早期乳腺癌术后豪华套餐：帕妥珠单抗＋曲妥珠单抗＋辅助化疗
前情提要
当帕妥珠单抗加入曲妥珠单抗和化疗，用于HER2阳性乳腺癌时，对于晚期转移病变患者可改善总生存（CLEOPATRA研究），对于早期患者术前新辅助治疗可改善病理学完全缓解率（NeoSphere研究），对于早期患者术后辅助治疗效果尚不明确。
2017年6月5日，美国麻省（马萨诸塞州）医学会《新英格兰医学杂志》在线发表德国乳腺研究组织（GBG）、英国苏格兰前沿科学、比利时布鲁塞尔自由大学朱尔博尔代研究所、乳腺国际组织（BIG）、乳腺欧洲辅助研究团队（BrEAST）数据中心、瑞士罗氏、伯尔尼大学医院、意大利米兰大学、欧洲肿瘤学研究所、匈牙利布达佩斯国家肿瘤研究院、法国卡昂弗朗索瓦巴克莱斯中心、巴西里约热内卢国家癌症研究所、美国田纳西肿瘤学、莎拉加农研究所、达纳法伯癌症研究所、哈佛大学医学院、哈佛大学陈曾熙公共卫生学院、波士顿前沿科学技术研究基金会、纪念斯隆凯特林癌症中心的APHINITY研究报告全文，调查了帕妥珠单抗加入曲妥珠单抗和辅助化疗，能否改善HER2阳性早期乳腺癌患者的转归。
APHINITY：A Study of Pertuzumab in Addition to Chemotherapy and Trastuzumab as Adjuvant Therapy in Participants With Human Epidermal Growth Receptor 2 (HER2)-Positive Primary Breast Cancer.
AFFINITY：根据莎拉·沃特斯同名小说、维多利亚三部曲最后一部《灵契》改编而成，讲述了女性与女性的故事……
该大样本双盲安慰剂对照Ⅲ期研究（APHINITY）于2011年11月～2013年8月入组淋巴结阳性或高风险淋巴结阴性的HER2阳性可手术乳腺癌患者4805例（其中，淋巴结阳性、激素受体阴性病变患者分别占63%、36%），按1∶1随机分配接受1年帕妥珠单抗（2400例）或安慰剂（2405例）＋标准辅助化疗＋1年曲妥珠单抗治疗。主要终点为无浸润性病变生存，定义为随机后至首次发生以下事件：同侧浸润性乳腺肿瘤复发、同侧局部浸润性病变复发、远处病变复发、对侧浸润性乳腺癌、任何原因死亡。根据乳腺癌国际研究组织（BCIRG）006研究结果，设定帕妥珠单抗、安慰剂的3年无浸润性病变生存率达到91.8%、89.2%，需要大约379例事件时，进行初步分析。
经过中位随访45.4个月（淋巴结阳性、阴性患者分别为44.5、48.3个月），结果发现，帕妥珠单抗组与安慰剂组相比：
所有患者的浸润性病变事件发生率分别为7.1%、8.7%
所有患者的3年无浸润性病变生存率分别为94.1%、93.2%
所有患者的浸润性病变复发风险减少19%（风险比：0.81，95%置信区间：0.66～1.00，P=0.045）
淋巴结阳性患者的3年无浸润性病变生存率分别为92.0%、90.2%
淋巴结阳性浸润性病变复发风险减少23%（风险比：0.77，95%置信区间：0.62～0.96，P=0.02）
淋巴结阴性患者的3年无浸润性病变生存率分别为97.5%、98.4%
淋巴结阴性浸润性病变复发风险增加13%（风险比：1.13，95%置信区间：0.68～1.86，P=0.64）
心衰、心源性死亡、心功能障碍均不常见
≥3级以上腹泻发生率分别为9.8%、3.7%（几乎全部发生于化疗期间之外）
因此，对于HER2阳性可手术乳腺癌患者，尤其对于淋巴结阳性患者，术后联合帕妥珠单抗＋曲妥珠单抗＋化疗显著提高了的无浸润性病变生存率。帕妥珠单抗与安慰剂相比，主要毒性反应为轻度腹泻。
本研究报告于2017年6月2至7日美国临床肿瘤学会第53届年会同时公布。
本研究得到霍夫曼罗氏和基因泰克的资助。
本研究在美国政府临床研究网站注册登记编号：NCT01358877。
N Engl J Med. 2017 Jun 5. [Epub ahead of print]
Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer.
Gunter von Minckwitz, Marion Procter, Evandro de Azambuja, Dimitrios Zardavas, Mark Benyunes, Giuseppe Viale, Thomas Suter, Amal Arahmani, Nathalie Rouchet, Emma Clark, Adam Knott, Istvan Lang, Christelle Levy, Denise A. Yardley, Jose Bines, Richard D. Gelber, Martine Piccart, Jose Baselga; APHINITY Steering Committee and Investigators.
German Breast Group, Neu-Isenburg, Germany; Frontier Science (Scotland), Kincraig, United Kingdom; Breast European Adjuvant Study Team (BrEAST) Data Center, Breast International Group, Institut Jules Bordet, Université Libre de Bruxelles, Brussels; Roche Pharma; Bern University Hospital, Bern, Switzerland; European Institute of Oncology, University of Milan, Milan; National Institute of Oncology, Budapest, Hungary; Centre Francois Baclesse, Caen, France; Sarah Cannon Research Institute, Tennessee Oncology, Nashville; Instituto Nacional de Cancer, Rio de Janeiro; Dana-Farber Cancer Institute, Harvard Medical School, Harvard T. H. Chan School of Public Health, Frontier Science and Technology Research Foundation, Boston; Memorial Sloan Kettering Cancer Center, New York.
BACKGROUND: Pertuzumab increases the rate of pathological complete response in the preoperative context and increases overall survival among patients with metastatic disease when it is added to trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. In this trial, we investigated whether pertuzumab, when added to adjuvant trastuzumab and chemotherapy, improves outcomes among patients with HER2-positive early breast cancer.
METHODS: We randomly assigned patients with node-positive or high-risk node-negative HER2-positive, operable breast cancer to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. We assumed a 3-year invasive-disease-free survival rate of 91.8% with pertuzumab and 89.2% with placebo.
RESULTS: In the trial population, 63% of the patients who were randomly assigned to receive pertuzumab (2400 patients) or placebo (2405 patients) had node-positive disease and 36% had hormone-receptor-negative disease. Disease recurrence occurred in 171 patients (7.1%) in the pertuzumab group and 210 patients (8.7%) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.66 to 1.00; P=0.045). The estimates of the 3-year rates of invasive-disease-free survival were 94.1% in the pertuzumab group and 93.2% in the placebo group. In the cohort of patients with node-positive disease, the 3-year rate of invasive-disease-free survival was 92.0% in the pertuzumab group, as compared with 90.2% in the placebo group (hazard ratio for an invasive-disease event, 0.77; 95% CI, 0.62 to 0.96; P=0.02). In the cohort of patients with node-negative disease, the 3-year rate of invasive-disease-free survival was 97.5% in the pertuzumab group and 98.4% in the placebo group (hazard ratio for an invasive-disease event, 1.13; 95% CI, 0.68 to 1.86; P=0.64). Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment groups. Diarrhea of grade 3 or higher occurred almost exclusively during chemotherapy and was more frequent with pertuzumab than with placebo (9.8% vs. 3.7%).
CONCLUSIONS: Pertuzumab significantly improved the rates of invasive-disease-free survival among patients with HER2-positive, operable breast cancer when it was added to trastuzumab and chemotherapy. Diarrhea was more common with pertuzumab than with placebo.
Funded by F. Hoffmann-La Roche/Genentech
APHINITY ClinicalTrials.gov number: NCT01358877
DOI: 10.1056/NEJMoa1703643