这项工作的目的是揭示HER2低、HER2零或HER2阳性乳腺癌在临床、遗传特征和新辅助化疗(NAC)反应方面的差异。共有来自七家医院的245名女性乳腺癌患者被回顾性纳入该研究。在NAC之前收集了穿刺活检(CNB)样本，并用商业基因面板进行了下一代测序。比较了HER2低、HER2零或HER2阳性乳腺癌的临床、遗传特征和NAC反应。采用非负矩阵分解(NMF)方法对纳入的病例的C-Score进行聚类，以揭示每个HER2亚组的内在特征。68例（27.8%）为HER2阳性，117例（47.8%）为HER2低，60例（24.5%）为HER2零。HER2低乳腺癌的病理完全缓解率（pCR）明显低于HER2阳性和HER2零乳腺癌（所有比较的p <0.050）。与HER2低乳腺癌相比，HER2阳性病例具有更高的TP53突变、TOP2A扩增和ERBB2扩增率，以及更低的MAP2K4突变、ESR1扩增、FGFR1扩增和MAPK通路改变率（所有比较的p <0.050）。在NMF方法的聚类下，HER2低病例中的56/117（47.9％）位于聚类1中，51/117（43.6％）位于聚类2中，10/117（8.5％）位于聚类3中。聚类2中的HER2低病例在三个聚类中具有最低的pCR率（p <0.050）。HER2低乳腺癌在遗传上与HER2阳性病例有显着差异。HER2低乳腺癌存在基因异质性，并影响了该亚组的NAC反应。©2023年。外科肿瘤学会。

The objective of this work is to reveal differences in clinical and genetic features, as well as neoadjuvant chemotherapy (NAC) response, between HER2-low and HER2-zero or HER2-positive breast cancers.A total of 245 female patients with breast cancer were retrospectively enrolled from seven hospitals. Core needle biopsy (CNB) samples were collected before NAC and used for next-generation sequencing by a commercial gene panel. Clinical and genetic features, as well as NAC response, were compared between HER2-low and HER2-zero or HER2-positive breast cancers. The nonnegative matrix factorization (NMF) method was applied to cluster the C-Score of enrolled cases to reveal the intrinsic features of each HER2 subgroup.A total of 68 (27.8%) cases are HER2-positive, 117 (47.8%) cases are HER2-low, and 60 (24.5%) cases are HER2-zero. HER2-low breast cancers have a significantly lower pathologic complete response (pCR) rate than HER2-positive and HER2-zero breast cancers (p < 0.050 for all comparisons). Compared with HER2-low breast cancers, HER2-positive cases have higher rates of TP53 mutation, TOP2A amplification, and ERBB2 amplification, as well as lower rates of MAP2K4 mutation, ESR1 amplification, FGFR1 amplification, and MAPK pathway alteration (p < 0.050 for all comparisons). After clustering HER2-low cases by the NMF method, 56/117 (47.9%) are in cluster 1, 51/117 (43.6%) are in cluster 2, and 10/117 (8.5%) are in cluster 3. HER2-low cases in cluster 2 have the lowest pCR rate among the three clusters (p < 0.050).HER2-low breast cancers have significant genetic differences from HER2-positive cases. Genetic heterogeneity exists in HER2-low breast cancers and impacts on NAC response in this subgroup.© 2023. Society of Surgical Oncology.