【原】乳腺癌HER2不一致与远处转移和生死

　　众所周知，人类表皮生长因子受体HER2是由ERBB2基因编码的蛋白质。大多数HER2阳性乳腺癌患者的肿瘤内HER2表达一致，不过将近四成HER2阳性乳腺癌患者的肿瘤内HER2表达不一致。既往研究发现，肿瘤内HER2表达不一致是HER2阳性乳腺癌术前抗HER2新辅助治疗近期效果的独立预测因素。

　　2020年4月25日，施普林格自然旗下《乳腺癌研究与治疗》在线发表美国俄亥俄州立大学、罗氏诊断的研究报告，探讨了肿瘤内HER2表达不一致对HER2阳性乳腺癌远处转移和患者生存死亡结局的影响。

　　该单中心队列研究对2009年1月～2015年12月俄亥俄州立大学韦克斯纳医学中心158例HER2阳性乳腺浸润癌患者活检组织切片进行ERBB2基因蛋白质测定，将肿瘤内HER2表达不一致分为两类：

• 基因扩增不一致：HER2阳性（ERBB2基因扩增且HER2蛋白质表达）、HER2阴性（ERBB2基因不扩增且HER2蛋白质不表达）肿瘤细胞混合

• 基因扩增一致：ERBB2基因扩增且HER2蛋白质表达、ERBB2基因扩增而HER2蛋白质不表达的肿瘤细胞混合

ABC：HER2表达一致

DEF：HER2表达不一致、基因扩增不一致

GHI：HER2表达不一致、基因扩增一致

　　随后，对肿瘤内HER2表达不一致与患者临床随访结局以及其他临床病理特征的相关性进行分析。

　　结果，肿瘤内HER2表达不一致患者57例（36%），其中基因扩增不一致19例、基因扩增不一致＋基因扩增一致8例、基因扩增一致30例。

　　多因素分析表明，远处转移的独立相关因素包括：

• 肿瘤较大

• 切除淋巴结阳性

• 孕激素受体阴性

• 肿瘤内HER2表达不一致

　　此外，多因素分析表明，患者总生存率较低（总死亡率较高）的独立相关因素包括：

• 肿瘤较大

• 肿瘤内HER2表达不一致

　　因此，该研究结果表明，肿瘤内HER2表达不一致是HER2阳性乳腺癌远处转移、患者生存死亡结局的独立相关因素。

Breast Cancer Res Treat. 2020 Apr 25. [Epub ahead of print]

HER2 intratumoral heterogeneity is independently associated with distal metastasis and overall survival in HER2-positive breast carcinomas.

Tiansheng Shen, Hiroaki Nitta, Lai Wei, Anil V. Parwani, Zaibo Li.

The Ohio State University, Columbus, OH, USA; Roche Tissue Diagnostics, Tucson, AZ, USA.

PURPOSE: Human epidermal growth factor receptor 2 (HER2) intratumoral heterogeneity (ITH) occurs in a subset of breast cancers. Our recent study revealed it as an independent predictive factor for the response to anti-HER2 neoadjuvant therapy. In this study, we aimed to investigate its association with distal metastasis.

METHODS: HER2 ITH was assessed using HER2 gene protein assay (GPA) on whole tissue sections of pretreatment biopsies from a cohort of 158 HER2-positive invasive breast carcinomas and correlated with patients' clinical follow-up outcomes along with other clinicopathologic characteristics.

RESULTS: Fifty-seven cases (36%) showed HER2 ITH including 19 with genetic, 8 with both genetic and non-genetic, and 30 with non-genetic ITH. Multivariate analysis demonstrated larger tumor size, positive resected lymph node(s), negative PR, and the presence of HER2 ITH were independently associated with distal metastasis. Additionally, multivariate analysis demonstrated larger tumor size and the presence of HER2 ITH were the only independent factors associated with decreased overall survival (death).

CONCLUSION: The presence of HER2 ITH is an independent factor associated with poor overall survival and increased distal metastasis in HER2-positive breast cancer patients.

KEYWORDS: HER2 gene protein assay, Breast carcinoma, HER2 intratumoral heterogeneity, Distal metastasis

DOI: 10.1007/s10549-020-05650-1