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| Home > Articles > Published articles > Patritumab deruxtecan in HER2-negative breast cancer : |
(Hospital Clínic i Provincial de Barcelona) (Universitat de Barcelona) (Hospital Clínic i Provincial de Barcelona) (Breast Cancer Biology Research Group. Biomedical Research Institute INCLIVA) (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol) (Hospital 12 de Octubre (Madrid)) (Hospital Clínic i Provincial de Barcelona) (Hospital Clínic i Provincial de Barcelona) (Vall d'Hebron Institut d'Oncologia) (Vall d'Hebron Institut d'Oncologia) (Reveal Genomics) (Vall d'Hebron Institut d'Oncologia) (Hospital 12 de Octubre (Madrid)) (Hospital Universitari Vall d'Hebron) (Vall d'Hebron Institut d'Oncologia) (Institut Català d'Oncologia) (Hospital Clínic i Provincial de Barcelona) (Daiichi Sankyo. Inc) (Vall d'Hebron Institut d'Oncologia) (Hospital Clínic i Provincial de Barcelona) (Hospital Clínic i Provincial de Barcelona) (Vall d'Hebron Institut d'Oncologia)
| Date: | 2024 |
| 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. |
| Grants: | Instituto de Salud Carlos III PI22/01017 |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Subject: | Adult ; Aged ; Animals ; Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; Breast Neoplasms ; Broadly Neutralizing Antibodies ; Camptothecin ; Female ; Humans ; Immunoconjugates ; Mice ; Middle Aged ; Mutation ; Receptor, ErbB-2 ; Receptor, ErbB-3 ; Trastuzumab ; Treatment Outcome ; Tumor Suppressor Protein p53 |
| Published in: | Nature communications, Vol. 15 Núm. 1 (december 2024) , p. 5826, ISSN 2041-1723 |
