Hatano Takaaki, Tanei Tomonori, Seno Shigeto, Sota Yoshiaki, Masunaga Nanae, Mishima Chieko, Tsukabe Masami, Yoshinami Tetsuhiro, Miyake Tomohiro, Shimoda Masafumi, Shimazu Kenzo
Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-15 Yamadaoka, Suita 565-0871, Osaka, Japan.
Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, 1-5 Yamadaoka, Suita 565-0871, Osaka, Japan.
Cancers (Basel). 2025 Jun 24;17(13):2126. doi: 10.3390/cancers17132126.
: 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. : 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. : 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) ( < 0.01). Multivariate analysis of pathological parameters revealed that the most significant predictor of pCR rate was HER2 ITH ( = 0.02). : 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.
乳腺癌肿瘤具有肿瘤内异质性（ITH），这与治疗耐药性相关。具有高ITH的肿瘤表现出人表皮生长因子受体2（HER2）异质性，影响HER2靶向治疗的有效性。我们最近的研究确定HER2 ITH是HER2阳性乳腺癌预后不良的独立预测因素。我们在此研究了HER2 ITH与抗HER2新辅助化疗（NAC）耐药性之间的关联。
本研究纳入了97例接受抗HER2 NAC治疗的原发性HER2阳性乳腺癌患者。在NAC前通过真空辅助乳腺活检获取乳腺肿瘤样本。使用荧光原位杂交（FISH）评估HER2基因扩增，并生成HER2基因拷贝数直方图。使用高斯混合模型，对直方图数据进行分析并分为高（HH）和低HER2异质性（LH）组。使用病理完全缓解（pCR）率评估HER2 ITH与治疗反应之间的关联。
在97例患者中，分别有18例（18.6%）和79例（81.4%）被分为HH组和LH组。HH组的pCR率显著低于LH组，分别为28%（5/18）和65%（51/79）（<0.01）。对病理参数的多变量分析显示，pCR率的最显著预测因素是HER2 ITH（=0.02）。
HER2 ITH评估在预测HER2阳性乳腺癌的治疗结果方面可能具有价值。我们使用FISH直方图的HER2 ITH方法的新方法可作为预测抗HER2 NAC耐药性的有用工具。
