文章：

高HER2肿瘤内异质性在早期及局部晚期HER2阳性乳腺癌中对抗HER2新辅助化疗具有耐药性

High HER2 Intratumoral Heterogeneity Is Resistant to Anti-HER2 Neoadjuvant Chemotherapy in Early Stage and Locally Advanced HER2-Positive Breast Cancer

原文发布日期：24 June 2025

DOI: 10.3390/cancers17132126

类型: Article

开放获取: 是

英文摘要：

Background/Objectives: Breast cancer tumors possess intratumoral heterogeneity (ITH), which is associated with therapeutic resistance. Tumors with high ITH exhibit human epidermal growth factor receptor 2 (HER2) heterogeneity, affecting the effectiveness of HER2-targeted therapies. Our recent study identified HER2 ITH as an independent prognostic factor for poor outcomes in HER2-positive breast cancer. We here investigated the association between HER2 ITH and anti-HER2 neoadjuvant chemotherapy (NAC) resistance.Methods: This study included 97 patients with primary HER2-positive breast cancer treated with anti-HER2 NAC. Breast tumor samples were obtained from vacuum-assisted breast biopsy before NAC. HER2 gene amplification was assessed using fluorescence in situ hybridization (FISH), and HER2 gene copy number histograms were generated. Using the Gaussian mixture model, histogram data were analyzed and categorized into the high (HH) and low HER2 heterogeneity (LH) groups. The association between HER2 ITH and treatment response was evaluated using the pathological complete response (pCR) rate.Results: Of the 97 patients, 18 (18.6%) and 79 (81.4%) were classified into the HH and LH groups, respectively. The pCR rate in the HH group was significantly lower at 28% (5/18) than that in the LH group at 65% (51/79) (p< 0.01). Multivariate analysis of pathological parameters revealed that the most significant predictor of pCR rate was HER2 ITH (p= 0.02).Conclusions: HER2 ITH assessment may be valuable in predicting therapeutic outcomes in HER2-positive breast cancer. Our novel approach of the HER2 ITH method using FISH histograms could serve as a useful tool for predicting anti-HER2 NAC resistance.

摘要翻译： 

背景/目的：乳腺癌肿瘤具有瘤内异质性，这与治疗耐药性相关。高瘤内异质性肿瘤表现出人表皮生长因子受体2异质性，影响HER2靶向治疗的效果。我们近期研究发现HER2瘤内异异性是HER2阳性乳腺癌不良预后的独立预测因子。本研究旨在探讨HER2瘤内异质性与抗HER2新辅助化疗耐药性的关联。 方法：本研究纳入97例接受抗HER2新辅助化疗的原发性HER2阳性乳腺癌患者。通过真空辅助乳腺活检获取新辅助化疗前的肿瘤样本。采用荧光原位杂交技术评估HER2基因扩增状态，并生成HER2基因拷贝数分布直方图。运用高斯混合模型分析直方图数据，将患者分为高HER2异质性组和低HER2异质性组。通过病理完全缓解率评估HER2瘤内异质性与治疗反应的相关性。 结果：在97例患者中，高HER2异质性组18例（18.6%），低HER2异质性组79例（81.4%）。高HER2异质性组的病理完全缓解率显著低于低HER2异质性组（28% [5/18] vs 65% [51/79]，p<0.01）。多因素病理参数分析显示，HER2瘤内异质性是预测病理完全缓解率的最显著指标（p=0.02）。 结论：HER2瘤内异质性评估对预测HER2阳性乳腺癌治疗效果具有重要价值。本研究建立的基于荧光原位杂交直方图的新型HER2瘤内异质性分析方法，可作为预测抗HER2新辅助化疗耐药性的有效工具。

原文链接：

High HER2 Intratumoral Heterogeneity Is Resistant to Anti-HER2 Neoadjuvant Chemotherapy in Early Stage and Locally Advanced HER2-Positive Breast Cancer