对于早期（尚未远处转移）乳腺癌，如果肿瘤较大、淋巴结转移，通常给予术前化疗，肿瘤和转移淋巴结可能缩小甚至消失，可以为保乳手术创造条件，还可为术后治疗方案提供参考；如果HER2阳性，需要联合曲妥珠单抗等HER2靶向治疗药物提高化疗效果；此外，二期临床研究NeoSphere和三期临床研究PEONEY已经证实，再联合帕妥珠单抗可进一步提高病理完全缓解率甚至无事件生存率以及无病变生存率。那么，如果术前曲妥珠单抗无效（原发耐药）怎么办？此前，山东大学第二医院余之刚教授团队通过临床前研究发现，中国原研HER1、HER2、HER4酪氨酸激酶不可逆抑制剂吡咯替尼可以增强曲妥珠单抗对曲妥珠单抗耐药细胞系的有效性，而帕妥珠单抗并未表现出相同的协同作用，故于2019年设计二期临床研究NeoPaTHer，首次对HER2阳性早期乳腺癌术前化疗联合曲妥珠单抗2个周期无效患者探讨联合吡咯替尼的有效性、安全性和生物学预测指标。该研究初步结果已于2024年美国临床肿瘤学会第60届年会公布。
NeoPaTHer (NCT03847818): Neoadjuvant Study of Pyrotinib and Trastuzumab Plus Chemotherapy in Patients With HER2 Positive Breast Cancer
Official Title: A Prospective, Open-label, Multicenter Phase II Study of Neoadjuvant Pyrotinib Plus Trastuzumab and Chemotherapy in Women With HER2 Positive Early Stage or Locally Advanced Breast Cancer
2025年1月29日，英国《自然》旗下《信号转导与靶向治疗》正式发表山东大学第二医院王斐①、王永久①、于理想、傅勤烨、李亮、张强、郑超、黄淑亚、刘丽媛、刘东旭、余之刚✉️、济宁医学院附属医院熊斌、滨州医学院附属医院杨振林、临沂市肿瘤医院王京芬、聊城市人民医院姚玉民等学者的NeoPaTHer研究报告全文。
该多中心前瞻非随机分组对照二期临床研究于2020年10月至2022年3月从5家医院入组HER2阳性乳腺癌、肿瘤大于2厘米、淋巴结转移或未转移、尚未远处转移、尚未手术患者129例，先给予多西他赛＋卡铂＋曲妥珠单抗治疗2个周期，随后进行磁共振成像检查：如果全部病灶最大直径缩小至少30%认为有效，那么继续上述方案治疗4个周期（A组）；否则认为无效，经过与患者面对面讨论，根据患者意愿分为2组：B组继续上述方案治疗4个周期，C组联合吡咯替尼治疗4个周期。最后，进行手术和病理检查，主要终点为乳房肿瘤和腋窝淋巴结病理完全缓解率。
该研究原先计划B组和C组所需样本量至少为32例和63例，由于2021年底之后中国开始常规采用曲妥珠单抗联合帕妥珠单抗，估计可能或许大概还受到3年大疫影响，导致提前终止入组，无法对各组病理完全缓解率进行正式的假设检验或统计学比较，以下P值为名义值。
结果：A组、B组、C组患者分别为62例、26例、41例，各组基线人口统计学和疾病特征大致相似：
二期乳腺癌：62.6%、61.5%、73.2%（P=0.57）
激素受体阳性：67.7%、76.9%、61.0%（P=0.40）
Ki67水平≥20%：82.3%、73.1%、78.0%（P=0.62）
HER2免疫组化评分3+：88.7%、96.2%、80.5%（P=0.16）
乳房肿瘤和腋窝淋巴结病理完全缓解率：
A组：30.6%（95%置信区间：20.6～43.0%）
B组：15.4%（95%置信区间：6.2～33.5%）
C组：29.3%（95%置信区间：17.6～44.5%）
由于该研究分组非随机，故对年龄、治疗前肿瘤和淋巴结分期、激素受体状态、绝经状态、HER2免疫组化评分、Ki67指数等其他影响因素进行多因素逻辑回归分析，A组与C组相比，乳房肿瘤和腋窝淋巴结病理完全缓解率相似（比值比：1.04，95%置信区间：0.40～2.70）。
联合吡咯替尼耐受性良好，未发现新的不良事件，腹泻为已知的主要可控不良事件。
生物学预测指标分析：
TP53和PIK3CA同时突变患者早期部分缓解率低于无或单基因突变患者（36.0%比60.0%，P=0.08）
病理完全缓解患者肿瘤突变负荷显著较高（P=0.01）
病理完全缓解患者RTK-RAS通路突变率显著较高（P=0.02）
因此，该小样本非随机二期临床研究结果表明，对于HER2阳性早期乳腺癌术前化疗联合曲妥珠单抗2个周期无效患者，联合吡咯替尼的病理完全缓解率提高1.9倍，接近曲妥珠单抗有效患者，TP53和PIK3CA同时突变、肿瘤突变负荷、RTK-RAS通路突变可能预测疗效，故有必要进一步开展大样本随机对照研究与帕妥珠单抗进行比较，并对联合吡咯替尼可能获益的生物学预测指标进行验证。
相关链接
Signal Transduct Target Ther. 2025 Jan 29;10:45. IF: 40.8
Neoadjuvant pyrotinib and trastuzumab in HER2-positive breast cancer with no early response (NeoPaTHer): efficacy, safety and biomarker analysis of a prospective, multicentre, response-adapted study.
Wang F, Wang Y, Xiong B, Yang Z, Wang J, Yao Y, Yu L, Fu Q, Li L, Zhang Q, Zheng C, Huang S, Liu L, Liu C, Sun H, Mao B, Liu DX, Yu Z.
The Second Hospital of Shandong University, Jinan, China; Shandong Key Laboratory of Cancer Digital Medicine, Jinan, China; Shandong Provincial Engineering Laboratory of Translational Research on Prevention and Treatment of Breast Disease, Jinan, China; Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan, China; Affiliated Hospital of Jining Medical University, Jining, China; Binzhou Medical University Hospital, Binzhou, China; Linyi Cancer Hospital, Linyi, China; Liaocheng People's Hospital, Liaocheng, China; Genecast Biotechnology Co.Ltd., Wuxi, China.
The potential benefits of pyrotinib for patients with trastuzumab-insensitive, HER2-positive early-stage breast cancer remain unclear. This prospective, multicentre, response-adapted study evaluated the efficacy and safety of adding pyrotinib to the neoadjuvant treatment of HER2-positive breast cancer patients with a poor response to initial docetaxel plus carboplatin and trastuzumab (TCbH). Early response was assessed using magnetic resonance imaging (MRI) after two cycles of treatment. Patients showing poor response, as defined by RECIST 1.1, could opt to receive additional pyrotinib or continue standard therapy. The primary endpoint was the total pathological complete response (tpCR; ypT0/isN0) rate. Of the 129 patients enroled, 62 (48.1%) were identified as MRI-responders (cohort A), 26 non-responders continued with four more cycles of TCbH (cohort B), and 41 non-responders received additional pyrotinib (cohort C). The tpCR rate was 30.6% (95% CI: 20.6-43.0%) in cohort A, 15.4% (95% CI: 6.2-33.5%) in cohort B, and 29.3% (95% CI: 17.6-44.5%) in cohort C. Multivariable logistic regression analyses demonstrated comparable odds of achieving tpCR between cohorts A and C (odds ratio = 1.04, 95% CI: 0.40-2.70). No new adverse events were observed with the addition of pyrotinib. Patients with co-mutations of TP53 and PIK3CA exhibited lower rates of early partial response compared to those without or with a single gene mutation (36.0% vs. 60.0%, P = 0.08). These findings suggest that adding pyrotinib may benefit patients who do not respond to neoadjuvant trastuzumab plus chemotherapy. Further investigation is warranted to identify biomarkers predicting patients' benefit from the addition of pyrotinib.
PMID: 39875376
DOI: 10.1038/s41392-025-02138-6
