Patritumab deruxtecan in HER2-negative breast cancer: part B results of the window-of-opportunity SOLTI-1805 TOT-HER3 trial and biological determinants of early response

作者：F. Brasó-Maristany, J. M. Ferrero-Cafiero, C. Falato, O. Martínez-Sáez, J. Cejalvo, M. Margelí, P. Tolosa, F. J. Salvador-Bofill, Josefina Cruz, B. González-Farré, E. Sanfeliu, Andreu Òdena, V. Serra, Francisco Pardo, A. M. Luna Barrera, M. Arumí, J. Guerra, G. Villacampa, R. Sánchez-Bayona, E. Ciruelos, M. Espinosa-Bravo, Y. Izarzugaza, P. Galván, J. Matito, S. Pernas, M. Vidal, Anu Santhanagopal, D. Sellami, S. Esker, Pang-Dian Fan, F. Suto, A. Vivancos, T. Pascual, A. Prat, Mafalda Oliveira · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-50056-y · 被引用次数：25 · 研究领域：Medicine

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....