激素受体阳性 (HR )/人表皮生长因子受体 2 (HER2)-低与 HR /HER2-0 中新辅助化疗 (NACT) 和内分泌治疗引起的基因表达和内在亚型 (IS) 变化的表征和比较迄今为止尚未进行乳腺癌（BC）检查。大多数关于 HR/HER2 阴性 BC 中 HER2 状态与病理反应和预后相关的证据都存在争议，并且仅限于 NACT 治疗的疾病。同样，仅通过 NACT 描述了 HER2 状态的时间异质性。我们回顾性招募了 186 名接受新辅助治疗 (NAT) 治疗的 I-IIIB HR/HER2 阴性 BC 患者的连续队列。现有的诊断活检和手术样本的主要病理特征、PAM50 IS 和 ROR-P 评分以及基因表达进行了表征。评估了与病理完全缓解、残余癌症负荷-0/I、无事件生存期 (EFS) 和基于 HER2 状态的总生存期 (OS) 的关联。对匹配样本中的术前/术后病理/分子变化进行分析。HER2-low (62.9%) 和 HER2-0 (37.1%) 队列在主要基线特征、治疗、保乳手术、病理完全缓解方面没有显着差异残余癌症负荷-0/I 率、EFS 和 OS。无论 HER2 状态如何，NAT 都会诱导雌激素受体/孕激素受体和 Ki67 水平显着降低、PAM50 增殖和管腔相关基因/特征的下调、选定免疫基因的上调以及向侵略性较低的 IS 和较低的 ROR-P。此外，25%的HER2-0转变为HER2-low，34%的HER2-low转变为HER2-0。 NACT 后（P < 0.001）而非新辅助内分泌治疗（P = 0.063）后 HER2 变化显着，且 ERBB2 mRNA 水平动态一致。 HER2 变化与 EFS/OS 无关。约 30% 的病例在 NAT 后（大多数在 NACT 后）发生 HER2-low 和 HER2-0 状态变化。应相应地研究有针对性的辅助策略。当前化疗/内分泌药物和免疫治疗的分子降期不应依赖于 HR/HER2 阴性 BC 中的 HER2 免疫组织化学水平。相反，应该探索 HER2 低靶向方法，以追求更有效和/或毒性更低的维度降期。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

The characterization and comparison of gene expression and intrinsic subtype (IS) changes induced by neoadjuvant chemotherapy (NACT) and endocrine therapy in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-low versus HR+/HER2-0 breast cancer (BC) has not been conducted so far. Most evidence on the association of HER2 status with pathologic responses and prognosis in HR+/HER2-negative BC is controversial and restricted to NACT-treated disease. Similarly, a temporal heterogeneity in HER2 status has been described only with NACT.We retrospectively recruited a consecutive cohort of 186 patients with stage I-IIIB HR+/HER2-negative BC treated with neoadjuvant therapy (NAT). Available diagnostic biopsies and surgical samples were characterized for main pathological features, PAM50 IS and ROR-P score, and gene expression. Associations with pathologic complete response, residual cancer burden-0/I, event-free survival (EFS) and overall survival (OS) based on HER2 status were assessed. Pre/post pathologic/molecular changes were analyzed in matched samples.The HER2-low (62.9%) and HER2-0 (37.1%) cohorts did not differ significantly in main baseline features, treatments administered, breast-conserving surgery, pathologic complete response and residual cancer burden-0/I rates, EFS, and OS. NAT induced, regardless of HER2 status, a significant reduction of estrogen receptor/progesterone receptor and Ki67 levels, a down-regulation of PAM50 proliferation- and luminal-related genes/signatures, an up-regulation of selected immune genes, and a shift towards less aggressive IS and lower ROR-P. Moreover, 25% of HER2-0 changed to HER2-low and 34% HER2-low became HER2-0. HER2 shifts were significant after NACT (P < 0.001), not neoadjuvant endocrine therapy (P = 0.063), with consistent ERBB2 mRNA level dynamics. HER2 changes were not associated with EFS/OS.HER2-low and HER2-0 status change after NAT in ∼30% of cases, mostly after NACT. Targeted adjuvant strategies should be investigated accordingly. Molecular downstaging with current chemo/endocrine agents and immunotherapy should not rely on HER2 immunohistochemical levels in HR+/HER2-negative BC. Instead, HER2-low-targeted approaches should be explored to pursue more effective and/or less toxic dimensional downstaging.Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.