目前，对于HER2阳性的转移性乳腺癌，标准的一线治疗方案为紫杉类化疗联合曲妥珠单抗+帕妥珠单抗治疗。但老年患者对紫杉类化疗的耐受性相对较差，需要探寻适用于老年患者的高效低毒方案。节拍化疗通过低剂量，频繁给药的方式，安全低毒，且疗效较好，是老年患者的优选治疗方案，值得深入研究。

——《壹篇》按

《柳叶刀肿瘤分册》2018年2月9日在线先发

帕妥珠单抗+曲妥珠单抗联合或不联合节拍化疗治疗HER2阳性转移性老年乳腺癌患者：一项来自“老年工作队/乳腺癌组”的开放标签、随机化、2期临床试验

背景

尽管在老年人群中转移性乳腺癌的发生率、死亡率高，但我们对老年癌症患者的最佳治疗策略所知甚少。为此，在HER2阳性转移性乳腺癌老年患者中，我们旨在评价双抗HER2治疗联合或不联合节拍化疗的疗效。

方法

我们在欧洲8个国家、30家医疗中心进行了一项多中心、开放标签、随机化2期临床试验，入组患者为：

1.经组织学证实的、HER2阳性转移性乳腺癌

2.既往未针对转移性肿瘤进行过化疗

3.年龄≥70岁

4.或者年龄≥60岁且有按照试验方案界定的确切的功能障碍

5.预期寿命超过12周

6.按照WHO（世卫组织）体能状况评分为0-3分。

基于最小化方法、通过一套在线随机化系统，将符合条件的患者随机分组（1:1），一组接受节拍口服环磷酰胺50毫克/日+曲妥珠单抗和帕妥珠单抗，另一组只接受曲妥珠单抗、帕妥珠单抗。曲妥珠单抗静脉给予一负荷剂量8mg/kg，序贯每三周6mg/kg；帕妥珠单抗静脉给予一负荷剂量840mg，序贯每三周420mg。根据激素受体阳性、既往HER2治疗情况和入组时老年病筛查情况对患者进行亚组分层。主要终点为研究者评价的6个月时的无进展生存率，按照实体瘤疗效评价标准（RECIST）1.1版本，判断无进展生存情况，寻求两组间≥10%的差异。根据意向性治疗进行疗效分析，在所有接受过一个剂量研究治疗的患者中评估安全性。一旦进展，向所有患者提供曲妥珠单抗-Emtansine偶联物（罗氏新药Kadcyla——译者注）。这项临床试验已在ClinicalTrials.gov网站注册，注册号NCT01597414，试验已完成。

结果

2013年7月2日至2016年5月10日，80名患者中有56名（70%）按照老年病筛查G8评分有潜在的身体状况差（≤14分），将这些患者随机分组，一组接受曲妥珠单抗+帕妥珠单抗（n=39），另一组接受曲妥珠单抗+帕妥珠单抗联合节拍口服环磷酰胺（(n=41）。曲妥珠单抗+帕妥珠单抗组估算的6个月时的无进展生存率为46.2%（95%CI，30.2–60.7），对比曲妥珠单抗+帕妥珠单抗联合节拍口服环磷酰胺组为73.4%（56.6–84.6）（风险比[HR]，0.65[95%CI，0.37-1.12]，p=0.12）。中位随访20.7个月（IQR，12.5–30.4）时，曲妥珠单抗+帕妥珠单抗组中位无进展生存期为5.6个月（95%CI，3.6–16.8），对比加用节拍口服环磷酰胺组为12.7个月（6.7–24.8）。最常见的3-4级不良事件有高血压（曲妥珠单抗+帕妥珠单抗组39名患者中有6名[15%]、对比曲妥珠单抗+帕妥珠单抗联合节拍口服环磷酰胺组41名患者中有5名[12%]）、腹泻（4名[10%]对比5名[12%]）、呼吸困难（2名[5%]对比4名[10%]）、疲劳（3名[8%]对比2名[5%]）、疼痛（2名[5%]对比2名[5%]）和血栓事件（0名[0%]对比4名[10%]）。两组中均偶尔观察到有严重心*毒脏**性。曲妥珠单抗+帕妥珠单抗组4名患者死亡但无进展，死于治疗期间的心脏骤停（n=1）、腹腔感染（n=1）、呼吸衰竭（n=1）以及无特定原因猝死（n=1）；曲妥珠单抗+帕妥珠单抗联合节拍口服环磷酰胺组，1名患者死于心衰。

解读

在HER阳性转移性乳腺癌且身体状况差的老年患者中，与单纯HER2双阻断相比，节拍口服环磷酰胺加入曲妥珠单抗+帕妥珠单抗延长中位无进展生存期7个月，且安全性可接受。曲妥珠单抗+帕妥珠单抗联合节拍口服环磷酰胺、肿瘤进展后序贯曲妥珠单抗-Emtansine偶联物，可以延缓或取代这类患者对紫杉醇化疗的需求。

《壹篇》田朋飞

Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2-positive metastatic breast cancer (EORTC 75111-10114): an open-label, randomised, phase 2 trial from the Elderly Task Force/Breast Cancer Group

http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30083-4/fulltext

Background

Despite the high incidence of metastatic breast cancer and its related mortality in the elderly population, our knowledge about optimal treatment for older patients with cancer is far from adequate. We aimed to evaluate the efficacy of dual anti-HER2 treatment with or without metronomic chemotherapy in older patients with HER2-positive metastatic breast cancer.

Methods

We did a multicentre, open-label, randomised, phase 2 trial in 30 centres from eight countries in Europe, in patients with histologically proven, HER2-positive metastatic breast cancer, without previous chemotherapy for metastatic disease, who were 70 years or older, or 60 years or older with confirmed functional restrictions defined by protocol, and had a life expectancy of more than 12 weeks and a performance status according to WHO scale of 0–3. Eligible patients were randomly assigned (1:1) by an online randomisation system based on the minimisation method to receive metronomic oral cyclophosphamide 50 mg per day plus trastuzumab and pertuzumab, or trastuzumab and pertuzumab alone. Trastuzumab was given intravenously with a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. Pertuzumab was given intravenously with a loading dose of 840 mg, followed by 420 mg every 3 weeks. Patients were stratified by hormone receptor positivity, previous HER2 treatment, and baseline geriatric screening. The primary endpoint was investigator-assessed progression-free survival at 6 months as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A difference of 10% or greater between the two groups was sought. Efficacy analyses were by intention to treat; safety was assessed in all patients who received at least one dose of study treatment. In case of progression, all patients were offered trastuzumab emtansine. This trial is registered with ClinicalTrials.gov, number NCT01597414, and is completed.

Findings

Between July 2, 2013, and May 10, 2016, 80 patients, of whom 56 (70%) had a potential frailty profile according to the geriatric screening G8 score (≤14), were randomly assigned to receive trastuzumab and pertuzumab (n=39) or trastuzumab and pertuzumab plus metronomic oral cyclophosphamide (n=41). Estimated progression-free survival at 6 months was 46·2% (95% CI 30·2–60·7) with trastuzumab and pertuzumab versus 73·4% (56·6–84·6) with trastuzumab and pertuzumab plus metronomic oral cyclophosphamide (hazard ratio [HR] 0·65 [95% CI 0·37–1·12], p=0·12). At a median follow-up of 20·7 months (IQR 12·5–30·4), the median progression-free survival was 5·6 months (95% CI 3·6–16·8) with trastuzumab and pertuzumab versus 12·7 months (6·7–24·8) with the addition of metronomic oral cyclophosphamide. The most frequent grade 3–4 adverse events were hypertension (in six [15%] of 39 patients in the trastuzumab and pertuzumab group vs five [12%] of 41 in the trastuzumab and pertuzumab plus metronomic oral cyclophosphamide group), diarrhoea (four [10%] vs five [12%]), dyspnoea (two [5%] vs four [10%]), fatigue (three [8%] vs two [5%]), pain (two [5%] vs two [5%]), and a thromboembolic event (0 [0%] vs four [10%]). Severe cardiac toxicities were occasionally observed in both groups. In the trastuzumab and pertuzumab group four patients died without progression, due to cardiac arrest during treatment (n=1), peritoneal infection (n=1), respiratory failure (n=1), and sudden death without a specified cause (n=1). In the trastuzumab and pertuzumab plus metronomic oral cyclophosphamide group, one patient died from heart failure.

Interpretation

Addition of metronomic oral cyclophosphamide to trastuzumab plus pertuzumab in older and frail patients with HER2-positive metastatic breast cancer increased median progression-free survival by 7 months compared with dual HER2 blockade alone, with an acceptable safety profile. Trastuzumab and pertuzumab plus metronomic oral cyclophosphamide, followed by trastuzumab emtansine after disease progression, might delay or supersede the need for taxane chemotherapy in this population.

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