PDF(Pubmed)
Abstract：
Patritumab deruxtecan (HER3-DXd) exhibits promising efficacy in breast cancer, with its activity not directly correlated to baseline ERBB3/HER3 levels. This research investigates the genetic factors affecting HER3-DXd\'s response in women with early-stage hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer. In the SOLTI-1805 TOT-HER3 trial, a single HER3-DXd dose was administered to 98 patients across two parts: 78 patients received 6.4 mg/kg (Part A), and 44 received a lower 5.6 mg/kg dose (Part B). The CelTIL score, measuring tumor cellularity and infiltrating lymphocytes from baseline to day 21, was used to assess drug activity. Part A demonstrated increased CelTIL score after one dose of HER3-DXd. Here we report CelTIL score and safety for Part B. In addition, the exploratory analyses of part A involve a comprehensive study of gene expression, somatic mutations, copy-number segments, and DNA-based subtypes, while Part B focuses on validating gene expression. RNA analyses show significant correlations between CelTIL responses, high proliferation genes (e.g., CCNE1, MKI67), and low expression of luminal genes (e.g., NAT1, SLC39A6). DNA findings indicate that CelTIL response is significantly associated with TP53 mutations, proliferation, non-luminal signatures, and a distinct DNA-based subtype (DNADX cluster-3). Critically, low HER2DX ERBB2 mRNA, correlates with increased HER3-DXd activity, which is validated through in vivo patient-derived xenograft models. This study proposes chemosensitivity determinants, DNA-based subtype classification, and low ERBB2 expression as potential markers for HER3-DXd activity in HER2-negative breast cancer.
摘要：
Patritumabderuxtecan（HER3-DXd）在乳腺癌中显示出有希望的疗效，其活性与基线ERBB3/HER3水平不直接相关。这项研究调查了影响早期激素受体阳性和HER2阴性（HR/HER2-）乳腺癌女性HER3-DXd反应的遗传因素。在SOLTI-1805TOT-HER3试验中,单一的HER3-DXd剂量在两个部分给予98名患者：78名患者接受6.4mg/kg（A部分），44接受较低的5.6mg/kg剂量(B部分)。CelTIL得分,从基线到第21天，测量肿瘤细胞数量和浸润淋巴细胞，用于评估药物活性。部分A显示在一剂量的HER3-DXd之后增加的CelTIL评分。在这里，我们报告了B部分的CelTIL评分和安全性。A部分的探索性分析涉及对基因表达的全面研究，体细胞突变,copy-numbersegments,和基于DNA的亚型，而B部分侧重于验证基因表达。RNA分析显示CelTIL应答之间存在显著相关性，高增殖基因(例如，CCNE1,MKI67),和管腔基因的低表达(例如，NAT1,SLC39A6)。DNA研究结果表明，CelTIL反应与TP53突变显著相关，扩散,非内腔特征,和不同的基于DNA的亚型(DNADX簇-3)。严重的,低HER2DXERBB2mRNA，与HER3-DXd活性增加相关，这是通过体内患者来源的异种移植模型验证的。这项研究提出了化学敏感性决定因素，基于DNA的亚型分类，和低ERBB2表达作为HER2阴性乳腺癌中HER3-DXd活性的潜在标志物。
