文章：

HER2低表达型管腔乳腺癌并非同质性的临床病理与分子实体

HER2-Low Luminal Breast Carcinoma Is Not a Homogenous Clinicopathological and Molecular Entity

原文发布日期：25 May 2024

DOI: 10.3390/cancers16112009

类型: Article

开放获取: 是

英文摘要：

Background: With the development of some new antibody–drug conjugates, the HER2 classification of breast carcinomas now includes the HER2-low (H2L) category: IHC 1+, 2+ non-amplified by ISH, and double-equivocal carcinomas, mostly luminal, expressing hormone receptors (HR+). Methods: We analyzed mutational status and transcriptomic activities of three HER2 effector pathways: PI3K-AKT, MAPK, and JAK-STAT, in association with clinicopathologic features, in 62 H2L carcinomas compared to 43 HER2-positive and 20 HER2-negative carcinomas, all HR+. Results: H2L carcinomas had significantly lower histoprognostic grades and mitotic and Ki67 proliferation indexes than HER2-positive carcinomas. TheirPIK3CAmutation rates were close to those of HER2-negative and significantly higher than in HER2-positive carcinomas, contrary toTP53mutations. At the transcriptomic level, we identified three distinct groups which did not reflect the new HER2 classification. H2L and HER2-negative carcinomas shared most of clinicopathological and molecular characteristics, except HER2 membrane expression (mRNA levels). The presence of a mutation in a signaling pathway had a strong pathway activation effect.PIK3CAmutations were more prevalent in H2L carcinomas, leading to a strong activation of the PI3K-AKT signaling pathway even in the absence of HER2 overexpression/amplification. Conclusion:PIK3CAmutations may explain the failure of conventional anti-HER2 treatments, suggesting that new antibody–drug conjugates may be more effective.

摘要翻译： 

背景：随着新型抗体药物偶联物的发展，乳腺癌的HER2分类现已纳入HER2低表达（H2L）类别：即免疫组化1+、2+且原位杂交未扩增，以及双重不确定的癌种，这些多为管腔型并表达激素受体（HR+）。方法：我们分析了62例H2L癌与43例HER2阳性及20例HER2阴性癌（均为HR+）中HER2三条效应通路——PI3K-AKT、MAPK和JAK-STAT的突变状态及转录组活性，并结合其临床病理特征进行研究。结果：与HER2阳性癌相比，H2L癌的组织学预后分级、有丝分裂指数及Ki67增殖指数均显著更低。其PIK3CA突变率接近HER2阴性癌，且显著高于HER2阳性癌，而TP53突变则呈现相反趋势。在转录组层面，我们识别出三个不同的组别，这些组别并未反映新的HER2分类。除HER2膜表达（mRNA水平）外，H2L癌与HER2阴性癌在临床病理和分子特征上高度相似。信号通路中的突变对通路激活具有强烈影响。PIK3CA突变在H2L癌中更为普遍，即使在缺乏HER2过表达/扩增的情况下，仍能显著激活PI3K-AKT信号通路。结论：PIK3CA突变可能解释了传统抗HER2治疗失败的原因，提示新型抗体药物偶联物可能具有更佳疗效。

原文链接：

HER2-Low Luminal Breast Carcinoma Is Not a Homogenous Clinicopathological and Molecular Entity