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对于HER2阳性早期乳腺癌患者，指南推荐首选紫杉醇＋曲妥珠单抗、多西他赛＋卡铂＋曲妥珠单抗、多西他赛＋卡铂＋曲妥珠单抗＋帕妥珠单抗，从单化疗药物＋单靶向药物发展到双化疗药物＋双靶向药物，已被证实可以显著提高生存率。不过，双化疗药物虽然效果较好，但是相关毒性也大大增加，促使人们探索降级策略，例如免化疗或者降低化疗强度。
二期临床研究PHERGain和WSG-ADAPT-HER2+/HR-表明，如果未进行化疗，对于曲妥珠单抗＋帕妥珠单抗靶向治疗早期缓解患者，病理完全缓解率可达34%～38%。此外，KRISTINE研究发现6个周期恩美曲妥珠单抗＋帕妥珠单抗治疗的病理完全缓解率可达44%。其他生物标志物指导的降级研究也发现，即使完全免化疗，早期缓解患者也可以获得有临床意义的病理完全缓解率。可是，免化疗方案与含化疗方案相比，病理完全缓解率仍然相对较低。
减量化疗＋靶向治疗方案可能是可行的降级策略。二期临床研究WSG-ADAPT-HER2+/HR-表明，对于HER2阳性激素受体阴性乳腺癌术前患者，紫杉醇单药化疗＋曲妥珠单抗＋帕妥珠单抗的病理完全缓解率高达91%。不过，该方案样本量仅42例患者。因此，需要进一步开展三期临床研究入组更多患者，以验证紫杉醇单药化疗联合双靶向药物治疗对HER2阳性乳腺癌患者术前治疗的潜力。
此外，紫杉醇和多西他赛等传统紫杉类化疗药物的水溶性较低，用药前需要加入聚氧乙基代蓖麻油或聚山梨酯80及无水乙醇助溶，这些助溶剂可引起不同程度的过敏反应、溶血反应，并抑制中枢神经系统，也可加重外周神经毒性，还影响药物分子向组织间扩散，延长滴注时间，降低抗肿瘤效果。白蛋白紫杉醇将紫杉醇与白蛋白结合，用药前不需要加入助溶剂，可以安全增加剂量、缩短输注时间、提高药物浓度。GeparSepto研究表明，对于早期乳腺癌，每周白蛋白紫杉醇与每周紫杉醇相比，病理完全缓解率和无浸润癌生存率显著提高。不过，对于HER2阳性患者亚组，病理完全缓解率和无浸润癌生存率提高不显著，可能由于样本量较小，限制了统计学意义。于是，中国学者针对HER2阳性早期乳腺癌术前患者，将标准治疗方案的紫杉醇替换为白蛋白紫杉醇，并且去掉卡铂，开展了全国多中心随机对照研究。
2024年11月26日，英国《柳叶刀》肿瘤学分册在线发表河南省肿瘤医院（郑州大学附属肿瘤医院）陈秀春、焦得闯、乔江华、王承正、孙献甫、卢振铎、李连方、张崇建、闫敏、刘真真✉️等学者的HELEN-006研究报告，首次证实每周白蛋白紫杉醇单药与每周紫杉醇＋卡铂两药相比，联合曲妥珠单抗＋帕妥珠单抗治疗HER2阳性早期乳腺癌术前患者的病理完全缓解率显著提高。该研究得到中国国家自然科学基金和河南省科技研究项目支持。
HELEN-006 (NCT04547907): A Comparison of Nab-PHP and TCbHP Efficacy in Neoadjuvant Therapy for HER2-positive Early Breast Cancer
Brief Title: Comparing the Efficacy of Nab-PHP and TCbHP in Neoadjuvant Therapy for HER2 Positive Operable Breast Cancer
Official Title: Comparing the Efficacy and Security of Nab-PHP and TCbHP in Neoadjuvant Chemotherapy for HER2 Positive Operable Breast Cancer, A Multicenter, Randomized, Phase III Clinical Trial
该全国多中心非盲随机对照三期临床研究于2020年9月20日至2023年3月1日从全国6家医院入组18至70岁、美国东部肿瘤学协作组（ECOG）体力状态评分为0或1分、尚未治疗且经组织学证实II至III期HER2阳性乳腺浸润癌患者669例（中位年龄50岁，四分位43至55岁，其中河南省肿瘤医院367例、河南科技大学第一附属医院95例、安阳市肿瘤医院79例、河南大学淮河医院57例、新乡市中心医院56例、中国医科大学附属第一医院15例）采用交互反馈系统并以肿瘤分期、淋巴结状态和激素受体状态进行分层，按1∶1的比例进行置换区组随机化（每个区组为4例）分为两组：
白蛋白紫杉醇组332例：每21天静脉注射白蛋白紫杉醇（125mg/m²，第1、8和15天）6个周期
多西他赛卡铂组337例：每21天静脉注射多西他赛（75mg/m²，第1天）卡铂（浓度时间曲线下面积6mg/mL每分钟，第1天）6个周期
两组患者每21天同时静脉注射曲妥珠单抗（首次剂量8mg/kg，维持剂量6mg/kg，第1天）帕妥珠单抗（首次剂量840mg，维持剂量420mg，第1天）。多西他赛卡铂组接受标准术前用药，即地塞米松，以预防多西他赛所致过敏反应，允许采用聚乙二醇重组人粒细胞集落刺激因子作为治疗相关中性粒细胞减少的一级和二级预防；白蛋白紫杉醇组可酌情采用非格司亭、聚乙二醇非格司亭、来格司亭等生长因子作为治疗相关中性粒细胞减少的二级预防。
本此报告对全部开始治疗（改良意向治疗）患者主要终点病理完全缓解（ypT0/isN0）进行最终分析。术后治疗随访仍在进行。
结果，中位随访26个月，四分位19至32个月，白蛋白紫杉醇组与多西他赛卡铂组相比：
病理完全缓解：220例、194例
病理完全缓解率：66.3%比57.6%（95%置信区间：61.2～71.4、52.3～62.9）
合并优势比：1.54（95%置信区间：1.10～2.14，分层P=0.011）
3～4级不良事件发生率：30%比38%
3～4级恶心发生率：7%比23%
3～4级腹泻发生率：8%比16%
3～4级神经病变发生率：13%比2%
严重药物相关不良事件发生率：1%比2%
治疗相关死亡发生率：0比0
A、全部患者；B、激素受体阴性患者；C、激素受体阳性患者
亚组分析表明，白蛋白紫杉醇组与多西他赛卡铂组相比，肿瘤较小、淋巴结阳性、激素受体阴性患者病理完全缓解率显著较高。
因此，该研究结果表明，对于HER2阳性早期乳腺癌术前治疗，白蛋白紫杉醇单药与多西他赛＋卡铂两药标准化疗方案相比，联合曲妥珠单抗＋帕妥珠单抗的病理完全缓解率显著提高，除了神经病变，其他不良事件较少，有望为此类患者术前治疗建立新标准。
Lancet Oncol. 2024 Nov 26. IF: 41.6
De-escalated neoadjuvant weekly nab-paclitaxel with trastuzumab and pertuzumab versus docetaxel, carboplatin, trastuzumab, and pertuzumab in patients with HER2-positive early breast cancer (HELEN-006): a multicentre, randomised, phase 3 trial.
Xiu-Chun Chen, De-Chuang Jiao, Jiang-Hua Qiao, Cheng-Zheng Wang, Xian-Fu Sun, Zhen-Duo Lu, Lian-Fang Li, Chong-Jian Zhang, Min Yan, Ya Wei, Bo Chen, Yue-Qing Feng, Miao Deng, Ming-De Ma, Jennifer K Plichta, You-Wen He, Zhen-Zhen Liu.
The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China; Anyang Tumor Hospital, Anyang, China; The First Hospital of China Medical University, Shenyang, China; Xinxiang Central Hospital, Xinxiang, China; The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China; Huaihe Hospital of Henan University, Kaifeng, China; Duke University School of Medicine, Durham, NC, USA.
BACKGROUND: A previous phase 2 trial showed promising outcomes for patients with HER2-positive early-stage breast cancer using neoadjuvant de-escalation chemotherapy with paclitaxel, trastuzumab, and pertuzumab. We aimed to evaluate the efficacy of weekly nab-paclitaxel compared with the standard regimen of docetaxel plus carboplatin, both with trastuzumab and pertuzumab, as neoadjuvant therapies for patients with HER2-positive breast cancer.
METHODS: HELEN-006 was a multicentre, randomised, phase 3 trial done at six hospitals in China. We enrolled patients aged 18-70 years with untreated, histologically confirmed stage II-III invasive HER2-positive breast cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1. Using an interactive response system, patients were randomly assigned (1:1) under a permuted block randomisation scheme (block size of four), stratified by tumour stage, nodal status, and hormone receptor status. Patients received either intravenous nab-paclitaxel (125 mg/m2 on days 1, 8, and 15) for six 3-week cycles, or intravenous docetaxel (75 mg/m2 on day 1) plus intravenous carboplatin (area under the concentration-time curve 6 mg/mL per min on day 1) for six 3-week cycles. Both groups also received concurrent intravenous trastuzumab, with an initial loading dose of 8 mg/kg and a maintenance dose of 6 mg/kg on day 1, as well as intravenous pertuzumab with a loading dose of 840 mg and a maintenance dose of 420 mg on day 1. This report is the final analysis of the primary endpoint, pathological complete response (ypT0/is ypN0), analysed in all patients who started treatment (modified intention to treat). The trial is registered with ClinicalTrials.gov, NCT04547907, and follow-up of the adjuvant phase is ongoing.
FINDINGS: Between Sept 20, 2020, and March 1, 2023, 789 patients were screened for eligibility, 689 of whom were randomly assigned (343 to the nab-paclitaxel group and 346 to the docetaxel plus carboplatin group). All 689 patients were Asian women. 669 patients received at least one dose of the study treatment and were included in the full analysis set (332 in the nab-paclitaxel group and 337 in the docetaxel plus carboplatin group). Median age of the patients was 50 years (IQR 43-55). Median follow-up time was 26 months (IQR 19-32). 220 (66.3% [95% CI 61.2-71.4]) patients in the nab-paclitaxel group had a pathological complete response, compared with 194 (57.6% [52.3-62.9]) in the docetaxel plus carboplatin group (combined odds ratio 1.54 [95% CI 1.10-2.14]; stratified p=0.011). 100 (30%) patients in the nab-paclitaxel group and 128 (38%) in the docetaxel plus carboplatin group had grade 3-4 adverse events. The most common grade 3-4 adverse events were nausea (22 [7%] in the nab-paclitaxel group vs 76 [23%] in the docetaxel plus carboplatin group), diarrhoea (25 [8%] vs 55 [16%]), and neuropathy (43 [13%] vs eight [2%]). Serious drug-related adverse events were reported in three (1%) patients in the nab-paclitaxel group and five (2%) in the docetaxel plus carboplatin group. No treatment-related deaths were reported in either group.
INTERPRETATION: These findings might suggest a potential advantage of nab-paclitaxel combined with trastuzumab and pertuzumab compared with the standard regimen in neoadjuvant therapy for patients with HER2-positive early breast cancer, suggesting that this new combination might establish a new standard for neoadjuvant treatment in this patient population.
FUNDING: National Natural Science Foundation of China, and Science and Technology Research Projects of Henan Province, China.
DOI: 10.1016/S1470-2045(24)00581-3
（来源：SIBCS）
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