Immune modulation of pathologic complete response after neoadjuvant HER2-directed therapies in the NeoSphere trial
Immune modulation of pathologic complete response after neoadjuvant HER2-directed therapies in the NeoSphere trial
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DOI：
10.1093/annonc/mdv395
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发表时间：
2015-12-01
影响因子：
50.5
通讯作者：
Gianni, L.
中科院分区：
文献类型：
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作者：
Bianchini, G.;Pusztai, L.;Gianni, L.
存在对新辅助曲妥珠单抗和/或含帕妥珠单抗治疗的应答的免疫调节，其在不同的方案中是不同的。免疫标志物表达较低的肿瘤从多西他赛/曲妥珠单抗/帕妥珠单抗（THP）中获益最多。PDL 1 mRNA表达与耐药性相关。背景：在NeoSphere试验中，研究多西他赛联合曲妥珠单抗（TH）、帕妥珠单抗（TP）或两者（THP）或单克隆抗体（HP）新辅助治疗后，免疫系统对乳腺病理完全缓解（pCRB）的作用。患者和方法：免疫基因mRNA表达（n = 350，83.8%）、淋巴细胞浸润（TIL，n = 243，58.3%）和免疫组化检测的PDL 1（n = 305，73.1%）与pCRB相关。我们研究了五种选定的基因（IFNG、PD 1、PDL 1、PDL 2、CTLA 4）和六种免疫元基因，对应于浆细胞（IGG）、T细胞（CD 8A）、抗原递呈细胞（MHC 2）以及MHC 1基因（MHC 1）、STAT 1共表达基因（STAT 1）和干扰素诱导基因（IF-I）。结果：TIL作为连续变量，PDL 1蛋白表达与pCRB无显著相关性。免疫基因/多基因表达与THP后pCRB的相关性与其他治疗后不同。在THP中，PD 1和STAT 1或PDL 1、CTLA 4、MHC 1和IF-I中的任何一种的较高表达与较低的pCRB相关。在TH/TP/HP联合治疗组中，在多变量分析中，PD 1、MHC 2和STAT 1的高表达与pCRB相关，而PDL 1、MHC 1或IF-I的高表达与pCRB的低表达相关。在NOAH，较高的STAT 1与较高的pCRB，较高的MHC 1和IF-I与较低的pCRB的类似关联被发现曲妥珠单抗/化疗，但不是化疗treatmentonly.Conclusions：免疫系统调节反应的治疗含有曲妥珠单抗和帕妥珠单抗。观察到THP的最大益处是一些免疫标志物（即MHC 1、CTLA 4）的低表达。PDL 1参与耐药性支持检测HER 2定向抗体和免疫检查点抑制剂的组合。
There is immune modulation of response to neoadjuvant trastuzumab and/or pertuzumab-containing therapies that is different with different regimens. Tumors with lower expression of immune markers benefit most from docetaxel/trastuzumab/pertuzumab (THP). PDL1 mRNA expression was associated with resistance. These findings support testing combinations of THP regimen with immune-checkpoint inhibitors.Background: To investigate in the NeoSphere trial the contribution of the immune system to pathologic complete response in the breast (pCRB) after neoadjuvant docetaxel with trastuzumab (TH), pertuzumab (TP), or both (THP), or monoclonal antibodies alone (HP).Patients and methods: Immune gene mRNA expression ( n = 350, 83.8%), lymphocyte infiltration ( TIL, n = 243, 58.3%), and PDL1 by immunohistochemistry ( n = 305, 73.1%) were correlated with pCRB. We studied five selected genes ( IFNG, PD1, PDL1, PDL2, CTLA4) and six immune metagenes corresponding to plasma cells ( IGG), T cells ( CD8A), antigen- presenting cells ( MHC2), and to MHC1 genes ( MHC1), STAT1 co- expressed genes ( STAT1), and interferon- inducible genes ( IF- I). Gene expression data from the NOAH trial were used for validation.Results: TIL as continuous variable and PDL1 protein expression were not significantly associated with pCRB. Expression of immune genes/metagenes had different association with pCRB after THP than after other therapies. With THP, higher expression of PD1 and STAT1, or any among PDL1, CTLA4, MHC1, and IF-I were linked with lower pCRB. In the combined TH/TP/HP treatment group, in multivariate analysis, higher expression of PD1, MHC2, and STAT1 were linked with pCRB, and higher PDL1, MHC1, or IF-I to lower pCRB. In the NOAH, a similar association of higher STAT1 with higher pCRB, and higher MHC1 and IF-I with lower pCRB was found for trastuzumab/chemotherapy but not for chemotherapy treatment only.Conclusions: The immune system modulates response to therapies containing trastuzumab and pertuzumab. Greatest benefit from THP is observed for low expression of some immune markers (i.e. MHC1, CTLA4). The involvement of PDL1 in resistance supports testing combinations of HER2-directed antibodies and immune-checkpoint inhibitors.