The addition of HER2-targeted agents to neoadjuvant chemotherapy has dramatically improved pathological complete response (pCR) rates in early-stage, HER2-positive breast cancer. Nonetheless, up to 50% of patients have residual disease after treatment, while others are likely overtreated. Here, we performed multiplex spatial proteomic characterization of 122 samples from 57 HER2-positive breast tumors from the neoadjuvant TRIO-US B07 clinical trial sampled pre-treatment, after 14–21 d of HER2-targeted therapy and at surgery. We demonstrated that proteomic changes after a single cycle of HER2-targeted therapy aids the identification of tumors that ultimately undergo pCR, outperforming pre-treatment measures or transcriptomic changes. We further developed and validated a classifier that robustly predicted pCR using a single marker, CD45, measured on treatment, and showed that CD45-positive cell counts measured via conventional immunohistochemistry perform comparably. These results demonstrate robust biomarkers that can be used to enable the stratification of sensitive tumors early during neoadjuvant HER2-targeted therapy, with implications for tailoring subsequent therapy.

在新辅助化疗中加入 HER2 靶向药物显着提高了早期 HER2 阳性乳腺癌的病理完全缓解 (pCR) 率。尽管如此，高达 50% 的患者在治疗后仍有残留病灶，而其他患者可能过度治疗。在这里，我们对来自新辅助 TRIO-US B07 临床试验的 57 个 HER2 阳性乳腺肿瘤的 122 个样本进行了多重空间蛋白质组学表征，这些样本来自 HER2 靶向治疗 14-21 天和手术前的新辅助 TRIO-US B07 临床试验样本。我们证明了在单周期 HER2 靶向治疗后蛋白质组学的变化有助于识别最终经历 pCR 的肿瘤，其表现优于治疗前措施或转录组学变化。我们进一步开发并验证了一个分类器，该分类器使用单个标记 CD45 稳健地预测 pCR，在治疗时测量，并表明通过常规免疫组织化学测量的 CD45 阳性细胞计数表现相当。这些结果证明了强大的生物标志物，可用于在新辅助 HER2 靶向治疗期间早期对敏感肿瘤进行分层，这对定制后续治疗具有重要意义。