LBPO.BCS01 · 生物信息与计算 · Late-Breaking

HER2阳性乳腺癌脑转移中与tucatinib暴露相关的基因组和转录组变化

Genomic and transcriptomic changes associated with tucatinib exposure in HER2-positive breast cancer brain metastases

编号 LB166 展板 8 时间 4/20 09:00–12:00 区域 Section 54 主讲 Savannah Roy, MD

分会场 Late-Breaking Research: Bioinformatics, Computational Biology, Systems Biology, and Convergent Science 1

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作者与单位 Authors & Affiliations

Savannah C. Roy, Anna Guarnieri, Pradeep Bhartiya, Thomas Danhorn, Andrew Goodspeed, Hannah Parris, Virginia F. Borges, James Costello, David R. Ormond, Elena Shagisultanova

University of Colorado Anschutz Medical Campus, Aurora, CO

摘要 Abstract

中文摘要

背景：在HER2CLIMB试验中，在曲妥珠单抗和卡培他滨基础上加用HER2导向的酪氨酸激酶抑制剂tucatinib，改善了HER2阳性（HER2+）乳腺癌脑转移患者的无进展生存期（PFS），tucatinib组1年PFS为24.9%，而安慰剂组为0%。尽管既往研究已证实脑转移灶与原发肿瘤之间存在基因组分化，但tucatinib在脑内的分子效应仍缺乏充分刻画，部分原因在于可获取的切除脑转移组织有限。我们比较了有和无tucatinib暴露的HER2+乳腺癌脑转移的基因组和转录组特征，以识别可能与tucatinib耐药相关的候选分子适应机制。方法：脑转移标本取自17例接受神经外科切除的HER2+乳腺癌患者。所有患者均在IRB批准的方案下同意捐献组织。经质量控制后，对10例肿瘤进行了核糖体RNA去除的RNA测序：5例为tucatinib治疗后进展的肿瘤，5例为未接受tucatinib暴露的肿瘤。差异基因表达分析针对脑转移的激素受体（HR）状态进行了校正。13例肿瘤通过全外显子测序（WES）进行分析：7例为tucatinib治疗后进展的肿瘤，6例为未接受tucatinib暴露的肿瘤。所有样本均有配对的正常组织可用于WES分析。体细胞变异使用SIFT和PolyPhen-2软件、NCBI ClinVar数据以及Ensembl Variant Effect Predictor的"impact"指标进行预测有害功能影响的注释，全局分析采用变异等位基因频率（VAF）> 10%的阈值。结果：利用RNAseq数据针对HR状态进行校正后，tucatinib暴露与未暴露肿瘤之间有127个基因差异表达。tucatinib治疗后进展的肿瘤显示出与干性、上皮-间质转化（EMT）和代谢重编程相关的转录程序富集。未观察到已知HER2耐药通路（包括MAPK或PI3K/AKT信号）的转录富集。基因组分析识别出17个在tucatinib暴露后于VAF≥10%时携带最多激活突变的基因，这些基因主要参与增殖、迁移、免疫逃逸和癌症干性。tucatinib暴露后，在VAF≥10%时未检出ERBB2看守突变（T798M、T798I）或常见的HER2驱动突变（V777L）。相反，tucatinib暴露的肿瘤更频繁地携带ERBB家族成员（ERBB3和ERBB4）、ERBIN和MET中潜在有害的突变，而ERBB2突变即使存在，也以低等位基因频率（<5%）出现。结论：在这个已切除HER2+乳腺癌脑转移的探索性队列中，tucatinib暴露与符合适应性重塑而非经典HER2耐药突变的基因组和转录组模式相关。更广泛的ERBB信号网络内的改变以及干性/EMT相关转录程序的激活，可能促成tucatinib在脑内的耐药，值得在更大规模的纵向数据集中进一步研究。

查看英文原文 English abstract

Background: In the HER2CLIMB trial, the addition of HER2-directed tyrosine kinase inhibitor tucatinib to trastuzumab and capecitabine improved progression-free survival (PFS) in patients with HER2-positive (HER2+) breast cancer brain metastases, with 1-year PFS of 24.9% on tucatinib versus 0% on placebo. While prior studies demonstrated genomic divergence between brain metastases and primary tumors, the molecular effects of tucatinib in the brain remain poorly characterized, in part due to limited availability of resected brain metastasis tissue. We compared genomic and transcriptomic features of HER2+ breast cancer brain metastases with and without tucatinib exposure to identify candidate molecular adaptations potentially relevant to tucatinib resistance. Methods: Brain metastases specimens were obtained from 17 patients with HER2+ breast cancer undergoing neurosurgical resection. All patients consented to donate tissue on an IRB-approved protocol. After quality control, ribosomal RNA-depleted RNA sequencing was performed on 10 tumors: 5 tumors that progressed after tucatinib treatment and 5 tucatinib-unexposed. Differential gene expression analysis was adjusted for hormone receptor (HR) status of brain metastases. Thirteen tumors were analyzed by Whole Exome Sequencing (WES): 7 tumors that progressed after tucatinib and 6 tucatinib-unexposed. Matched normal tissue was available for all samples for WES analyses. Somatic variants were annotated for predicted deleterious functional impact using SIFT and PolyPhen-2 software, as well as data from NCBI ClinVar and the “impact” metric from the Ensembl Variant Effect Predictor, and a variant allele frequency (VAF) threshold of > 10 % was applied for global analyses. Results: After adjustment for HR status using the RNAseq data, 127 genes were differentially expressed between tucatinib-exposed and unexposed tumors. Tumors progressing on tucatinib showed enrichment of transcriptional programs related to stemness, epithelial-mesenchymal transition (EMT), and metabolic reprogramming. No transcriptional enrichment of established HER2 resistance pathways, including MAPK or PI3K/AKT signaling, was observed. Genomic profiling identified 17 genes with the highest number of activating mutations at VAF≥10% after tucatinib exposure that were predominantly involved in proliferation, migration, immune evasion and cancer stemness. No ERBB2 gatekeeper mutations (T798M, T798I) or common HER2 driver mutations (V777L) were detected at VAF≥10% after tucatinib exposure. Instead, tucatinib-exposed tumors more frequently harbored potentially deleterious mutations in ERBB family members (ERBB3 and ERBB4), ERBIN, and MET, whereas ERBB2 mutations, when present, occurred at low allelic frequency (<5%). Conclusion: In this exploratory cohort of resected HER2+ breast cancer brain metastases, tucatinib exposure was associated with genomic and transcriptomic patterns consistent with adaptive remodeling rather than classic HER2 resistance mutations. Alterations within the broader ERBB signaling network and activation of stemness / EMT-associated transcriptional programs may contribute to tucatinib resistance in the brain and warrant further investigation in larger longitudinal datasets.

利益披露 Disclosure

S. C. Roy, None. A. Guarnieri, Cogent Biosciences, Inc. Employment. P. Bhartiya, None.. T. Danhorn, None.. A. Goodspeed, None.. H. Parris, None. V. F. Borges, Gilead Sciences Independent Contractor, ). Olema Oncology Independent Contractor, ). Pfizer Inc. Independent Contractor, ). AstraZeneca Independent Contractor, ). J. Costello, OncoRx Insights LLC Employment, g., Board of Directors, non-salaried role). D. R. Ormond, None. E. Shagisultanova, Pfizer Inc. g., Board of Directors, non-salaried role), ). TerSera Therapeutics LLC g., Board of Directors, non-salaried role). Genentech Inc. g., Board of Directors, non-salaried role). Novartis AG ).

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