Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy.
Platform of Integrated Biology, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy.
Br J Cancer. 2018 Dec;119(12):1487-1494. doi: 10.1038/s41416-018-0318-0. Epub 2018 Nov 27.
Optimising the selection of HER2-targeted regimens by identifying subsets of HER2-positive breast cancer (BC) patients who need more or less therapy remains challenging. We analysed BC samples before and after treatment with 1 cycle of trastuzumab according to the response to trastuzumab.
Gene expression profiles of pre- and post-treatment tumour samples from 17 HER2-positive BC patients were analysed on the Illumina platform. Tumour-associated immune pathways and blood counts were analysed with regard to the response to trastuzumab. HER2-positive murine models with differential responses to trastuzumab were used to reproduce and better characterise these data.
Patients who responded to single-agent trastuzumab had basal tumour biopsies that were enriched in immune pathways, particularly the MHC-II metagene. One cycle of trastuzumab modulated the expression levels of MHC-II genes, which increased in patients who had a complete response on treatment with trastuzumab and chemotherapy. Trastuzumab increased the MHC-II-positive cell population, primarily macrophages, only in the tumour microenvironment of responsive mice. In patients who benefited from complete trastuzumab therapy and in mice that harboured responsive tumours circulating neutrophil levels declined, but this cell subset rose in nonresponsive tumours.
Short treatment with trastuzumab induces local and systemic immunomodulation that is associated with clinical outcomes.
通过确定需要更多或更少治疗的 HER2 阳性乳腺癌（BC）患者亚组来优化 HER2 靶向治疗方案的选择仍然具有挑战性。我们根据曲妥珠单抗的反应，分析了 17 例 HER2 阳性 BC 患者治疗前和治疗后 1 个周期曲妥珠单抗后的肿瘤样本。根据曲妥珠单抗的反应，分析了肿瘤相关免疫途径和血细胞计数。使用对曲妥珠单抗反应不同的 HER2 阳性小鼠模型来再现和更好地描述这些数据。
在 Illumina 平台上分析了 17 例 HER2 阳性 BC 患者治疗前和治疗后肿瘤样本的基因表达谱。根据曲妥珠单抗的反应，分析了肿瘤相关免疫途径和血细胞计数。使用对曲妥珠单抗反应不同的 HER2 阳性小鼠模型来再现和更好地描述这些数据。
对单药曲妥珠单抗有反应的患者的基础肿瘤活检富含免疫途径，特别是 MHC-II 元基因。一个周期的曲妥珠单抗调节了 MHC-II 基因的表达水平，在接受曲妥珠单抗和化疗完全缓解的患者中增加。曲妥珠单抗仅在有反应的小鼠的肿瘤微环境中增加 MHC-II 阳性细胞群体，主要是巨噬细胞。在完全受益于曲妥珠单抗治疗的患者和携带反应性肿瘤的小鼠中，循环中性粒细胞水平下降，但该细胞亚群在无反应性肿瘤中升高。
短时间的曲妥珠单抗治疗可诱导与临床结局相关的局部和全身免疫调节。
