PO.TB09.02 · 肿瘤生物学
携带ERBB2或PIK3CA突变的HER2阳性乳腺癌在新辅助治疗下的克隆演化轨迹
Clonal evolutionary trajectory of HER2-positive breast cancer with ERBB2 or PIK3CA mutations under neoadjuvant treatment
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：ERBB2和PIK3CA是HER2阳性乳腺癌中最常突变的基因之一，也是已知的HER2靶向治疗耐药介导因子。然而，这些突变肿瘤在治疗下的分子演化仍知之甚少。在本研究中，我们分析了来自随机化PREDIX HER2试验的ERBB2和PIK3CA突变肿瘤的多组学图谱，该试验在早期HER2阳性疾病中比较了新辅助曲妥珠单抗-美坦新偶联物（T-DM1）与双重HER2阻断加化疗。
方法：新鲜冷冻肿瘤活检用于RNA测序和全外显子组测序（WES），而FFPE活检用于Xenium 5K空间转录组学。使用高斯混合效应模型分析纵向差异基因表达。使用五亚型单样本预测器（SSP.Subtype）分配肿瘤亚型。使用GATK4 Mutect2和GISTIC2分析体细胞突变和拷贝数改变。使用5%变异等位基因频率（VAF）临界值对体细胞突变进行过滤和整理。
结果：在190例有WES数据的患者中，分别有7例（3.7%）和49例（25.8%）患者携带非同义ERBB2突变（VAF中位数=0.28）和PIK3CA突变（VAF中位数=0.21）。在未达到病理完全缓解（pCR）的患者（63%）中，我们识别出两个ERBB2突变（S310Y和R143*），在治疗前、治疗期间和治疗后均被持续检出，均位于细胞外结构域。值得注意的是，两个肿瘤在治疗期间均维持HER2富集亚型和ERBB2扩增，提示突变可能影响曲妥珠单抗结合并阻断HER2信号。同样，我们识别出10例在治疗期间持续存在PIK3CA突变的患者，均为已知的功能获得性改变。四个肿瘤中仅一个保留了HER2富集亚型，提示在治疗选择压力下分子表型可能发生转变。系统发育分析进一步揭示了涉及PIK3CA的反复克隆扩增和获得性KLB突变，后者与胆固醇代谢的调控有关。KLB-FGF21信号的进一步体外验证正在进行中。
结论：这项对ERBB2或PIK3CA突变的HER2+乳腺癌的纵向演化分析表明，肿瘤在HER2靶向治疗下发生异质性演化，揭示了致病性ERBB2和PIK3CA突变的正向选择。
查看英文原文 English abstract
Background : ERBB2 and PIK3CA are among the most commonly mutated genes in HER2-positive breast cancer and are known mediators of resistance to HER2-targeted therapies. However, the molecular evolution of these mutant tumors under treatment remains poorly understood. In this study, we profiled the multi-omics landscape of ERBB2- and PIK3CA-mutant tumors from the randomized PREDIX HER2 trial, which compared neoadjuvant trastuzumab emtansine (T-DM1) with dual HER2 blockade plus chemotherapy in early-stage HER2-positive disease.
Methods : Fresh-frozen tumor biopsies were used for RNA sequencing and whole-exome sequencing (WES), while FFPE biopsies were used for Xenium 5K spatial transcriptomics. Longitudinal differential gene expressions were analyzed using Gaussian mixed-effects models. Tumor subtypes were assigned with a five-subtype single-sample predictor (SSP.Subtype). Somatic mutations and copy number alterations were profiled using GATK4 Mutect2 and GISTIC2. Somatic mutations were filtered and curated using a 5% variant allele frequency (VAF) cut-off.
Results : Of the 190 patients with available WES data, 7 (3.7%) and 49 (25.8%) patients carried non-synonymous ERBB2 mutations (median VAF = 0.28) and PIK3CA mutations (median VAF = 0.21), respectively. In those patients who did not achieve pathological complete response (pCR) (63%), we identified two ERBB2 mutations (S310Y and R143*) that were consistently detected prior to, during, and after treatment, all located in the extracellular domain. Notably, both tumors maintained the HER2-enriched subtype and ERBB2 amplification during treatment, suggesting mutations may influence trastuzumab binding and blocking HER2 signals. Similarly, we identified 10 patients with persistent PIK3CA mutations during treatment, all of which were known gain-of-function alterations. Only one out of four tumors retained the HER2-enriched subtype, suggesting a potential shift in molecular phenotype under therapeutic selective pressure. Phylogenetic analysis further revealed recurrent clonal expansion involving PIK3CA and acquired KLB mutations, the latter implicated in the regulation of cholesterol metabolism. Further in vitro validation of KLB-FGF21 signaling is ongoing.
Conclusion : This longitudinal evolutionary analysis of ERBB2- or PIK3CA-mutant, HER2+ breast cancer suggests that tumors evolve heterogeneously under HER2-targeted therapies, revealing the positive selection of pathogenic ERBB2 and PIK3CA mutations.
利益披露 Disclosure
K. Wang, None.
I. Zerdes,
Gilead ).
Novartis Speaker.
E. Sifakis, None..
D. Salgkamis, None..
J. Bergh, None..
T. Hatschek, None..
A. Matikas, None..
T. Foukakis, None.