Clinical and Molecular Evaluation of HER2-Low and HER2-Ultralow Breast Cancer in the Penelope-B Clinical Trial Cohort

Denkert C, Rachakonda S, Pehl A, Marmé F, Martin M, Karn T, Untch M, Bonnefoi H, Kim SB, Hirmas N, Bear H, Witkiewicz AK, Im SA, DeMichele A, Van't Veer L, McCarthy N, Stiewe T, Jank P, Gelmon KA, García-Sáenz JA, Westhoff C, Kelly CM, Reimer T, Olivé MM, Knudsen ES, van Mackelenbergh M, Rojo F, Frickel N, Fasching P, Teply-Szymanski J, Toi M, Rugo HS, Gnant M, Makris A, Felder B, Nekljudova V, Loibl S (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 39

Article Number: 101006

Journal Issue: 6

DOI: 10.1016/j.modpat.2026.101006

Abstract

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.

Authors with CRIS profile

Involved external institutions

Universidad Complutense de Madrid (UCM) Spain (ES) Goethe-Universität Frankfurt am Main Germany (DE) Arbeitsgemeinschaft Gynäkologische Onkologie e.V. (AGO) Germany (DE) Université de Bordeaux France (FR) Asan Medical Center / 서울아산병원 Korea, Republic of (KR) GBG Forschungs GmbH (German Breast Group) Germany (DE) Virginia Commonwealth University (VCU) United States (USA) (US) Roswell Park Cancer Institute United States (USA) (US) Seoul National University (SNU) / 서울대학교 Korea, Republic of (KR) Penn Medicine United States (USA) (US) University of California San Francisco (UCSF) United States (USA) (US) University of Queensland Australia (AU) Philipps-Universität Marburg Germany (DE) Hospital Clínico San Carlos Spain (ES) Universitätsklinikum Mannheim / University Medical Centre Mannheim (Universitätsmedizin Mannheim) Germany (DE) Mater Private Hospital / Ospidéal Príobháideach an Mater Ireland (IE) Universität Rostock Germany (DE) Hospital Universitari Sant Joan de Reus Spain (ES) Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE) Spanish Breast Cancer Group / Grupo Español de Investigación en Cáncer de Mama (GEICAM) Spain (ES) Kyoto University / 京都大学 Kyōto daigaku Japan (JP) City of Hope Medical Center United States (USA) (US) Medizinische Universität Wien Austria (AT) East and North Hertfordshire NHS Trust United Kingdom (GB)

How to cite

APA:

Denkert, C., Rachakonda, S., Pehl, A., Marmé, F., Martin, M., Karn, T.,... Loibl, S. (2026). Clinical and Molecular Evaluation of HER2-Low and HER2-Ultralow Breast Cancer in the Penelope-B Clinical Trial Cohort. Modern Pathology, 39(6). https://doi.org/10.1016/j.modpat.2026.101006

MLA:

Denkert, Carsten, et al. "Clinical and Molecular Evaluation of HER2-Low and HER2-Ultralow Breast Cancer in the Penelope-B Clinical Trial Cohort." Modern Pathology 39.6 (2026).

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