Clinical and molecular evaluation of HER2-low and HER2-ultralow breast cancer in the Penelope-B clinical trial cohort
Abstact - The DestinyBreast (DB)04 and DB06 trials have shown clinical activity of trastuzumab-deruxtecan (T-DXd) in HER2-low and HER2-ultralow metastatic breast cancer. The identification of HER2-low and HER2-ultralow breast cancer is therefore essential for personalized therapy with T-DXd. We eval...
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| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Article (Journal) |
| Lenguaje: | inglés |
| Publicado: |
June 2026
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| In: |
Modern pathology
Year: 2026, Volumen: 39, Número: 6, Pages: 1-11 |
| ISSN: | 1530-0285 |
| DOI: | 10.1016/j.modpat.2026.101006 |
| Acceso en línea: | Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.modpat.2026.101006 Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S0893395226000499 
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| Notas de Autor: | Carsten Denkert, Sivaramakrishna Rachakonda, Anika Pehl, Frederik Marmé, Miguel Martin, Thomas Karn, Michael Untch, Hervé Bonnefoi, Sung-Bae Kim, Nader Hirmas, Harry Bear, Agnieszka K. Witkiewicz, Seock-Ah Im, Angela DeMichele, Laura Van't Veer, Nicole McCarthy, Thorsten Stiewe, Paul Jank, Karen A. Gelmon, José A. García-Sáenz, Christina Westhoff, Catherine M. Kelly, Toralf Reimer, Mireia M. Olivé, Erik S. Knudsen, Marion van Mackelenbergh, Federico Rojo, Nadine Frickel, Peter A. Fasching, Julia Teply-Szymanski, Masakazu Toi, Hope S. Rugo, Michael Gnant, Andreas Makris, Bärbel Felder, Valentina Nekljudova, Sibylle Loibl |
| Sumario: | Abstact - The DestinyBreast (DB)04 and DB06 trials have shown clinical activity of trastuzumab-deruxtecan (T-DXd) in HER2-low and HER2-ultralow metastatic breast cancer. The identification of HER2-low and HER2-ultralow breast cancer is therefore essential for personalized therapy with T-DXd. We evaluated 723 residual tumors from the Penelope-B trial (NCT01864746) and correlated different levels of HER2 protein expression with prognosis and messenger RNA (mRNA) profiles, including HER2 transcripts. In Penelope-B, 57.68% (n = 417) of 723 residual tumors were HER2 low. The HER2-ultralow category was assigned to 109 (15.08%) tumors, and 197 (27.25%) tumors were completely HER2 negative (HER2 0). In Kaplan-Meier analysis, there were no survival differences among these 3 subgroups. There was no significant difference in HER2 mRNA expression between HER2-0 and HER2-ultralow tumors (P = .08). In contrast, there was a highly significant difference in HER2 mRNA expression between HER2-ultralow and HER2-low tumors (P < .0001) and between HER2-low and HER2-positive tumors (P < .0001). The extracellular protease cathepsin L, which has been suggested as a biomarker for extracellular cleavage of T-DXd, was detectable in all HER2-related subgroups and was a negative prognostic factor for invasive disease-free survival and overall survival (P = .0001) in preneoadjuvant core biopsies. In our study, we were able to characterize HER2 low as a clinically relevant and molecular defined tumor group with significantly increased HER2 expression. In contrast, for HER2 ultralow, we did not observe a defined molecular phenotype, despite the clinically relevant regulatory approval of T-DXd also in the ultralow subgroup. Additional investigations are needed to identify biomarkers beyond HER2 for T-DXd response as a basis for refined criteria for treatment eligibility. |
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| Notas: | Online verfügbar: 21. April 2026, Artikelversion: 22. Mai 2026 Gesehen am 23.07.2026 |
| Descripción Física: | Online Resource |
| ISSN: | 1530-0285 |
| DOI: | 10.1016/j.modpat.2026.101006 |