90%置信区间：1.15～1.76）
无远处复发生存率：93.2%比94.2%（风险比：1.24，90%置信区间：0.93～1.65）
总生存率：94.7%比95.9%（风险比：1.36，90%置信区间：0.98～1.89）
无心脏疾病生存率：86.6%比87.5%（风险比：1.16，90%置信区间：0.96～1.40）
心脏不良事件发生率：2%比4%（22例比42例，P=0.01）
心力衰竭发生率：2%比3%（21例比36例）
左心室射血分数：63%比61%（P<0.001）
此外，该研究还发现多西他赛剂量与无复发生存之间存在相互影响，曲妥珠单抗9周组与1年组相比：
多西他赛 80mg/m²治疗： 9周无复发生存率较低
多西他赛100mg/m²治疗：两者无复发生存率相似
因此，该研究结果表明，当给予相似化疗时，曲妥珠单抗9周组与1年组相比，主要结局稍逊，未达预设非劣效临界值。不过，9周组的心脏安全性较好。与曲妥珠单抗同时使用时的多西他赛剂量需要进一步研究。
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JAMA Oncol. 2018 May 31. [Epub ahead of print]
Effect of Adjuvant Trastuzumab for a Duration of 9 Weeks vs 1 Year With Concomitant Chemotherapy for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: The SOLD Randomized Clinical Trial.
Heikki Joensuu, Judith Fraser, Hans Wildiers, Riikka Huovinen, Paivi Auvinen, Meri Utriainen, Paul Nyandoto, Kenneth K. Villman, Paivi Halonen, Helena Granstam-Bjorneklett, Lotta Lundgren, Liisa Sailas, Taina Turpeenniemi-Hujanen, Minna Tanner, Jeffrey Yachnin, Diana Ritchie, Oskar Johansson, Teppo Huttunen, MSci; Patrick Neven, Peter Canney, Vernon J. Harvey, Pirkko-Liisa, Kellokumpu-Lehtinen, Henrik Lindman.
Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom; University Hospitals Leuven, Leuven, Belgium; Turku University Central Hospital, Turku, Finland; Kuopio University Hospital, Kuopio, Finland; Paijat-Hame Central Hospital, Lahti, Finland; Orebro University Hospital, Orebro, Sweden; Vasteras Central Hospital, Vasteras, Sweden; Skane University Hospital, Lund, Sweden; Vaasa Central Hospital, Vaasa, Finland; North Carelia Central Hospital, Joensuu, Finland; Oulu University Hospital, Oulu, Finland; Tampere University Hospital, Tampere, Finland; Eskilstuna Hospital, Eskilstuna, Sweden; Landspitali University Hospital, Reykjavik, Iceland; 4Pharma, Turku, Finland; Auckland City Hospital, Auckland, New Zealand; Uppsala University Hospital, Uppsala, Sweden.
This randomized clinical trial evaluates the efficacy and safety of adjuvant trastuzumab continued beyond chemotherapy for a duration of 9 weeks vs 1 year in women with HER2-positive early breast cancer treated with up-front chemotherapy containing a taxane and trastuzumab.
QUESTION: Does administration of trastuzumab concomitantly with a taxane for a brief period (9 weeks) lead to similar survival outcomes as chemotherapy and 1 year of trastuzumab in women with early human epidermal growth factor receptor 2-positive breast cancer?
FINDINGS: In this randomized clinical trial including 2174 women, both treatments were associated with high 5-year distant disease-free survival and overall survival rates, but the 9-week trastuzumab regimen resulted in a shorter disease-free survival than the 1-year regimen. The shorter treatment was associated with fewer cardiac adverse effects and better maintained cardiac function.
MEANING: Trastuzumab continued beyond chemotherapy increases efficacy but may lead to more cardiac adverse effects.
IMPORTANCE: Trastuzumab plus chemotherapy is the standard adjuvant treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. While the standard duration of trastuzumab treatment is 12 months, the benefits and harms of trastuzumab continued beyond the chemotherapy are unclear.
OBJECTIVE: To evaluate the efficacy and safety of adjuvant trastuzumab continued beyond chemotherapy in women treated with up-front chemotherapy containing a taxane and trastuzumab.
DESIGN, SETTING, AND PARTICIPANTS: Open-label, randomized (1:1) clinical trial including women with HER2-positive breast cancer. Chemotherapy was identical in the 2 groups, consisting of 3 cycles of 3-weekly docetaxel (either 80 or 100 mg/m²) plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide. Thereafter, no trastuzumab was administered in the 9-week group, whereas controls received trastuzumab to complete 1 year of administration. Disease-free survival (DFS) was compared between the groups using a Cox model and the noninferiority approach. The estimated sample size was 2168 patients (1-sided testing, with a relative noninferiority margin of 1.3). From January 3, 2008, to December 16, 2014, 2176 patients were accrued from 7 countries.
INTERVENTION: Docetaxel plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide in both groups. Controls continued trastuzumab to 1 year.
MAIN OUTCOMES AND MEASURES: The primary objective was DFS; secondary objectives included distant disease-free survival, overall survival, cardiac DFS, and safety.
RESULTS: In the 2174 women analyzed, median age was 56 (interquartile range [IQR], 48-64) years. The median follow-up was 5.2 (IQR, 3.8-6.7) years. Noninferiority of the 9-week treatment could not be demonstrated for DFS (hazard ratio, 1.39; 2-sided 90% CI, 1.12-1.72). Distant disease-free survival and overall survival did not differ substantially between the groups. Thirty-six (3%) and 21 (2%) patients in the 1-year and the 9-week groups, respectively, had cardiac failure; the left ventricle ejection fraction was better maintained in the 9-week group. An interaction was detected between the docetaxel dose and DFS; patients in the 9-week group treated with 80 mg/m² had inferior and those treated with 100 mg/m² had similar DFS as patients in the 1-year group.
CONCLUSIONS AND RELEVANCE: Nine weeks of trastuzumab was not noninferior to 1 year of trastuzumab when given with similar chemotherapy. Cardiac safety was better in the 9-week group. The docetaxel dosing with trastuzumab requires further study.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00593697
DOI: 10.1001/jamaoncol.2018.1380
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