赫赛汀可能用于治疗HER2阴性乳腺癌

作者：朱贵东

众所周知，大约百分之二十的乳腺癌呈人类表皮细胞受体2（HER2）阳性，大量临床结果证明，使用罗氏制药的单克隆抗体赫赛汀（Herceptin，通用名：Trastuzumab）治疗，尤其在手术摘除肿瘤后和其它抗肿瘤药物联合配用，能显著延长患者的生存期。

但是，长久以来人们一直认为赫赛汀只对HER2阳性的乳腺癌患者有效，道理很简单，赫赛汀是靶向HER2的单克隆抗体。现在这个概念受到挑战。美国密执安大学癌症综合研究中心的研究人员经过整理、分析过去临床实验结果发现，一部分HER2阴性的乳腺癌患者曾被错误地诊断为HER2阳性，因而得到赫赛汀治疗，而且疗效和HER2阳性的乳腺癌患者类似。体外以及动物实验表明，HER2对传统归类为HER2阴性的乳腺癌也起着关键性作用，赫赛汀能抑制这类肿瘤的生长和扩散。除此之外，密执安大学的科学家还给出解释这个令人惊讶结果的分子机理。如果这个结果得以在临床实验中证实，将改革现行乳腺癌的治疗模式。研究还表明，对于HER2阴性的乳腺癌，骨转移的HER2表达要更高。这些研究结果发表在今天上线的《癌症研究》（Cancer Research）杂志上。

【原文摘要】

HER2 Drives Luminal Breast Cancer Stem Cells in the Absence of HER2 Amplification: Implications for Efficacy of Adjuvant Trastuzumab

Although current breast cancer treatment guidelines limit the use of HER2-blocking agents to tumors with HER2 gene amplification, recent retrospective analyses suggest that a wider group of patients may benefit from this therapy. Using breast cancer cell lines, mouse xenograft models and matched human primary and metastatic tissues, we show that HER2 is selectively expressed in and regulates self-renewal of the cancer stem cell (CSC) population in estrogen receptor-positive (ERþ), HER2_ luminal breast cancers. Although trastuzumab had no effects on the growth of established luminal breast cancer mouse xenografts, administration after tumor inoculation blocked subsequent tumor growth. HER2 expression is increased in luminal tumors grown in mouse bone xenografts, as well as in bone metastases from patients with breast cancer as compared with matched primary tumors. Furthermore, this increase in HER2 protein expression was not due to gene amplification but rather was mediated by receptor activator of NF-kB (RANK)-ligand in the bone microenvironment. These studies suggest that the clinical efficacy of adjuvant trastuzumab may relate to the ability of this agent to target the CSC population in a process that does not require HER2 gene amplification. Furthermore, these studies support a CSC model in which maximal clinical benefit is achieved when CSC targeting agents are administered in the adjuvant setting. Cancer Res; 73(5); 1–11. _2013 AACR.

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