Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Institute of Pathology Nordhessen, Kassel, Germany.
Mod Pathol. 2014 Jan;27(1):4-18. doi: 10.1038/modpathol.2013.103. Epub 2013 Jun 28.
Trastuzumab-containing therapy is a standard of care for patients with HER2+ breast cancer. HER2 status is routinely assigned using in situ hybridization to assess HER2 gene amplification, but interpretation of in situ hybridization results may be challenging in tumors with chromosome 17 polysomy or intratumoral genetic heterogeneity. Apparent chromosome 17 polysomy, defined by increased chromosome enumeration probe 17 (CEP17) signal number, is a common genetic aberration in breast cancer and represents an alternative mechanism for increasing HER2 copy number. Some studies have linked elevated CEP17 count ('polysomy') with adverse clinicopathologic features and HER2 overexpression, although there are numerous discrepancies in the literature. There is evidence that elevated CEP17 ('polysomy') count might account for trastuzumab response in tumors with normal HER2:CEP17 ratios. Nonetheless, recent studies establish that apparent 'polysomy' (CEP17 increase) is usually related to focal pericentromeric gains rather than true polysomy. Assigning HER2 status may also be complex where multiple cell subclones with distinct HER2 amplification characteristics coexist within the same tumor. Such genetic heterogeneity affects up to 40% of breast cancers when assessed according to a College of American Pathologists guideline, although other definitions have been proposed. Recent data have associated heterogeneity with unfavorable clinicopathologic variables and poor prognosis. Genetically heterogeneous tumors harboring HER2-amplified subclones have the potential to benefit from trastuzumab, but this has yet to be evaluated in clinical studies. In this review, we discuss the implications of apparent polysomy 17 and genetic heterogeneity for assigning HER2 status in clinical practice. Among our recommendations, we support the use of mean HER2 copy number rather than HER2:CEP17 ratio to define HER2 positivity in cases where coamplification of the centromere might mask HER2 amplification. We also highlight a need to harmonize in situ hybridization scoring methodology to support accurate HER2 status determination, particularly where there is evidence of heterogeneity.
曲妥珠单抗为基础的治疗是 HER2 阳性乳腺癌患者的标准治疗方法。HER2 状态通常通过原位杂交来评估 HER2 基因扩增，但是在染色体 17 三倍体或肿瘤内遗传异质性的肿瘤中，原位杂交结果的解释可能具有挑战性。染色体 17 三倍体是乳腺癌中常见的遗传异常，代表了增加 HER2 拷贝数的另一种机制，其定义为染色体计数探针 17（CEP17）信号数量增加。一些研究将升高的 CEP17 计数（“三倍体”）与不良临床病理特征和 HER2 过表达联系起来，尽管文献中有许多差异。有证据表明，升高的 CEP17（“三倍体”）计数可能与 HER2：CEP17 比值正常的肿瘤中曲妥珠单抗的反应有关。尽管如此，最近的研究表明，明显的“三倍体”（CEP17 增加）通常与局灶性着丝粒周围增益有关，而不是真正的三倍体。在同一肿瘤中存在多个具有不同 HER2 扩增特征的细胞亚克隆时，HER2 状态的分配也可能很复杂。当根据美国病理学家学院的指南进行评估时，这种遗传异质性会影响高达 40%的乳腺癌，尽管已经提出了其他定义。最近的数据将异质性与不利的临床病理变量和预后不良相关联。存在 HER2 扩增亚克隆的遗传异质性肿瘤有可能从曲妥珠单抗中获益，但这尚未在临床研究中得到评估。在这篇综述中，我们讨论了染色体 17 三倍体和遗传异质性对临床实践中 HER2 状态评估的影响。在我们的建议中，我们支持在中心体可能掩盖 HER2 扩增的情况下，使用平均 HER2 拷贝数而不是 HER2：CEP17 比值来定义 HER2 阳性。我们还强调需要协调原位杂交评分方法，以支持准确的 HER2 状态确定，特别是在存在异质性证据的情况下。
