三阳性乳腺癌雌激素受体、孕激素受体、HER2同时阳性，大约占全部HER2阳性乳腺癌半数以上，与激素受体阴性的HER2阳性乳腺癌相比，对术前标准新辅助治疗效果较差。针对HER2阳性乳腺癌的疗法，对三阳性乳腺癌患者疗效有限。根据回顾研究报道，三阳性乳腺癌新辅助化疗联合曲妥珠单抗病理完全缓解率仅为20%，在全部HER2阳性乳腺癌亚组中最低，表明三阳性乳腺癌管理所需治疗策略优化迫在眉睫。不过，关注三阳性乳腺癌新辅助治疗的研究极少。
2022年11月17日，英国《自然》旗下《自然通讯》在线发表中国医科大学附属盛京医院刘彩刚教授牵头，该院牛楠、邱芳、徐乾时、何贵金、顾玺、赵毅、陈光磊、薛今琦、蒋小凡，大连医科大学附属大连市中心医院郭文斌、大连大学附属中山医院张殿龙、哈尔滨医科大学附属肿瘤医院李志高、黄元夕、刘通，中国医科大学附属第五医院本溪市中心医院李勇、鞍山市肿瘤医院李科、中国医科大学附属肿瘤医院辽宁省肿瘤医院张昊、徐宏，包头市肿瘤医院张培礼、张钢龄，辽河油田总医院韩洪斌、大连医科大学附属第一医院蔡振刚、延安市人民医院李鹏飞、中国医科大学附属第一医院李金时、郑新宇，江苏恒瑞医药霍仕文、李华军等学者的MUKDEN01研究报告，首次探讨了吡咯替尼＋来曲唑＋达尔西利全口服免化疗方案新辅助治疗三阳性乳腺癌术前患者的有效性和安全性。
MUKDEN01 (NCT04486911): Pyrotinib Maleate, CDK4/6 Inhibitor and Letrozole in Combination for Treatment of Stage II-III Triple-positive Breast Cancer: a Phase II Clinical Trial
该多中心单组二期临床研究于2020年7月27日～2022年5月13日从全国12家医院入组卡氏体力评分≥70的II～III期三阳性乳腺癌术前患者81例，口服吡咯替尼＋来曲唑＋达尔西利进行术前新辅助治疗。主要终点为乳房＋腋窝病理完全缓解患者比例。次要终点包括残癌负荷-0或残癌负荷-I、客观缓解率、乳房病理完全缓解、安全性和分子靶点Ki67从基线到手术的变化。
结果，其中79例完成5轮4周治疗达到主要终点，乳房＋腋窝病理完全缓解24例，达30.4%（95%置信区间：21.3～41.3）。残癌负荷-0或残癌负荷-I达55.7%（95%置信区间：44.7～66.1）。客观缓解率达87.4%（95%置信区间：78.1～93.2），乳房病理完全缓解率达35.4%（95%置信区间，25.8～46.5）。
Ki67表达平均值从基线时40.4%降至手术时17.9%（P<0.001）。
发生率较高的3或4级不良事件为中性粒细胞减少（53%）、白细胞减少（20%）和腹泻（17%）。未见严重不良事件或治疗相关死亡。
因此，该研究结果表明，这种全口服免化疗三联疗法有望成为三阳性乳腺癌新辅助治疗的替代方案，故有必要进一步开展多中心大样本随机对照三期临床研究进行验证。
Nat Commun. 2022 Nov 17;13:6918. IF: 17.694
A multicentre single arm phase 2 trial of neoadjuvant Pyrotinib and letrozole plus dalpiciclib for triple-positive breast cancer.
Nan Niu, Fang Qiu, Qianshi Xu, Guijin He, Xi Gu, Wenbin Guo, Dianlong Zhang, Zhigao Li, Yi Zhao, Yong Li, Ke Li, Hao Zhang, Peili Zhang, Yuanxi Huang, Gangling Zhang, Hongbin Han, Zhengang Cai, Pengfei Li, Hong Xu, Guanglei Chen, Jinqi Xue, Xiaofan Jiang, Alireza Hamidian Jahromi, Jinshi Li, Yu Zhao, Eduardo de Faria Castro Fleury, Shiwen Huo, Huajun Li, Guy Jerusalem, Domenico Tripodi, Tong Liu, Xinyu Zheng, Caigang Liu.
Shengjing Hospital of China Medical University, Shenyang, China; Innovative Cancer Drug Research and Development Engineering Centre of Liaoning Province, Shenyang, China; Dalian Municipal Central Hospital, Affiliated Hospital of Dalian Medical University, Dalian, China; Affiliated Zhongshan Hospital of Dalian University, Dalian, China; Cancer Hospital of Harbin Medical University, Harbin, China; Benxi Central Hospital, The Fifth Affiliated Hospital of China Medical University, Benxi, China; Anshan Cancer Hospital, Anshan, China; Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China; Baotou Cancer Hospital, Baotou, China; Liaohe Oilfield General Hospital, Affiliated Hospital of China Medical University, Panjin, China; First Affiliated Hospital of Dalian Medical University, Dalian, China; Yan'an People's Hospital, Yan'an, China; First Affiliated Hospital of China Medical University, Shenyang, China; Jiangsu Hengrui Pharmaceuticals, Shanghai, China; Temple University Medical Center, Philadelphia, PA, USA; Mayo Clinic College of Medicine, Rochester, MN, USA; Instituto BRASileiro de Controle do Cancer Oncologia (IBCC Oncologia), Sao Paulo, Brazil; CHU Liège and Liège University, Liege, Belgium; Sapienza University of Rome, Rome, Italy.
Current therapies for HER2-positive breast cancer have limited efficacy in patients with triple-positive breast cancer (TPBC). We conduct a multi-center single-arm phase 2 trial to test the efficacy and safety of an oral neoadjuvant therapy with pyrotinib, letrozole and dalpiciclib (a CDK4/6 inhibitor) in patients with treatment-naive, stage II-III TPBC with a Karnofsky score of ≥70 (NCT04486911). The primary endpoint is the proportion of patients with pathological complete response (pCR) in the breast and axilla. The secondary endpoints include residual cancer burden (RCB)-0 or RCB-I, objective response rate (ORR), breast pCR (bpCR), safety and changes in molecular targets (Ki67) from baseline to surgery. Following 5 cycles of 4-week treatment, the results meet the primary endpoint with a pCR rate of 30.4% (24 of 79; 95% confidence interval (CI), 21.3-41.3). RCB-0/I is 55.7% (95% CI, 44.7-66.1). ORR is 87.4%, (95% CI, 78.1-93.2) and bpCR is 35.4% (95% CI, 25.8-46.5). The mean Ki67 expression reduces from 40.4% at baseline to 17.9% (P<0.001) at time of surgery. The most frequent grade 3 or 4 adverse events are neutropenia, leukopenia, and diarrhoea. There is no serious adverse event- or treatment-related death. This fully oral, chemotherapy-free, triplet combined therapy has the potential to be an alternative neoadjuvant regimen for patients with TPBC.
DOI: 10.1038/s41467-022-34838-w
