PO.CL01.12 · 临床研究
空间转录组学揭示戈沙妥珠单抗在转移性乳腺癌中的潜在耐药和应答因素
Spatial transcriptomics revealed potential resistance and response factors of sacituzumab govitecan in metastatic breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：戈沙妥珠单抗（SG）是一种靶向TROP2的抗体药物偶联物，已获批用于转移性和局部晚期激素受体阳性HER2阴性乳腺癌及三阴性乳腺癌。其临床试验显示临床获益显著改善，但报告的客观缓解率约为30%。与SG应答或耐药相关的生物标志物尚不明确。
方法：对来自17例SG治疗的转移性乳腺癌患者活检组织制备的组织转移阵列进行GeoMx® DSP分析。治疗时间长（≥10个周期）的患者被视为应答者（N=7），而治疗时间短（≤4个周期）的患者被视为非应答者（N=10）。在细胞角蛋白标记的肿瘤区段和基质区段内，对由超过18,000个基因代表的全人类转录组表达进行了分析。使用带有Benjamini-Hochberg校正的线性混合模型计算应答者与非应答者之间的差异表达基因。使用Reactome通路数据库进行基因集富集分析（GSEA）。
结果：117个区段中超过10,000个基因靶点通过了质量控制流程，因此用于分析。在肿瘤区段中，7个基因在应答者中上调，包括免疫球蛋白重链基因IGHG2、IGHG3和IGHG4。25个基因在非应答者中上调，包括编码细胞外基质（ECM）蛋白的基因（TNC、MMP11、MMP14、COL1A、FKBP10和POSTN）。GSEA表明，ECM组织和蛋白聚糖调节通路在非应答者中高表达，而真核翻译终止通路、鸟氨酸脱羧酶调节以及有丝分裂G1期和G1/S期转换通路在应答者中上调。在基质区段中，6个基因在应答者中上调，包括免疫相关基因（C7、IGHG2、IGHG3和IGHG4）和脂质代谢调节基因APOC1。11个基因在非应答者中上调，包括ECM蛋白编码基因（MMP11、COL11A1、COL12A1和CA2）和免疫相关基因（HLA-DQA1、PIP和TSPAN1）。GSEA还显示，ECM组织通路和弹性纤维形成通路在非应答者中上调，而真核翻译终止、干扰素α/β信号、B细胞相关信号以及血浆脂蛋白组装、重塑和清除通路在基质区段的应答者中上调。
结论：我们的研究识别了SG应答与耐药肿瘤之间的差异表达基因。具体而言，免疫相关基因的上调与应答相关，而ECM组织和重塑的上调与耐药相关。这些观察结果的验证正在进行中。
查看英文原文 English abstract
Background: Sacituzumab govitecan (SG) is a TROP2-targeting antibody-drug conjugated that is approved in metastatic and locally advanced hormone-receptor positive HER2 negative and triple negative breast cancer. Its clinical trials showed significant improvement in clinical benefits, but the reported objective response rates were about 30%. Biomarkers associated with response or resistance to SG are poorly understood.
Methods: GeoMx® DSP was performed on tissue transfer arrays generated from 17 biopsies of SG-treated metastatic breast cancer patients. Patients with long time-on-treatment (≥ 10 cycles) were considered responders (N = 7) whereas patients with short time-on-treatment (≤ 4 cycles) were considered non-responders (N = 10). Expression of the whole human transcriptome represented by over 18,000 genes were profiled within the cytokeratin labeled tumor segments and stroma segments. Differentially expressed genes between responders and non-responders were calculated using the linear mixed model with Benjamini-Hochberg procedure. Gene set enrichment analysis (GSEA) was performed using the Reactome pathway database.
Results: Over 10,000 gene targets in 117 segments passed the quality control pipeline and therefore used for analysis. In the tumor segments, 7 genes were upregulated in responders including immunoglobin heavy chain genes IGHG2, IGHG3, and IGHG4. 25 genes were upregulated in non-responders, including genes encoding for extracellular matrix (ECM) proteins (TNC, MMP11, MMP14, COL1A, FKBP10, and POSTN). GSEA indicated that ECM organization and proteoglycan regulating pathways are highly expressed in non-responders whereas eukaryotic translation termination pathways, regulation of ornithine decarboxylase, and mitotic G1 phase and G1/S phase transition pathways are upregulated in responders. In the stroma segments, 6 genes were upregulated in the responders including immune related genes (C7, IGHG2, IGHG3, and IGHG4) and lipid metabolism regulating gene APOC1. 11 genes were upregulated in the non-responders, including ECM protein encoding genes (MMP11, COL11A1, COL12A1, and CA2) and immune related genes (HLA-DQA1, PIP, and TSPAN1). GSEA also showed that ECM organization pathways and elastic fiber formation pathways are upregulated in non-responders whereas eukaryotic translation termination, interferon alpha/beta signaling, B cell related signaling, and plasma lipoprotein assembly, remodeling and clearance pathways are upregulated in responders in the stroma segments.
Conclusions: Our study identified differential expressed genes between SG-responding and -resistance tumors. Specifically, the upregulation of immune-related genes is associated with response and upregulation of ECM organizations and remodeling are associated with resistance. Validation of these observations is underway.
利益披露 Disclosure
M. He, None.