HER2-low breast cancer is immune-cold: insights into tumor-infiltrating immune cells and implications for immunotherapy
This study investigated, for the first time, the association between HER2 expression, immune infiltration inferred by CIBERSORTx, and immunotherapy response in HER2-negative early breast cancer (EBC). Gene expression was analyzed in prospective discovery (n = 104), confirmatory (n = 81), and independent (ABiM, n = 318) cohorts. HER2 expression was measured using a 20-gene signature yielding progressively higher scores from HER2-0 to HER2-low, as routinely defined. Increased HER2 expression was consistently associated with reduced immune-infiltration, especially cytotoxic (CD8<sup>+</sup>) T cells and M1 macrophages; and hormone receptor (HR)-specific depletions with significant interactions for mast cells resting and neutrophils. In analysis of covariance, HER2 expression independently predicted low B-naïve and plasma cell abundance. In a neoadjuvant immunotherapy real-world cohort (n = 111), HER2-low primary tumors had numerically lower midcourse (28% vs. 44%) and pathological complete response (64% vs. 72%) compared to HER2-0. These findings show that HER2 expression defines immune-cold HER2-negative EBC, hindering immunotherapy and supporting HER2-targeted combination in HER2-low EBC patients.
Authors
- Serena Di Cosimo (ORCID: https://orcid.org/0000-0002-4666-8052)
- Adriana Blanda
- Maria Carmen De Santis (ORCID: https://orcid.org/0000-0003-3131-3969)
- Silvia Brich (ORCID: https://orcid.org/0000-0002-6359-1712)
- Marilena V. Iorio (ORCID: https://orcid.org/0000-0002-6058-1527)
- Paolo Verderio (ORCID: https://orcid.org/0000-0002-9231-1281)
- Cinzia De Marco (ORCID: https://orcid.org/0000-0003-1153-270X)
- Andrea Vingiani (ORCID: https://orcid.org/0000-0002-9827-3976)
- Valeria Molinaro
- Pamela Minicozzi (ORCID: https://orcid.org/0000-0002-7273-7947)
- Grazia Arpino (ORCID: https://orcid.org/0000-0002-4074-2530)
- Maria Grazia Carnevale (ORCID: https://orcid.org/0000-0003-3251-0139)
- Laura Cortesi (ORCID: https://orcid.org/0000-0001-8950-8561)
- Alessia Bertolotti (ORCID: https://orcid.org/0000-0002-5562-3817)
- Valentina Appierto (ORCID: https://orcid.org/0000-0002-8726-6981)
- Loris De Cecco (ORCID: https://orcid.org/0000-0002-7066-473X)
- Mario Giuliano (ORCID: https://orcid.org/0000-0003-0835-3153)
- Giancarlo Pruneri (ORCID: https://orcid.org/0000-0002-7963-7172)
- Sara Pizzamiglio (ORCID: https://orcid.org/0000-0002-7759-0550)
- Elisa Gasparini (ORCID: https://orcid.org/0000-0002-6982-5727)
- B Re
Institutions
- University of Milan (IT)
- Azienda Sanitaria Unità Locale di Reggio Emilia (IT)
- Federico II University Hospital (IT)
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
Publication Details
- Journal
- npj Breast Cancer
- Published
- 2025-12-03
- DOI
- https://doi.org/10.1038/s41523-025-00867-z
- Primary Topic
- HER2/EGFR in Cancer Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00