国色天香：亚洲乳腺癌双靶新辅助治疗
芍药属（paeonia）是芍药科（paeoniaceae）唯一属，主要观赏花卉为牡丹。英语和其他欧洲语言的牡丹和芍药是同一个词（paeony或peony）。此名来自古希腊神话阿波罗之子医神阿斯克勒庇厄斯的门徒庇恩（Paeon），其医术高明，先后治愈了战神阿瑞斯、冥王哈迪斯，随后得到众神青睐，比如阿波罗之母黑暗女神勒托就赐了他一株奥林匹斯山的神圣药草，这引起了阿斯克勒庇俄斯的嫉妒，准备干掉庇恩，宙斯听说以后，赶紧把庇恩变成了芍药以免遭毒手。芍药一般可以存活数年，牡丹可以存活30～60年，两者均可入药。清朝曾将牡丹定为国花。2019年7月15日，中国花卉协会发布《征求牡丹为我国国花意见的通知》（中花协字【2019】16号）。2019年10月24日，《美国医学会杂志》肿瘤学分册在线发表了以PEONY命名的亚洲乳腺癌双靶新辅助治疗研究简报。
2012年和2016年英国《柳叶刀》肿瘤学分册发表的NEOSPHERE国际多中心随机非盲对照二期临床研究短期和长期分析报告，已经证实了帕妥珠单抗＋曲妥珠单抗＋多西他赛新辅助治疗早期或局部晚期HER2阳性乳腺癌术前患者的有效性、安全性和耐受性，与曲妥珠单抗＋多西他赛相比，病理完全缓解率显著提高（45.8%比29.0%）。不过，该研究的亚洲患者比例仅占22.78%。
2019年10月24日，《美国医学会杂志》肿瘤学分册在线发表复旦大学附属肿瘤医院邵志敏和李俊杰、哈尔滨医科大学附属黑龙江省肿瘤医院庞达、中国科学院大学附属浙江省肿瘤医院杨红健、吉林大学白求恩第一医院李薇、中山大学附属肿瘤医院王树森、郑州大学附属河南省肿瘤医院崔树德、广东省医学科学院广东省人民医院廖宁、山东省医学科学院山东省肿瘤医院王永胜、福建医科大学附属协和医院王川、马偕纪念医院张源清、中国医药大学附设医院王惠畅、上海交通大学医学院附属瑞金医院沈坤炜、解放军总医院第五医学中心江泽飞、韩国亚洲大学医学院姜锡润、高丽大学九老医院徐在弘、泰国宋卡王子大学医院、罗氏全球药品开发上海中心、美国基因泰克的PEONY研究简报，比较了帕妥珠单抗或安慰剂＋曲妥珠单抗＋多西他赛新辅助治疗亚洲早期或局部晚期HER2阳性乳腺癌术前患者的有效性、安全性和耐受性。
PEONY (A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Phase III Study to Evaluate Pertuzumab in Combination With Docetaxel and Trastuzumab as Neoadjuvant Therapy, and Pertuzumab in Combination With Trastuzumab as Adjuvant Therapy After Surgery and Chemotherapy in Patients With Early-Stage or Locally Advanced HER2-Positive Breast Cancer): Study in Participants With Early-Stage or Locally Advanced Human Epidermal Growth Factor Receptor (HER) 2-Positive Breast Cancer to Evaluate Treatment With Trastuzumab Plus (+) Pertuzumab + Docetaxel Compared With Trastuzumab + Placebo + Docetaxel (NCT02586025)
该亚洲多中心随机双盲安慰剂对照三期临床研究于2016年3月14日～2017年3月13日从中国大陆和台湾、韩国、泰国入组原发肿瘤大于2厘米的早期（T2-3、N0-1、M0）或局部晚期（T2-3、N2-3，M0；T4、任何N、M0）HER2阳性乳腺癌女性患者329例，按2∶1随机分为两组，术前每3周静脉注射帕妥珠单抗（首次840毫克、随后420毫克）或安慰剂、曲妥珠单抗（每公斤体重首次8毫克、随后6毫克）、多西他赛（每平方米体表面积75毫克）共计12周；术后每3周静脉注射氟尿嘧啶＋表柔比星＋环磷酰胺共计9周，随后每3周静脉注射帕妥珠单抗或安慰剂＋曲妥珠单抗共计39周，整个疗程长达1年。
帕妥珠组219例：术前帕妥珠＋曲妥珠＋多西他赛 → 术后氟尿嘧啶＋表柔比星＋环磷酰胺 → 帕妥珠＋曲妥珠
安慰剂组110例：术前安慰剂＋曲妥珠＋多西他赛 → 术后氟尿嘧啶＋表柔比星＋环磷酰胺 → 安慰剂＋曲妥珠
本文对截至2017年10月23日的数据进行分析：对意向治疗患者进行主要终点分析，对实际治疗患者进行不良事件分析。主要终点为独立评审委员会评定的总体病理完全缓解率。按疾病分类和激素受体状态进行分层，通过双侧分层卡方检验，对两组患者进行比较。
结果，意向治疗患者共计329例，平均年龄48.8±9.5岁，中国大陆＋台湾患者比例占88.75%；帕妥珠单抗组剔除1例不符合条件的患者，实际治疗患者共计328例。
帕妥珠单抗组与安慰剂组相比：
总体病理完全缓解率：39.3%比21.8%（相差17.5%，95%置信区间：6.9%～28.0%，P=0.001）
≥3级中性粒细胞减少发生率：38.1%比32.7%
严重不良事件发生率：10.1%比8.2%
因此，该研究结果表明，对于亚洲早期或局部晚期HER2阳性乳腺癌患者，帕妥珠单抗＋曲妥珠单抗＋多西他赛与安慰剂＋曲妥珠单抗＋多西他赛相比，术前新辅助治疗的总体病理完全缓解率显著较高。不良事件数据符合已知的帕妥珠单抗安全性，两组患者大多数不良事件的发生率相似，除了帕妥珠单抗组≥3级中性粒细胞减少发生率和严重不良事件发生率稍高。该研究进一步扩充了帕妥珠单抗治疗方案的获益数据总量。
相关阅读
JAMA Oncol. 2019 Oct 24. [Epub ahead of print]
Efficacy, Safety, and Tolerability of Pertuzumab, Trastuzumab, and Docetaxel for Patients With Early or Locally Advanced ERBB2-Positive Breast Cancer in Asia: The PEONY Phase 3 Randomized Clinical Trial.
Zhimin Shao, Da Pang, Hongjian Yang, Wei Li, Shusen Wang, Shude Cui, Ning Liao, Yongsheng Wang, Chuan Wang, Yuan-Ching Chang, Hweichung Wang, Seok Yun Kang, Jae Hong Seo, Kunwei Shen, Suphawat Laohawiriyakamol, Zefei Jiang, Junjie Li, Julian Zhou, Betsy Althaus, Yixiang Mao, Jennifer Eng-Wong.
Fudan University Shanghai Cancer Center, Shanghai, China; Harbin Medical University Cancer Hospital, Harbin, China; Zhejiang Cancer Hospital, Hangzhou, China; The First Hospital of Jilin University, Changchun, China; Sun Yat-sen University Cancer Center, Guangzhou, China; Henan Cancer Hospital, Zhengzhou, China; Guangdong General Hospital, Guangzhou, China; Shandong Cancer Hospital, Jinan, China; Fujian Medical University Union Hospital, Fuzhou, China; Mackay Memorial Hospital, Taipei City, Taiwan; China Medical University Hospital, Taichung City, Taiwan; Ajou University School of Medicine, Suwon, Korea; Korea University Guro Hospital, Seoul, Korea; Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Songklanagarind Hospital, Songkhla, Thailand; The Affiliated Hospital of Military Medical Sciences (The 307th Hospital of Chinese People's Liberation Army), Beijing, China; Roche Product Development, Shanghai, China; Genentech, Inc, South San Francisco, California.
This phase 3 randomized clinical trial compares the efficacy, safety, and tolerability of adding pertuzumab to trastuzumab and docetaxel vs placebo, trastuzumab, and docetaxel in Asian patients with ERBB2-positive early or locally advanced breast cancer.
QUESTION: Do Asian patients with ERBB2-positive early or locally advanced breast cancer benefit from the addition of pertuzumab to trastuzumab and docetaxel in the neoadjuvant setting, compared with placebo, trastuzumab, and docetaxel?
FINDINGS: In this randomized clinical trial of 329 women with early or locally advanced breast cancer, total pathologic complete response rates were 39.3% with pertuzumab and 21.8% with placebo, a significant difference. Safety data were generally comparable between groups.
MEANING: Pertuzumab, trastuzumab, and docetaxel significantly improved total pathologic complete response rate vs placebo, trastuzumab, and docetaxel in the neoadjuvant setting; this study adds to the totality of the data showing the benefit of the pertuzumab regimen.
IMPORTANCE: Prospective assessment of treatments known to benefit patients in global clinical trials in specific racial groups is essential.
OBJECTIVE: To compare the efficacy, safety, and tolerability of adding pertuzumab to trastuzumab and docetaxel vs placebo, trastuzumab, and docetaxel in Asian patients with ERBB2-positive early or locally advanced breast cancer.
DESIGN, SETTING, AND PARTICIPANTS: This multicenter, double-blind, placebo-controlled phase 3 trial enrolled 329 women with ERBB2-positive early (T2-3, N0-1, M0) or locally advanced breast cancer (T2-3, N2 or N3, M0; T4, any N, M0) and primary tumor larger than 2 cm from March 14, 2016, to March 13, 2017. Analysis of the primary end point was performed on an intention-to-treat basis.
INTERVENTIONS: Before surgery, patients received 4 cycles of intravenous pertuzumab (840-mg loading dose and 420-mg maintenance doses), trastuzumab (8-mg/kg loading dose and 6-mg/kg maintenance doses), and docetaxel (75 mg/m2) or intravenous placebo, trastuzumab, and docetaxel every 3 weeks. After surgery, patients received 3 cycles of intravenous fluorouracil, epirubicin, and cyclophosphamide followed by 13 cycles of the same intravenous anti-ERBB2 therapy (pertuzumab and trastuzumab or placebo and trastuzumab) for up to 1 year.
MAIN OUTCOMES AND MEASURES: The primary end point was independent review committee-assessed total pathologic complete response rate. The 2-sided Cochran-Mantel-Haenszel test, stratified by disease category and hormone receptor status, was used to compare rates between treatment groups.
RESULTS: In total, 329 female patients were randomized (pertuzumab, 219; and placebo, 110; mean [SD] age, 48.8 [9.5] years). In the intention-to-treat population, total pathologic complete response rates were 39.3% (86 of 219) in the pertuzumab group and 21.8% (24 of 110) in the placebo group (difference, 17.5% [95% CI, 6.9%-28.0%]; P = .001). Of the most common grade 3 or higher adverse events, there was a higher incidence of neutropenia in the pertuzumab group (83 of 218 [38.1%] vs 36 of 110 [32.7%]). Serious adverse events were reported in 10.1% of patients (22 of 218) in the pertuzumab group and 8.2% of patients (9 of 110) in the placebo group.
CONCLUSIONS AND RELEVANCE: Treatment with pertuzumab, trastuzumab, and docetaxel resulted in a statistically significant improvement in the total pathologic complete response rate vs placebo, trastuzumab, and docetaxel for the neoadjuvant treatment of ERBB2-positive early or locally advanced breast cancer in Asian patients. Safety data were in line with the known pertuzumab safety profile and generally comparable between treatment groups. The PEONY trial adds to the totality of data showing the benefit of the pertuzumab regimen.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02586025
DOI: 10.1001/jamaoncol.2019.3692