Ma Ding, Dai Lei-Jie, Wu Xiang-Rong, Liu Cheng-Lin, Zhao Shen, Zhang Hang, Chen Li, Xiao Yi, Li Ming, Zhao Yi-Zhi, Yang Lin, Zhou Tong, Li Jun-Jie, Yang Wen-Tao, Jiang Yi-Zhou, Shao Zhi-Ming
Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
Cancer Cell. 2025 Jun 9;43(6):1061-1075.e7. doi: 10.1016/j.ccell.2025.03.017. Epub 2025 Apr 10.
Selecting optimal candidates for next-generation anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugates (ADCs) remains challenging. We conduct a prespecified translational study to identify treatment biomarkers in SHR-A1811-treated HER2-positive breast cancer patients from the phase 2 neoadjuvant FASCINATE-N trial using DNA and RNA sequencing, computational pathology, and single-cell in situ spatial imaging. In the hormone receptor (HR)-negative subgroup, a higher proportion and more infiltration of immune cells (i.e., tumor-infiltrating lymphocytes [TILs]), particularly cytotoxic T cells, are associated with better treatment responses. In the HR-positive subgroup, the closeness and aggregation of HER2-strong-positive tumor cells, as opposed to a uniform distribution, are linked to a lower response rate and HER2 luminal-like (HER2-LUM) subtype, which more closely resembles HR+/HER2- breast cancer. In addition, we develop a clinically practical predictive model capable of predicting neoadjuvant treatment responses to SHR-A1811 and other novel ADCs based on clinicopathological characteristics and pathological images.
为下一代抗人表皮生长因子受体2（HER2）抗体药物偶联物（ADC）选择最佳候选者仍然具有挑战性。我们进行了一项预先指定的转化研究，以从2期新辅助FASCINATE-N试验中接受SHR-A1811治疗的HER2阳性乳腺癌患者中，使用DNA和RNA测序、计算病理学和单细胞原位空间成像来识别治疗生物标志物。在激素受体（HR）阴性亚组中，免疫细胞（即肿瘤浸润淋巴细胞 [TILs]），特别是细胞毒性T细胞的比例更高且浸润更多，与更好的治疗反应相关。在HR阳性亚组中，HER2强阳性肿瘤细胞的紧密程度和聚集，而非均匀分布，与较低的反应率以及HER2腔面样（HER2-LUM）亚型相关，后者更类似于HR+/HER2-乳腺癌。此外，我们基于临床病理特征和病理图像开发了一种临床实用的预测模型，能够预测对SHR-A1811和其他新型ADC的新辅助治疗反应。
