André Céline, Bertaut Aurélie, Ladoire Sylvain, Desmoulins Isabelle, Jankowski Clémentine, Beltjens Françoise, Charon-Barra Céline, Bergeron Anthony, Richard Corentin, Boidot Romain, Arnould Laurent
Unit of Pathology, Department of Tumor Biology and Pathology, Georges-François Leclerc Cancer Center, 21000 Dijon, France.
Unit of Pathology, University Hospital Center, 21000 Dijon, France.
Cancers (Basel). 2024 May 25;16(11):2009. doi: 10.3390/cancers16112009.
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+).
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+.
H2L carcinomas had significantly lower histoprognostic grades and mitotic and Ki67 proliferation indexes than HER2-positive carcinomas. Their mutation rates were close to those of HER2-negative and significantly higher than in HER2-positive carcinomas, contrary to mutations. 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. mutations 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.
mutations may explain the failure of conventional anti-HER2 treatments, suggesting that new antibody-drug conjugates may be more effective.
随着一些新型抗体药物偶联物的发展，乳腺癌的HER2分类现在包括HER2低表达（H2L）类别：免疫组化（IHC）1+、ISH检测未扩增的2+以及双不确定癌，大多为管腔型，表达激素受体（HR+）。
我们分析了62例H2L癌、43例HER2阳性癌和20例HER2阴性癌（均为HR+）中三种HER2效应通路（PI3K - AKT、MAPK和JAK - STAT）的突变状态和转录组活性，并与临床病理特征相关联。
H2L癌的组织预后分级、有丝分裂和Ki67增殖指数显著低于HER2阳性癌。其突变率与HER2阴性癌相近，且显著高于HER2阳性癌，与 突变情况相反。在转录组水平，我们识别出三个不同的组，它们并未反映新的HER2分类。H2L癌和HER2阴性癌共享了大部分临床病理和分子特征，但HER2膜表达（mRNA水平）除外。信号通路中突变的存在具有强烈的通路激活效应。 突变在H2L癌中更为普遍，即使在没有HER2过表达/扩增的情况下也会导致PI3K - AKT信号通路的强烈激活。
突变可能解释了传统抗HER2治疗的失败，提示新型抗体药物偶联物可能更有效。
